A Phase 3, Multicenter, Double-blind, Randomized, Active-controlled Clinical Study to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam (MK-7625A) Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infection
Phase: PHASE3
Conditions: Complicated Intra-abdominal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03830333 
Document Date: 
24-JUL-2020
A Phase 3, Multicenter, Double-blind, Randomized, Active-
controlled Clinical Study to Evaluate the Efficacy and Safety of 
Ceftolozane/Tazobactam (MK-7625A) plus Metronidazole Versus 
Meropenem in Chinese Participants with Complicated 
Intraabdominal Infection

PRODUCT: MK-7625A 
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 3, Multicenter, Double-blind, Randomized, Active-controlled 
Clinical Study to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam (MK-7625A) 
plus Metronidazole Versus Meropenem in Chinese Participants with Complicated Intra-
abdominal Infection
Protocol Number: 015-02
Compound Number: MK-7625A
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
Approval Date: 24 July 2020
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
7625A-015-02
24-JUL-2020
Amendment 02
7625A-015-01
17-JAN-2020
Amendment 01 
7625A-015-00
11-SEP-2018
Original Protocol
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Update the allowed contraceptive methods according to the TransCelerate Common Protocol Template guidelines for contraception 
and pregnancy testing based upon Clinical Trial Facilitation Group (CTFG) recommendations. 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria
10.5.2 Contraception 
Requirements
To update the contraceptive 
requirements with updated template 
wording in the inclusion criteria and the 
allowed contraceptive methods to highly 
effective methods in Appendix 5.
For alignment with recent revisions to the TransCelerate 
Common Protocol Template guidelines for contraception 
and pregnancy testing based upon CTFG 
recommendations.
1.3 Schedule of Activities
Urine for Urinalysis
Added footnote “d” to “Urine for 
Urinalysis” at Screening.
Urinalysis performed prior to signing the informed 
consent may be used if collected during the routine care 
of the patient, as long as they were conducted within 24 
hours prior to randomization.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities (SoA)................................................................................17
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................23
Pharmaceutical and Therapeutic Background .............................................23
Preclinical and Clinical Studies ...................................................................26
2.2.2.1
Pre-clinical Studies ............................................................................26
2.2.2.2
Clinical Studies..................................................................................27
Ongoing Clinical Studies.............................................................................30
Information on Other Study-related Therapy ..............................................30
2.3
Benefit/Risk Assessment......................................................................................30
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................34
Rationale for Endpoints ...............................................................................34
4.2.1.1
Efficacy Endpoints.............................................................................34
4.2.1.2
Safety Endpoints................................................................................35
Rationale for the Use of Concomitant/Comparator/Placebo .......................36
4.3
Justification for Dose...........................................................................................37
Starting Dose for This Study........................................................................37
Maximum Dose/Exposure for This Study ...................................................38
Rationale for Dose Interval and Study Design ............................................38
4.4
Beginning and End of Study Definition .............................................................38
Clinical Criteria for Early Study Termination .............................................38
5
STUDY POPULATION ................................................................................................38
5.1
Inclusion Criteria.................................................................................................39
5.2
Exclusion Criteria................................................................................................41
5.3
Lifestyle Considerations......................................................................................44
5.4
Screen Failures.....................................................................................................44
 
 
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5.5
Participant Replacement Strategy......................................................................44
6
STUDY INTERVENTION............................................................................................45
6.1
Study Intervention(s) Administered...................................................................46
6.2
Preparation/Handling/Storage/Accountability .................................................48
Dose Preparation..........................................................................................48
Handling, Storage, and Accountability........................................................48
6.3
Measures to Minimize Bias: Randomization and Blinding..............................49
Intervention Assignment..............................................................................49
Stratification.................................................................................................49
Blinding........................................................................................................49
6.4
Study Intervention Compliance..........................................................................50
6.5
Concomitant Therapy..........................................................................................50
Rescue Medications and Supportive Care ...................................................51
6.6
Dose Modification (Escalation/Titration/Other)...............................................51
6.7
Intervention After the End of the Study............................................................52
6.8
Clinical Supplies Disclosure................................................................................52
6.9
Standard Policies..................................................................................................53
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................53
7.1
Discontinuation of Study Intervention...............................................................53
7.2
Participant Withdrawal From the Study...........................................................54
7.3
Lost to Follow-up .................................................................................................54
8
STUDY ASSESSMENTS AND PROCEDURES........................................................54
8.1
Administrative and General Procedures ...........................................................55
Informed Consent.........................................................................................55
8.1.1.1
General Informed Consent.................................................................55
Inclusion/Exclusion Criteria ........................................................................56
Participant Identification Card.....................................................................56
Medical History ...........................................................................................56
Prior and Concomitant Medications Review...............................................56
8.1.5.1
Prior Medications...............................................................................56
8.1.5.2
Concomitant Medications..................................................................57
Assignment of Screening Number...............................................................57
Assignment of Treatment/Randomization Number.....................................57
Study Intervention Administration ..............................................................57
8.1.8.1
Timing of Dose Administration.........................................................57
Discontinuation and Withdrawal .................................................................59
Participant Blinding/Unblinding..................................................................59
 
 
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Domiciling ...................................................................................................60
Calibration of Equipment.............................................................................60
8.2
Efficacy Assessments ...........................................................................................60
Clinical Response.........................................................................................60
Microbiological Response ...........................................................................61
8.3
Safety Assessments...............................................................................................63
Physical Examinations.................................................................................63
Vital Signs....................................................................................................63
Height and Weight .......................................................................................64
Surgical wound examination........................................................................64
APACHE II Score........................................................................................64
Abdominal symptoms and signs..................................................................64
Radiographic examination (Ultrasound, X-ray or CT etc) ..........................65
Diagnosis of target disease and site of infection..........................................65
Record any blood or blood product transfusions .........................................65
Record summary of operative procedures and operative notes ...................65
Clinical Safety Laboratory Assessments .....................................................66
Criteria for Baseline Culture........................................................................67
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................67
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................68
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......69
Follow-up of AE, SAE, and Other Reportable Safety Event Information...70
Regulatory Reporting Requirements for SAE .............................................70
Pregnancy and Exposure During Breastfeeding ..........................................70
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................71
Events of Clinical Interest (ECIs)................................................................71
8.5
Treatment of Overdose........................................................................................71
8.6
Pharmacokinetics.................................................................................................71
8.7
Pharmacodynamics..............................................................................................71
8.8
Future Biomedical Research Sample Collection...............................................71
8.9
Planned Genetic Analysis Sample Collection....................................................72
8.10
Biomarkers ...........................................................................................................72
8.11
Health Economics Medical Resource Utilization and Health Economics.......72
8.12
Visit Requirements...............................................................................................72
Screening (Visit 1).......................................................................................72
 
 
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Treatment Period (Visit 2 to Visit 6) ...........................................................72
Follow-up Period (Visit 7)...........................................................................72
9
STATISTICAL ANALYSIS PLAN .............................................................................73
9.1
Statistical Analysis Plan Summary.....................................................................73
9.2
Responsibility for Analyses/In-house Blinding .................................................74
9.3
Hypotheses/Estimation ........................................................................................75
9.4
Analysis Endpoints...............................................................................................76
Efficacy Endpoints.......................................................................................76
Safety Endpoints..........................................................................................77
9.5
Analysis Populations............................................................................................77
Efficacy Analysis Populations.....................................................................77
Safety Analysis Population..........................................................................78
9.6
Statistical Methods...............................................................................................78
Statistical Methods for Efficacy Analyses...................................................78
Statistical Methods for Safety Analyses ......................................................80
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................82
9.7
Interim Analyses ..................................................................................................82
9.8
Multiplicity ...........................................................................................................84
9.9
Sample Size and Power Calculations .................................................................84
Sample Size and Power for Efficacy Analyses............................................84
9.10
Subgroup Analyses and Effect of Baseline Factors ..........................................85
9.11
Compliance (Medication Adherence).................................................................86
9.12
Extent of Exposure...............................................................................................86
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................87
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........87
Code of Conduct for Clinical Trials.............................................................87
Financial Disclosure.....................................................................................89
Data Protection.............................................................................................89
10.1.3.1
Confidentiality of Data ......................................................................90
10.1.3.2
Confidentiality of Participant Records...............................................90
10.1.3.3
Confidentiality of IRB/IEC Information............................................90
Committees Structure...................................................................................90
Publication Policy........................................................................................90
Compliance with Study Registration and Results Posting Requirements ...91
Compliance with Law, Audit, and Debarment ............................................91
Data Quality Assurance ...............................................................................92
 
 
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Source Documents .......................................................................................93
Study and Site Closure.................................................................................93
10.2
Appendix 2: Clinical Laboratory Tests..............................................................94
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................98
Definition of AE ..........................................................................................98
Definition of SAE ........................................................................................99
Additional Events Reported.......................................................................100
Recording AE and SAE .............................................................................100
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................104
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................105
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................106
Definitions..................................................................................................106
Contraception Requirements......................................................................107
Pregnancy Testing......................................................................................109
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................110
10.7
Appendix 7: Country-specific Requirements..................................................111
10.8
Appendix 8:  APACHE II Severity of Disease Classification System –
APACHE II Score Form ...................................................................................112
10.9
Appendix 9: Abbreviations ...............................................................................115
11
REFERENCES.............................................................................................................117
 
 
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LIST OF TABLES
Table 1
Summary of Primary, Secondary and Exploratory Efficacy Endpoints 
and Components of a Favorable Response................................................35
Table 2
Study Interventions....................................................................................46
Table 3
Administration Dosage of Ceftolozane/Tazobactam According to 
Renal Function...........................................................................................51
Table 4
Administration Dosage of Meropenem According to Renal Function ......52
Table 5
Clinical Response Categories at the EOT and TOC Visits........................61
Table 6
Microbiological Outcome Categories........................................................62
Table 7
Emergent Infection.....................................................................................62
Table 8
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................69
Table 9
Clinical response rate at TOC visit............................................................76
Table 10
Analysis Strategy for Key Efficacy Variables...........................................80
Table 11
Analysis Strategy for Safety Parameters....................................................82
Table 12
Sample Size Adjustments based on Interim Blinded Review of Clinical 
Response Rate at TOC Visit ......................................................................83
Table 13
Power (%) Under Various Assumptions (With 268 participants (134 
per arm) into the study and NI margin of -12.5%) ....................................84
Table 14
Precision (Minimum Observed Difference and Two-sided 95% CI) 
Under Various Assumptions (With 268 participants (134 per arm) 
enrolled into the study) ..............................................................................85
Table 15
Laboratory Tests ........................................................................................94
Table 16
Contraceptive Methods ............................................................................108
 
 
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................16
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Double-blind, Randomized, Active-controlled 
Clinical Study to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam (MK-7625A) 
plus Metronidazole Versus Meropenem in Chinese Participants with Complicated Intra-
abdominal Infection
Short Title: MK-7625A plus Metronidazole vs. Meropenem for China Participants with cIAI
Acronym: 7625A CN Phase3
Hypotheses, Objectives, and Endpoints:
The following objectives and endpoints will be evaluated in adult participants diagnosed with 
complicated intra-abdominal infection (cIAI).
Objectives
Endpoints
Primary
•
Objectives: To evaluate the efficacy of 
ceftolozane/tazobactam plus
metronizazole versus meropenem with 
respect to clinical response at the test of 
cure (TOC) visit for participants 
diagnosed with cIAI in the clinically
evaluable (CE) population.
Hypothesis:  Ceftolozane/tazobactam
plus metronizazole is non-inferior to 
meropenem in participants with cIAI, as 
measured by the clinical response rate at 
TOC visit in the CE population. 
•
Clinical response: A favorable clinical 
response is clinical cure (see Section 
8.2.1).
Secondary
•
Objective:  To evaluate the efficacy of 
ceftolozane/tazobactam plus
metronizazole versus meropenem with 
respect to clinical response for 
participants diagnosed with cIAI.
•
Clinical response at the TOC visit 
in the intent-to-treat (ITT) 
population
•
Clinical response at the end of 
therapy (EOT) visit in the ITT and 
CE population
•
Clinical response
 
 
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Objectives
Endpoints
•
Objective:  To evaluate the efficacy of 
ceftolozane/tazobactam plus
metronizazole versus meropenem with 
respect to microbiological response for 
participants diagnosed with cIAI
•
Per-subject microbiological response 
at the TOC visit in the expanded 
microbiologically evaluable (EME)
population
•
Per-pathogen microbiological 
response at the TOC visit in the EME 
population
•
Per-subject microbiological response: 
For a favorable overall 
microbiological response (i.e., 
eradication or presumed eradication), 
each baseline pathogen for the 
participant must have a favorable 
microbiological outcome (see Section 
8.2.2).
•
Per-pathogen microbiological 
response: A favorable microbiological 
responses include “eradication” or 
“presumed eradication” (see Section 
8.2.2).
•
Objective:  To evaluate the safety and 
tolerability of ceftolozane/tazobactam 
plus metronizazole in participants 
diagnosed with cIAI.
•
Adverse events (AEs)
•
Study treatment discountinuation due 
to AE
Exploratory
•
Objective:  To evaluate the efficacy of 
ceftolozane/tazobactam plus 
metronizazole versus meropenem with 
respect to clinical response for 
participants diagnosed with cIAI.
•
Clinical response at TOC visit in the 
microbiological intent-to-treat (MITT) 
population and microbiologically 
evaluable (ME) population 
•
Clinical response at EOT visit in the 
MITT population
•
Clinical response
 
 
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Objectives
Endpoints
•
Objective:  To evaluate the efficacy of 
ceftolozane/tazobactam plus
metronizazole versus meropenem with 
respect to microbiological response for 
participants diagnosed with cIAI.
•
Per-subject microbiological response 
at the TOC visit in the ME and MITT
population
•
Per-subject microbiological response 
at the EOT visit in the ME, EME and 
MITT population
•
Per-pathogen microbiological 
response at the TOC visit in the ME
and MITT population
•
Per-pathogen microbiological 
response at the EOT visit in the ME, 
EME and MITT population
•
Per-subject microbiological response
•
Per-pathogen microbiological 
response
TOC = test of cure; EOT = end of therapy; CE = clinically evaluable; ITT = intent-to-treat; MITT = 
microbiological intent-to-treat; ME= microbiologically evaluable; EME = expanded ME 
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Complicated Intra-abdominal Infections
Population
Adult patients with cIAI
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control plus placebo
Study Blinding
Double-blind
Masking
Participant; Investigator; Outcomes Assessor; Data 
Analyst
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 20 months from the time the first 
participant signs the informed consent until the last 
participant’s last study-related telephone call or visit.
 
 
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Number of Participants:
Approximately 268 participants will be randomized to obtain 200 evaluable participants as 
described in Section 9.9.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
1
ceftolozane/
tazobactam
1500 mg 
(ceftolozane 
1000 mg 
/tazobactam 
500 mg)
750 mg
†
(ceftolozane 
500 mg 
/tazobactam 
250 mg)
q8h
IV
infusion
60 min 
intravenous  
infusion/4-
14 days
Study drug
Metronidazole
500 mg
q8h
IV
infusion
60 min 
intravenous  
infusion/4-
14 days
Concomitant
drug
2
Meropenem
1000 mg
q8h
OR
q12h
†
IV 
infusion
60 min 
intravenous  
infusion/4-
14 days
Comparator
Saline
NA
q8h
IV 
infusion
60 min 
intravenous  
infusion/4-
14 days
Placebo
Abbreviations: q8h=every 8 hours; IV=intravenous; NA=not applicable; q12h=every 12 hours.
†For participants with CrCL :30 to ≤ 50 mL/min.
In order to maintain double dummy of the study, the placebo (saline) need to be administered in the participant 
with CrCL 30 to ≤50 mL/min in both arms.
Total 
Number
Two groups
Duration of 
Participation
Each participant will participate in the study for approximately 31 days at 
maximum from the time the participant signs the Informed Consent Form 
(ICF) through the final contact. After a screening phase of maximal 24
hours, each participant will receive ceftolozane/tazobactam plus 
metronidazole, or meropenem plus placebo for 4-14 days. An End-of 
Treatment (EOT) visit will be performed within 24 hours after the last dose 
of study drug, a Test-of-Cure (TOC) will be performed at 26 to 30 days after 
the first dose of study drug. All adverse events (AEs) and serious adverse 
events (SAEs) will be reported by the investigator through the TOC 
evaluation.
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
 
 
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1.3
Schedule of Activities (SoA)
Study Period
Screening
Intervention
Post-
treatment
Notes
Visit Number/Title
1
Screening
2
Randomization
3
4
5
6
(EOT)
7
(TOC)
Visit 1 and Visit 2 can be done on 
the same day.
If treatment ends before Day 14, 
then will go to the Visit 6 directly 
for EOT visit.
Scheduled Hour and Day:
≤ 24 hours 
prior to 
randomization
Day 1
Day 
2
Day 3
Day 4-
13
Day 14
/EOT/Early 
Discontinuation 
visit
Day 28
Scheduling Window:
-
-
-
-
+24 hrs
±2 days
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Medical History
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
Intervention Allocation or 
Randomization 
X
Ceftolozane/tazobactam +
metronidazole OR meropenem
+ placebo
Administration/Dispensing
Daily administered IV 
IV study medication cannot be 
changed to oral antibiotics.
Efficacy Procedures
Clinical Response Assessment
(Assessment of clinical 
outcome)
X
X
 
 
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Study Period
Screening
Intervention
Post-
treatment
Notes
Visit Number/Title
1
Screening
2
Randomization
3
4
5
6
(EOT)
7
(TOC)
Visit 1 and Visit 2 can be done on 
the same day.
If treatment ends before Day 14, 
then will go to the Visit 6 directly 
for EOT visit.
Scheduled Hour and Day:
≤ 24 hours 
prior to 
randomization
Day 1
Day 
2
Day 3
Day 4-
13
Day 14
/EOT/Early 
Discontinuation 
visit
Day 28
Scheduling Window:
-
-
-
-
+24 hrs
±2 days
Clinical and Safety Procedures/Assessments
Full physical examination 
X
Xa
Directed Physical 
Examination
Daily at the discretion of the investigator  
X
Skin test 
X
If required by local clinical 
regulations, skin test will be 
conducted during screening if no 
prior history of allergic reaction 
to beta-lactam antibacterial.
Vital Signs (pulse rate, blood 
pressure, temperature, 
respiratory rate)
Xd
Daily during IV study therapy
X
X
Height and Weight
Xd
Surgical Wound Examination
X
Daily during IV study therapy
X
X
The surgical wound examination 
will be performed and findings 
are recorded only for participants 
who have a surgical wound.
APACHE II Score
Xd
Abdominal symptoms and 
signs
Xd
Daily during IV study therapy
X
X
 
 
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Study Period
Screening
Intervention
Post-
treatment
Notes
Visit Number/Title
1
Screening
2
Randomization
3
4
5
6
(EOT)
7
(TOC)
Visit 1 and Visit 2 can be done on 
the same day.
If treatment ends before Day 14, 
then will go to the Visit 6 directly 
for EOT visit.
Scheduled Hour and Day:
≤ 24 hours 
prior to 
randomization
Day 1
Day 
2
Day 3
Day 4-
13
Day 14
/EOT/Early 
Discontinuation 
visit
Day 28
Scheduling Window:
-
-
-
-
+24 hrs
±2 days
Radiographic examination 
(Ultrasound, X-ray or CT etc.)
Xa, d
Xa
Xa
Xa
Xa
Xa
Xa
Diagnosis of target disease 
and site of infection
X
Record blood or blood 
product transfusions
X
X
X
X
X
X
X
Record summary of operative 
procedures and operative 
notes 
Xa
Xa
Xa
Xa
Xa
Xa
Xa
AE/SAE review
X
Daily during IV study therapy
X
X
AEs/SAEs and other reportable 
safety events must be reported by 
the investigator from the time of 
informed consent through TOC 
visit.
Laboratory Procedures/Assessments
Serum Pregnancy Test 
(Woman of Childbearing 
Potential [WOCBP] only)
X
X
Prior documentation of a negative 
serum β-HCG within 48 hours of 
enrollment is acceptable.  If 
documentation is not available,  a 
serum β-HCG must be collected 
and sent to the local Laboratory.  
Blood for Hematology, 
Coagulation and Chemistry
Xd
X
X
X
Local laboratory data are used for 
inclusion/exclusion laboratory 
test. 
 
 
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Study Period
Screening
Intervention
Post-
treatment
Notes
Visit Number/Title
1
Screening
2
Randomization
3
4
5
6
(EOT)
7
(TOC)
Visit 1 and Visit 2 can be done on 
the same day.
If treatment ends before Day 14, 
then will go to the Visit 6 directly 
for EOT visit.
Scheduled Hour and Day:
≤ 24 hours 
prior to 
randomization
Day 1
Day 
2
Day 3
Day 4-
13
Day 14
/EOT/Early 
Discontinuation 
visit
Day 28
Scheduling Window:
-
-
-
-
+24 hrs
±2 days
Blood for Assessment of 
Creatinine and Creatinine 
Clearance (CrCL)
Xd
X
X
X
Xa
Xa
Xa
Local laboratory is used for 
assessment of Creatinine;
On V1,V4,V6 and V7, perform if 
creatinine assessment not already 
done as part of ‘blood for 
chemistry’ assessment.
Urine for Urinalysis
Xd
Xa
Xa
Xa
When clinically indicated at visit 
4,6 and 7. Local laboratory is 
used for Urinalysis.
Culture for sample of 
infection site and 
determination of pathogen
Xb, d
X b
Xa
Xa
Xa
Xa
Xa
Local microbiological laboratory 
will be used for culture of infection 
site specimen and determination of 
pathogen per local standards. Any 
suspected causative bacterial 
pathogen from the local 
microbiological laboratory culture 
must be isolated and available for 
submission to the Central 
Microbiology Reference 
Laboratory.  Suspected causative 
bacterial pathogens should also be 
stored at the local microbiology 
laboratory for future testing if 
applicable.
 
 
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Study Period
Screening
Intervention
Post-
treatment
Notes
Visit Number/Title
1
Screening
2
Randomization
3
4
5
6
(EOT)
7
(TOC)
Visit 1 and Visit 2 can be done on 
the same day.
If treatment ends before Day 14, 
then will go to the Visit 6 directly 
for EOT visit.
Scheduled Hour and Day:
≤ 24 hours 
prior to 
randomization
Day 1
Day 
2
Day 3
Day 4-
13
Day 14
/EOT/Early 
Discontinuation 
visit
Day 28
Scheduling Window:
-
-
-
-
+24 hrs
±2 days
Culture for blood sample and 
determination of pathogenc
Xa
Xa
Xa
Xa
Xa
Xa
Xa
a.
When clinically indicated, the assessments with footnote “a” in the table must be performed.
b.
Sample collection should be done at initial operative intervention. For subjects who are enrolled after surgery, collection of an intrabdominal specimen is 
mandatory for participants who are failures of a previous antibiotic regimen.
c.
Culture for blood sample at screening is conducted as clinically indicated in participants with 1) hospital-acquired infections; 2) for those who have failed 
prior antibacterial therapy; or 3) who have signs of severe sepsis as assessed by the investigator.
In addition, if signs of sepsis appear or the subject is assessed as a treatment failure at any time on study (including EOT, TOC visit), a blood culture should 
be taken. At each blood culture collection, two sets (from two separate blood draws) of blood cultures (each set consisting of an aerobic and an anaerobic 
bottle) are collected. Blood culture is conducted at appropriate frequency until negative. 
Local microbiological laboratory will be used for culture for blood sample and determination of pathogen per local standards. Any suspected causative 
bacterial pathogen from the local microbiological laboratory culture must be isolated and available for submission to the Central Microbiology Reference 
Laboratory. Suspected causative bacterial pathogens should also be stored at the local microbiology laboratory if possible for future testing if applicable.
d.
Assessments performed prior to signing the informed consent may be used if collected during the routine care of the patient, as long as they were conducted 
within 24 hours prior to randomization.
 
 
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2
INTRODUCTION
2.1
Study Rationale
This study is designed to demonstrate the non-inferiority of ceftolozane/tazobactam (1500 
mg q8h) plus metronidazole (500 mg q8h) compared to meropenem (1000 mg, q8h) plus 
placebo, with respect to clinical response rate in order to support the market authorization of 
ceftolozane/tazobactam in China. Ceftolozane/tazobactam has been approved in US and EU 
for the treatment of cIAI (used in combination with metronidazole), and cUTI including 
pyelonephritis. The prior global cIAI Phase 2 and 3 studies were conducted outside of China; 
hence there is a need for an additional study in China for this indication.
Gram-negative pathogens, including ESBL producing organisms, are important causes of 
cIAI. The most commonly isolated pathogens in cIAI are Escherichia coli., other 
Enterobacteriaceae, Pseudomonas spp. and Bacteroides fragilis. These infections are 
typically polymicrobial, also involving anaerobes such as Bacteroides fragilis.  The spectrum 
of activity of ceftolozane/tazobactam plus metronidazole supports its use in treatment of 
pathogens commonly isolated in cIAI.
The safety and efficacy of ceftolozane/tazobactam plus metronidazole for the treatment of 
cIAI was demonstrated in 2 large, identical, multicenter, randomized, double-blind, active-
controlled Phase 3 studies (CXA-cIAI-10-08 and CXA-cIAI-10-09). Ceftolozane/tazobactam 
plus metronidazole demonstrated non-inferiority to meropenem, a standard of care for the 
treatment of cIAIs [Solomkin, J. S., et al 2010]. 
As described previously, ceftolozane/tazobactam is active against the most common infecting 
pathogens encountered in cIAIs, and the efficacy and safety of ceftolozane/tazobactam in 
participants with cIAI was demonstrated in global, active-controlled Phase 3 studies. Based 
on the efficacy and safety of ceftolozane/tazobactam demonstrated in the global Phase 3
studies, it is considered appropriate to conduct a Phase 3 cIAI study in the Chinese patient 
population, to evaluate ceftolozane/tazobactam in the Chinese patient population since China 
did not participate in the global studies.
To ensure that there is comparability between the Chinese participants in this study and the 
non-Chinese participants in the global studies with respect to the safety and efficacy of 
ceftolozane/tazobactam, as done in Japan cIAI study (MK-7625A-013), the proportion of 
participants with moderate renal insufficiency (CrCL 30 to ≤ 50 mL/min) will be capped at 
15% in this study. In a subgroup analysis of Phase 3 cIAI studies (CXA-cIAI-10-08 and 
CXA-cIAI-10-09), clinical response rates were lower in participants with baseline creatinine 
clearance (CrCL) of 30 to ≤ 50 mL/min (47.8%, 11/23 participants) compared to those with 
CrCL >50 mL/min (85.2%, 312/366 participants). A similar trend was also seen in the cUTI 
studies. Participants with moderate renal insufficiency in the global study had somewhat
worse baseline health, compared to the rest of the participant population, and required dose 
adjustment of ceftolozane/tazobactam. However, in the Japan cIAI study, the clinical 
response rate in the CrCL ≤50 mL/min subgroup (88.9%, 8/9) was slightly lower than 
CrCL >50 mL/min subgroup (92.4%, 73/79). Therefore, the enrollment of the participants 
with CrCL (30 to ≤ 50 mL/min) is limited up to approximately 15% (40 participants) of the 
 
 
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total enrollment in this study in order toachieve a similar proportion of these participants as 
the global studies and to collect more data in Chinese participants with moderate renal 
insufficiency. 
In the cIAI studies (CXA-cIAI-10-08 and CXA-cIAI-10-09), approximately 50% of ITT and 
CE participants had a primary focus of infection in the appendix, compared to a maximum of 
30% recommended in the Addendum to Guideline CPMP/EWP/558/95 Rev 2 and a 
maximum of 50% recommended in the FDA Guidance for Industry (Complicated Intra-
Abdominal Infections: Developing Drugs for Treatment, 2018). Considering epidemiology 
and clinical practice in China, the number of participants with localized complicated 
appendicitis will be limited to approximately 50% (134 participants) of the randomized 
population.
In addition to the results of this study, the data from the prior global studies and the Japan 
study as described above may be utilized to support China filing for this indication.
2.2
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on ceftolozane/tazobactam.
Pharmaceutical and Therapeutic Background
Ceftolozane/tazobactam is a fixed-dose combination of a novel antipseudomonal 
cephalosporin (ceftolozane) and a well-established β-lactamase inhibitor (BLI), with potent 
in vitro activity against most extended spectrum β-lactamase (ESBL)–producing 
Enterobacteriaceae and drug-resistant Pseudomonas aeruginosa.
Ceftolozane shares the basic chemical and biological attributes and mechanism of action with 
other β-lactam antibiotics. The primary mechanism of action is inhibition of the 
transpeptidation step of bacterial peptidoglycan biosynthesis by inactivation of penicillin 
binding proteins (PBPs). Ceftolozane is a member of the cephalosporin class of antibiotics, 
which are well characterized in terms of their safety, efficacy, and general antimicrobial 
profile. Cephalosporin antibiotics have been widely used in clinical practice for many years 
for their broad antibacterial spectrum, bactericidal activity, and excellent safety profile. A 
number of third and fourth generation parenteral cephalosporin antibiotics continue to be 
widely used (e.g., ceftriaxone, cefepime, and ceftazidime), although expanding resistance 
erodes their reliability. Ceftolozane exhibits time-dependent killing activity against various 
gram-negative organisms, including drug-resistant Pseudomonas aeruginosa.  Ceftolozane 
has been shown to be potent against strains of Pseudomonas aeruginosa that are resistant to 
carbapenems, cephalosporins, fluoroquinolones, and/or aminoglycosides, including the 
majority of multiple drug-resistant (MDR) isolates.  Like most cephalosporins, ceftolozane 
itself is poorly active against enterococci, ESBL-producing Enterobacteriaceae, and gram-
negative anaerobes.
 
 
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Tazobactam is a potent inhibitor of chromosomal- and plasmid-mediated bacterial class A 
and some class C β-lactamases that, by binding to the active site of these enzymes, protects 
ceftolozane from hydrolysis, broadening its spectrum to include most extended-spectrum β-
lactamase (ESBL) -producing Escherichia coli., Klebsiella pneumoniae, and other 
Enterobacteriaceae, as well as some important anaerobic pathogens (i.e., Bacteroides 
fragilis).
Ceftolozane/tazobactam does not adequately cover some pathogens implicated in cIAIs, such 
as gram-positive pathogens (enterococci, Staphylococcus aureus), and anaerobes other than 
Bacteroides fragilis.
Epidemiology and Clinical Manifestations of Complicated Intra -Abdominal Infection
Complicated intra-abdominal infection (cIAI) encompasses a wide variety of serious 
infections ranging from appendiceal abscesses to more severe conditions such as intestinal 
perforation with diffuse fecal peritonitis. In cIAI, the infectious process proceeds beyond the 
organ that is the source of the infection, and causes either localized peritonitis, also referred 
to as abdominal abscess, or diffuse peritonitis, depending on the ability of the host to contain 
the process within a part of the abdominal cavity. Patients with intra-abdominal infection 
typically present with rapid-onset abdominal pain and symptoms of gastrointestinal 
dysfunction (loss of appetite, nausea, vomiting, bloating, and/or obstipation), with or without
signs of inflammation (pain, tenderness, fever, tachycardia, and/or tachypnea). signs of 
inflammation (pain, tenderness, fever, tachycardia, and/or tachypnea).
Complicated IAIs, those requiring both operative intervention and antimicrobial therapy, are 
very common infections encountered in general surgery, and cIAIs are an important cause of 
morbidity and are frequently associated with a poor prognosis. According to a global 
epidemiological survey of bacterial pathogens in patients with cIAI (the complicated intra-
abdominal infections worldwide observational study, CIAOW study) which was conducted 
worldwide including China [Sartelli, M., et al 2014], the overall mortality rate was 10.1%. 
The immediate post-operative clinical course was a significant parameter for predicting 
mortality: the rate of patient mortality was 54.9% among critically ill patients (patients 
presenting with septic shock and severe sepsis post-operatively), but the mortality rate was 
only 3.3% for clinically stable patients.
Although the bacteriology of cIAI depends on the anatomic origin of the infection, these 
infections are usually polymicrobial and involve a wide variety of gram-negative and gram-
positive aerobic and anaerobic organisms. Pathogens most commonly encountered in cIAI 
are Escherichia coli., other common Enterobacteriaceae, Pseudomonas aeruginosa, and 
Bacteroides fragilis.
The threat of antimicrobial resistance is one of the major challenges associated with the 
antimicrobial management of cIAI. The growing emergence of multidrug-resistant bacteria 
and the limited availability of new antibiotics to counteract them have brought about an 
impending crisis with alarming implications (especially regarding gram-negative
microorganisms).
 
 
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The main resistance threat in intra-abdominal infections is posed by ESBL-producing 
Enterobacteriaceae, which are becoming increasingly common in community acquired 
infections [Lee, Y. R., et al 2015]. The percentage of ESBL-positive Escherichia coli.
isolates collected from patients with IAI significantly increased from 9% in 2002 to 23% in 
2011, while the number of ESBL-positive Klebsiella pneumoniae isolates significantly 
increased from 13% in 2002 to 31% in 2007. According to the CIAOW study, among the 
intra-operative isolates, ESBL-producing Escherichia coli. isolates comprised 13.7% of all 
Escherichia coli. isolates, while ESBL-positive Klebsiella pneumoniae isolates represented 
18.6% of all Klebsiella pneumoniae isolates.
Based on the SMART (Study Monitoring Antimicrobial Resistance Trends) study, in a 
surveillance of antimicrobial susceptibility of aerobic and facultative gram-negative bacilli 
isolated from participants with intra-abdominal infections in China (SMART China) from 
2002 to 2009 [Yang, Q., et al 2010], the most common three pathogens for cIAI are the 
following, Escherichia coli. (49.2%), Klebsiella pneumoniae (16.9%), and Pseudomonas 
aeruginosa (8.4%), accounting for about 70% of all isolates.  Among the most common 
Enterobacteriaceae (Escherichia coli. and Klebsiella pneumoniae), the percentage of ESBL-
positive Escherichia coli. isolates increased from 20.8% in 2002 to 64.9% in 2009, and the 
percentage of ESBL –positive Klebsiella pneumoniae increased from 24.0% in 2002 to 
46.8% in 2009. According to the data from SMART China 2011, among the gram-negative
pathogens causing IAIs, Escherichia coli. (47.3%) was the most commonly isolated, 
followed by Klebsiella pneumoniae (17.2%), Pseudomonas aeruginosa (10.1%), and 
Acinetobater baumannii (8.3%). Enterobacteriaceae comprised 78.8% (1521/1929) of the 
total isolates. The ESBL rates among Escherichia coli., Klebsiella pneumoniae were 68.8% 
and 38.1%, respectively [Zhang, H., et al 2014].
Similar results also be found in a national survey on bacterial resistance, conducted by 
National Health and Family Planning Committee (Former Ministry of Health), the IAI data in 
2008 indicated that the most common three isolates are Escherichia coli. (23%), Feces 
Enterococcus (7.6%) and Pseudomonas aeruginosa (7.3%), and ESBL positive for 
Escherichia coli. and Klebsiella pneumoniae are 47.1% and 35.5% [Qiao-juan, H., et al 
2010].
Treatment of Complicated Intra -Abdominal Infection
While cIAI is an important cause of morbidity and frequently associated with a poor 
prognosis, an early diagnosis, followed by adequate source control to stop ongoing 
contamination and restore anatomical structures and physiological function, as well as 
prompt initiation of appropriate empirical therapy, can limit the associated mortality.
Surgery is the most important therapeutic recourse for controlling IAI. The choice of the 
procedure depends on the anatomical source of infection, on the degree of peritoneal 
inflammation, on the generalized septic response and on the patient’s general conditions.
Antimicrobial therapy plays an integral role in the management of cIAI. Empiric antibiotic 
therapy should account for the most frequently isolated microorganisms as well as local 
trends of antibiotic resistance.
 
 
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In general, primary peritonitis is typically mono-microbial (e. g., due to streptococci, 
Escherichia coli., staphylococci), whereas secondary and tertiary peritonitis are 
polymicrobial mixtures of aerobic and anaerobic bacteria, and occasionally fungi in case of 
tertiary peritonitis). In community-acquired secondary peritonitis, gram-positive and gram-
negative and aerobic organisms often are implicated in infections derived from the stomach, 
duodenum, biliary system, and proximal small bowel. On the other hand, in hospital-acquired 
peritonitis, nosocomial isolates particular to the site of previous surgery and to the specific 
hospital and unit may determine which organisms are responsible.
For treatment of cIAI, clinical guidelines including diagnosis and management have already 
been established in the United States and Europe. Empiric treatment is suggested by US 
IDSA guideline and recommendations for treatment modification are based upon local 
microbiological findings. The treatment with penicillins, cephalosporins, carbapenems, 
monobactams, and new quinolones with or without metronidazole are recommended under 
different situations [Solomkin, J. S., et al 2010].
A cIAI clinical guideline is not available in China. To cover the most common pathogens in 
cIAI( i.e. Enterobacteriaceae and anaerobes), referring to US/EU guidelines[Solomkin, J. S., 
et al 2010], the current treatment options in China clinical practice include anti-pseudomonal 
BL/BLI combinations (piperacillin/tazobactam, cefoperazone/sulbactam), fluoroquinolones, 
carbapenems (imipenem-cilastatin and meropenem), and 3rd or 4th generation cephalosporins 
± metronidazole.
Preclinical and Clinical Studies
2.2.2.1
Pre-clinical Studies
Ceftolozane/tazobactam has been well characterized in a comprehensive series of in vitro and 
in vivo nonclinical studies.
Ceftolozane has excellent in vitro activity (more potent than other cephalosporins) against 
Pseudomonas aeruginosa. Ceftolozane also displays potent antibacterial activity against 
common gram-negative and selected gram-positive organisms, including pathogens involved 
in respiratory and other community-acquired and nosocomial infections, such as streptococci, 
Haemophilus influenzae, Moraxella catarrhalis, the majority of pathogenic enteric bacilli, 
and selected gram-positive anaerobic species. Ceftolozane has proven to be highly 
efficacious in various animal models of infection caused by either gram-positive or 
gramnegative bacteria, including drug-resistant strains of Pseudomonas aeruginosa.
Ceftolozane and tazobactam (from historical data in combination with piperacillin) each 
displays an excellent safety profile in animals when tested individually or in combination. In 
studies of ceftolozane alone, the no-observed-adverse-effect level for both rats and dogs was 
considered to be 300 mg/kg/day. Intravenous (IV) toxicity studies of up to 6 months’ 
duration have been performed with tazobactam alone and in combination with piperacillin in 
rats and dogs. Tazobactam appears to be very well-tolerated, with no drug-related mortalities 
or serious clinical abnormalities. The potential target organs identified in these studies were 
the hematological, hepatic, and GI systems; however, only relatively minor changes were 
 
 
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observed in each of these organ systems. The combination of ceftolozane and tazobactam did 
not increase the toxicity of the individual compounds in rats after 4 weeks of repeated dosing. 
The combination of ceftolozane and tazobactam did not alter the PK profile of the individual 
compounds in a dog study.
Refer to the Investigator’s Brochure (IB) for additional information on the nonclinical 
experience with ceftolozane/tazobactam.
2.2.2.2
Clinical Studies
To date, MK-7625A has been evaluated in 10 completed Phase 1 studies (CXA-201-01, 
CXA-MD-11-07, CXA-QT-10-02, CXA-ELF-10-03, CXA-DDI-12-10, CXA-201-02, CXA-
REN-11-01 and CXA-EB-13-05, CXA-ICU-14-01, CXA-PEDS-13-08), 1 completed Phase 2 
study (CXA-IAI-10-01), 5 completed global Phase 3 studies (CXA-cUTI-10-04, CXA-cUTI-
10-05, CXA-cIAI-10-08 [MK-7625A-003], CXA-cIAI-10-09 [MK-7625A-004] and CXA-
NP-11-04 [MK-7625A-008]) and two local Phase 3 Japanese studies (MK-7625A-013 and 
MK-7625A-014). Healthy young participants as well as participants with varying degrees of 
renal insufficiency have been studied, including participants with end stage renal disease 
(ESRD) on hemodialysis.  Of note, MK-7625A-008 evaluated a higher dosing regimen of 
3000 mg ceftolozane/tazobactam every 8 hours for 8-14 days for the treatment of nosocomial
pneumonia.
Additional details of the Phase 1 studies and the Phase 2/3 studies involving cIAI are 
provided below. Refer to the Investigator’s Brochure for additional information.
Phase 1 studies
Phase 1 studies show that ceftolozane exposure (Cmax and AUC) was approximately dose-
proportional when administered IV over a 1-hour period to healthy volunteers with normal 
renal function following single doses ranging from 250 mg to 3000 mg and multiple (10-day) 
doses of 500 mg to 2000 mg every 8 hours and 1500 mg every 12 hours. The PK parameters 
for ceftolozane/tazobactam were similar following single and multiple doses, given alone or 
coadministered, demonstrating lack of accumulation or PK interaction. Ceftolozane 
elimination half-life (t½) was independent of dose and ranged from approximately 2 to 3 
hours with no observed accumulation with 8 hourly dosing, thus supporting 3 times daily 
administration. The plasma protein binding of ceftolozane in humans ranges from 
approximately 16% to 21%; plasma protein binding for tazobactam is approximately 30%. 
Ceftolozane is eliminated in the urine as unchanged parent drug and thus does not appear to 
be metabolized to any appreciable extent. The beta-lactam ring of tazobactam is hydrolyzed 
to form the pharmacologically inactive tazobactam metabolite M1. Ceftolozane and the 
tazobactam metabolite M1 are eliminated by the kidneys. Following administration of a 
single ceftolozane/tazobactam 1500 mg intravenous dose to healthy male adults, greater than 
95% of ceftolozane was excreted in the urine as unchanged parent drug. More than 80% of 
tazobactam was excreted as the parent compound with the remainder excreted as the 
tazobactam M1 metabolite. Ceftolozane is eliminated by the kidney via glomerular filtration. 
The ceftolozane dose normalized geometric mean AUC increased up to 1.26-fold, 2.5-fold, 
and 5-fold in participants with mild, moderate, and severe renal impairment, respectively, 
 
 
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compared to healthy participants with normal renal function. The respective tazobactam dose 
normalized geometric mean AUC increased approximately up to 1.3-fold, 2-fold, and 4-fold.
The pharmacokinetics of ceftolozane/tazobactam is dose independent and similar between 
Japanese, Chinese and Caucasian healthy participants. Ceftolozane/tazobactam was safe and 
well-tolerated overall.
Phase 2 study in participants with cIAI (CXA-cIAI-10-01)
Study CXA-IAI-10-01 evaluated the comparative efficacy and safety study of 
ceftolozane/tazobactam (1500 mg every 8 hours) plus metronidazole versus meropenem 
(1000 mg every 8 hours) in adult participants with cIAI. The primary objective was to 
determine the clinical response 7 to 14 days after a 4- to 7-day treatment regimen in 
hospitalized participants with cIAI.
Ceftolozane/tazobactam plus metronidazole was therapeutically effective, and its activity was 
comparable to meropenem. Clinical cure rates in the ME population were 88.7% (47 of 53 
participants) and 95.8% (23 of 24 participants) in the ceftolozane/tazobactam and 
meropenem treatment groups, respectively. Microbiological success rates in the ME 
population were 90.6% and 95.8% for participants in the ceftolozane/tazobactam and 
meropenem groups, respectively. Clinical curerates were similar for low-risk and high-risk 
participants, including the elderly, those with elevated APACHE II scores, those with failure 
of prior therapy, and participants with decreased renal function. Ceftolozane/tazobactam plus
metronidazole was well tolerated and generally safe in this study. A similar proportion of 
participants in the ceftolozane/tazobactam plus metronidazole (41 of 82 participants, 50%) 
and meropenem (19 of 39 participants, 48.8%) groups experienced at least one AE. The 
incidence of SAEs was higher in the ceftolozane/tazobactam plus metronidazole group (14 
participants, 17.1%) compared to the meropenem group (2 participants, 5.1%). All SAEs 
were reported in 1 participant each and all were assessed as unrelated to study treatment. The 
most common post-baseline shifts in clinical laboratory parameters in both treatment groups 
were elevated liver enzymes (GGT, AST, and ALT); which were consistent with known 
experience with β-lactam therapy. Details are in the investigator brochure.
Phase 3 study in participants with cIAI (CXA-cIAI-10-08 and CXA-cIAI-10-09)
Two large, identical, global, multicenter, randomized, double-blind, active-controlled Phase 
3 studies were initiated in participants with cIAI (CXA-cIAI-10-08 and CXA-cIAI-10-09). 
The data for these 2 studies were prospectively pooled to form a single adequately powered 
Phase 3 dataset, reported in a single clinical study report. 
Adult participants with a diagnosis of cIAI requiring surgical intervention were randomly 
assigned in a 1:1 ratio to receive ceftolozane/tazobactam (1500 mg IV every 8 hours) plus
metronidazole (500 mg IV every 8 hours) or meropenem (1000 mg IV every 8 hours) plus  
placebo (IV every 8 hours) for 4 to 10 days. Participants were stratified at randomization by 
primary site of infection (bowel versus other site of IAI). A total of 970 participants were 
included in the ITT population, of which 476 participants were randomized to receive 
ceftolozane/tazobactam plus metronidazole and 494 participants randomized to receive 
 
 
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meropenem. 472 and 485 participants received at least 1 dose of ceftolozane/tazobactam plus 
metronidazole and meropenem plus placebo, respectively. 
In both the US FDA and EMA analyses, ceftolozane/tazobactam plus metronidazole 
demonstrated noninferiority compared to meropenem for the primary and key secondary 
efficacy variables in the treatment of adult participants with cIAI [Solomkin, J., et al 2015].  
Clinical cure rates at the TOC visit in the primary efficacy analysis population (MITT) were 
83.0% (323/389) and 87.3% (364/417) for ceftolozane/tazobactam plus metronidazole and 
meropenem plus placebo, respectively. Clinical cure rates at the TOC visit in the CE 
population were 94.1% (353/375) and 94.0% (375/399) for ceftolozane/tazobactam plus 
metronidazole and meropenem plus placebo, respectively. Clinical cure rates the TOC visit in 
the ITT population were 83.6% (407/487) and 86.2% (436/506) for ceftolozane/tazobactam
plus metronidazole and meropenem plus placebo, respectively. Microbiological response rate 
at the TOC visit in MITT population were 85.3% (332/389) and 88.7% (370/417) for 
ceftolozane/tazobactam plus metronidazole and meropenem plus placebo, respectively. 
Microbiological response rate at the TOC visit in MITT population were 85.3% (332/389) 
and 88.7% (370/417) for ceftolozane/tazobactam plus metronidazole and meropenem plus 
placebo, respectively. Additionally, ceftolozane/tazobactam plus metronidazole demonstrated 
high clinical cure rates in participants with common intra-abdominal pathogens including 
Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus 
mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, 
Streptococcus constellatus, and Streptococcus salivarius.
Ceftolozane/tazobactam plus metronidazole was well tolerated and generally safe in this 
study. The proportion of participants who had one or more AEs was similar in both treatment 
groups [44.0 % (212/482) for ceftolozane/tazobactam with metronidazole, 42.7% (212/497) 
for meropenem plus placebo].  The proportion of participants who had one or more SAEs 
was comparable in both treatment groups [2.7% (13/482) for ceftolozane/tazobactam with 
metronidazole, 2.2% (11/497) for meropenem plus placebo]. The proportion of participants 
who had AEs that led to death was comparable in both treatment groups [2.3% (11/482) for 
ceftolozane/tazobactam with metronidazole, 1.6% (8/497) for meropenem plus placebo]. 
The most common intra-abdominal gram-negative aerobic baseline pathogens were 
Escherichia coli., Klebsiella pneumoniae, and Pseudomonas aeruginosa, in addition to other 
pathogens such as Bacteroides fragilis and Streptococcus spp., with approximately 70% of 
participants having a polymicrobial infection. In the cIAI study, there was no emergence of 
decreased susceptibility or resistance in either treatment arm.
Phase 3 study in Japanese participants with cIAI (MK-7625A-013)
MK-7625A-013 was a multicenter, open-label, noncomparative Phase 3 study in Japanese
participants with cIAI. Adult participants received ceftolozane/tazobactam 1500 mg (1000
mg of ceftolozane and 500 mg of tazobactam) plus metronidazole 500 mg IV for 1 hour 
every 8 hours for 4 to 14 days. The primary efficacy endpoint was the clinical response rate 
at TOC in the CE population and was defined in the same way as in CXA-cIAI-10-08/09.
 
 
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A total of 100 participants were enrolled, 98 of whom completed the study. Ninety- six 
participants completed the study medication. For the primary endpoint, 
ceftolozane/tazobactam demonstrated a clinical response rate [95% CI] at TOC in the CE 
population of 92.0% (81/88 participants) [84.3, 96.7], which was similar to that observed in 
CXA-cIAI-10-08/09.
High response rates were also observed for the key secondary endpoints. The clinical
response rates [95% CI] at EOT and LFU visits in the CE population were 94.6% (87/92
participants) [87.8, 98.2] and 90.6% (77/85 participants) [82.3, 95.8], respectively.
The microbiological response rates per-subject [95% CI] at EOT and TOC visits in the
expanded microbiologically evaluable population (EME) were 93.8% (61/65 participants) 
[85.0, 98.3] and 90.2% (55/61 participants) [79.8, 96.3], respectively.
Against the most common baseline-infecting pathogens, microbiological response rates [95%
CI] at the TOC visit were 90.2% (37/41 participants) [76.9, 97.3] for Escherichia coli.,
91.7% (11/12 participants) [61.5, 99.8] for Klebsiella pneumoniae, 100.0% (11/11 
participants) [71.5, 100.0] for Streptococcus anginosus, 90.0% (9/10 participants) [55.5, 
99.7] for Streptococcus constellatus and 95.2% (20/21 participants) [76.2, 99.9] for 
Bacteroides fragilis.
Ongoing Clinical Studies
As date of 15Nov2019, there are 2 ongoing clinical studies with ceftolozane/tazobactam: a 
Phase 2 study (MK-7625A-034) in pediatric participants with cUTI, and a Phase 2 study
(MK-7625A-035) in pediatric participants with cIAI.  A Phase 1 study (MK-7625A-036) in 
pediatric participants with nosocomial pneumonia is planned. Additional details may be 
found in the accompanying Investigators Brochure (IB).
Information on Other Study-related Therapy
Intravenous metronidazole will be used in participants who are randomized to ceftolozane/ 
tazobactam in this study. In order to maintain study blind, a placebo will be administered to 
participants randomized to meropenem.  Metronidazole and placebo will be infused 
following ceftolozane/tazobactam and meropenem, respectively.  An appropriate surgical 
intervention for target diseases will be done for all participants based on the investigators’ 
decision, as inclusion in this study requires surgical intervention (e.g., laparotomy, 
laparoscopic surgery, or percutaneous draining of an abscess) within 24 hours of (before or 
after) the first dose of ceftolozane/tazobactam.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
 
 
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The following objectives and endpoints will be evaluated in adult participants diagnosed with 
complicated intra-abdominal infection (cIAI).
Objectives
Endpoints
Primary
•
Objectives: To evaluate the efficacy of 
ceftolozane/tazobactam plus
metronizazole versus meropenem with 
respect to clinical response at the test of 
cure (TOC) visit for participants 
diagnosed with cIAI in the clinically
evaluable (CE) population.
Hypothesis:  Ceftolozane/tazobactam
plus metronizazole is non-inferior to 
meropenem in participants with cIAI, 
as measured by the clinical response 
rate at TOC visit in the CE population. 
•
Clinical response: A favorable clinical 
response is clinical cure (see Section 
8.2.1).
Secondary
•
Objective:  To evaluate the efficacy of 
ceftolozane/tazobactam plus
metronizazole versus meropenem with 
respect to clinical response for 
participants diagnosed with cIAI.
•
Clinical response at the TOC 
visit in the intent-to-treat (ITT)
population
•
Clinical response at the end of 
therapy (EOT) visit in the ITT
and CE population
•
Clinical response
 
 
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Objectives
Endpoints
•
Objective:  To evaluate the efficacy of 
ceftolozane/tazobactam plus
metronizazole versus meropenem with 
respect to microbiological response for 
participants diagnosed with cIAI
•
Per-subject microbiological 
response at the TOC visit in the 
expanded microbiologically 
evaluable (EME) population
•
Per-pathogen microbiological 
response at the TOC visit in the 
EME population
•
Per-subject microbiological response: 
For a favorable overall microbiological 
response (i.e., eradication or presumed 
eradication), each baseline pathogen for 
the participant must have a favorable 
microbiological outcome (see Section 
8.2.2).
•
Per-pathogen microbiological response: 
A favorable microbiological responses 
include “eradication” or “presumed 
eradication” (see Section 8.2.2).
•
Objective:  To evaluate the safety and 
tolerability of ceftolozane/tazobactam
plus metronizazole in participants 
diagnosed with cIAI.
•
Adverse events (AEs)
•
Study treatment discountinuation due to 
AE
Exploratory
•
Objective:  To evaluate the efficacy of 
ceftolozane/tazobactam plus 
metronizazole versus meropenem with 
respect to clinical response for 
participants diagnosed with cIAI.
•
Clinical response at TOC visit in 
the microbiological intent-to-treat 
(MITT) population and 
microbiologically evaluable (ME)
population 
•
Clinical response at EOT visit in 
the MITT population
•
Clinical response
 
 
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Objectives
Endpoints
•
Objective:  To evaluate the efficacy of 
ceftolozane/tazobactam plus
metronizazole versus meropenem with 
respect to microbiological response for 
participants diagnosed with cIAI.
•
Per-subject microbiological 
response at the TOC visit in the ME
and MITT population
•
Per-subject microbiological 
response at the EOT visit in the 
ME, EME and MITT population
•
Per-pathogen microbiological 
response at the TOC visit in the ME
and MITT population
•
Per-pathogen microbiological 
response at the EOT visit in the 
ME, EME and MITT population
•
Per-subject microbiological response
•
Per-pathogen microbiological response
TOC = test of cure; EOT = end of therapy; CE = clinically evaluable; ITT = intent-to-treat; MITT = 
microbiological intent-to-treat; ME= microbiologically evaluable; EME = expanded ME
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active-controlled, multicenter, double-blind study of ceftolozane/ 
tazobactam intravenous IV infusion (1500 mg q8h) plus metronidazole (500 mg q8h) IV 
infusion vs. meropenem IV (1000 mg q8h) plus placebo (IV saline q8h) in participants with 
complicated intra-abdominal infection (cIAI) requiring surgical intervention to be conducted 
in conformance with Good Clinical Practices. Administration dosage of 
ceftolozane/tazobactam and meropenem will be adjusted according to participant’s renal 
function. Approximately 268 adult Chinese participants with a diagnosis of cIAI will be 
enrolled in this study; participants will be randomized in a 1:1 ratio to receive one of two 
treatment arms of the study: Treatment Group 1 (ceftolozane/tazobactam 1500 mg
[ceftolozane 1000 mg/tazobactam 500 mg] plus metronidazole 500 mg) or Treatment Group 
2 (meropenem 1000 mg plus placebo). After a screening (baseline period) of 24 hours or less, 
randomized participants in each treatment group will receive assigned treatment for 4 to 14 
days. All study drugs in both treatments will be administered intravenously (IV) q8h over 60-
min infusions separately. Following the completion of IV study therapy, all participants have 
an EOT visit within 24 hours after last dose of study drug. In addition, a TOC (Day 28, ±2 
days) visit will be performed in all participants. Efficacy assessments (clinical response) will 
be conducted at the TOC visit, as well as EOT visit. Participants will be followed for safety 
until the TOC visit. All participants will remain in the study for a total of approximately 31 
 
 
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days at maximum. In this study, no switch from IV study therapy to an oral antibacterial 
therapy is allowed.
Randomization will be stratified based on anatomic site of infection (bowel [small or large] 
vs. other site of cIAI). Participants with appendix, stomach, or duodenum as the anatomic site 
of infection, will be stratified to the “other site” group during the randomization process. The 
number of participants with localized complicated appendicitis will be limited to 
approximately 50% (134 participants) of the randomized population. The enrollment of the 
participants with CrCL (30 to ≤ 50 mL/min) is limited up to approximately 15% (40 
participants) of the total enrollment.
In order to maintain the blind, placebo for metronidazole infusions must be given to those 
participants assigned to meropenem treatment. Placebo for meropenem must be administered 
to participants in the ceftolozane/tazobactam treatment group with CrCL 30 to ≤ 50mL/min 
due to a dose adjustment of meropenem to maintain the study blind. In addition, the infusion 
frequency of placebos will be adjusted according to CrCL value  to ensure double dummy 
nature of the study. Referring to section 8.1.8 for details.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint in this study is the clinical response rate at the TOC visit in 
the CE population. Based on the FDA guidance (2015) for cIAI and to conduct a comparable 
analysis to the global cIAI studies (CXA-cIAI-10-08 and CXA-cIAI-10-09), TOC is the 
primary time point for efficacy. Moreover, for the same reason, in order to estimate the 
efficacy at the end of treatment, EOT is set as secondary time points for efficacy.
The analysis population for primary efficacy objective of this study is the CE population as
the case for the Japan cIAI study. The CE population will minimize confounding factors and 
its efficacy analysis is expected to reflect the study drug activity. In contrast, the MITT 
population that is a medically complex, more heterogenous population than the CE 
population due to the acuity of illness, necessity for surgical precedures, and potential of 
acquiring other nosocomial bacterial infections. Consistent with the above expectations, in 
the global adult studies[Solomkin, J., et al 2015], a higher cure rate was observed in the CE 
population compared to the MITT population.
The analysis population of microbiological response for sencondary efficacy objective is 
EME population which is more inclusive and provides a broader set of pathogen data and 
may reflect more of a real word setting when treated before susceptibility results. In contrast, 
 
 
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the ME population is more stringent and may provide a better assessment of the drug’s 
activity, but will limit the dataset.
Additional study populations have been pre-specified to be analyzed to provide a better 
understanding of the robustness of the primary efficacy endpoint. The analysis populations in 
the secondary study objectives are similar to those of global cIAI studies (CXA-cIAI-10-08 
and CXA-cIAI-10-09) and Japan cIAI study.
Refer to Table 1 for a summary favorable response by efficacy endpoint and analysis 
population.
Table 1
Summary of Primary, Secondary and Exploratory Efficacy Endpoints and 
Components of a Favorable Response
Objective
Endpoint
Timing
Favorable Response
Analysis 
Population
References
(Section/Table)
Primary 
Endpoint 
Clinical Response
TOC 
Clinical cure
CE
Section 8.2.1/
Table 5
Secondary 
Endpoint
Clinical Response
TOC 
Clinical cure
ITT
Section 8.2.1/
Table 5
Clinical Response 
EOT
Clinical cure 
ITT and 
CE 
Section 8.2.1 /
Table 5
Micrological 
response
TOC
Eradication or 
presumed eradication
EME
Section 8.2.2 / 
Table 6
Exploratory 
Endpoint
Clinical Response
TOC
Clinical cure
MITT and 
ME
Section 8.2.1/
Table 5
Clinical Response
EOT
Clinical cure
MITT
Section 8.2.1/
Table 5
Micrological 
response
TOC
Eradication or 
presumed eradication
ME and 
MITT 
Section 8.2.2 / 
Table 6
Microbiological 
Response
EOT
Eradication or 
presumed eradication
ME, EME 
and MITT
Section 8.2.2 / 
Table 6
TOC = test of cure; EOT = end of therapy; CE = clinically evaluable; ITT = intent-to-treat; MITT = 
microbiological intent-to-treat; ME= microbiologically evaluable; EME=expanded microbiologically 
evaluable.
4.2.1.2
Safety Endpoints
In support of the secondary objective to evaluate the safety and tolerability profile of 
ceftolozane/tazobactam, the safety and tolerability of ceftolozane/tazobactam (as well as the 
safety of the comparator, meropenem) will be assessed by clinical evaluation of adverse 
events and inspection of other study parameters including vital signs, physical examinations, 
and standard laboratory safety tests at time points specified in the SoA.  Participants may be 
asked to return for unscheduled visits in order to perform additional safety monitoring.
 
 
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Rationale for the Use of Concomitant/Comparator/Placebo
Metronidazole will be used in combination for all participants enrolled into the ceftolozane/
tazobactam arm of this study. Ceftolozane/tazobactam demonstrates activity against the 
major pathogens implicated in cIAIs such as gram-negative bacteria including 
Enterobacteriaceae including Escherichia coli., Klebsiella pneumoniae and Pseudomonas
aeruginosa, some of gram-positive bacteria such as streptococci spp., and the anaerobe
Bacteroides fragilis. Ceftolozane/tazobactam has limited activity against other bacteroides 
species beyond Bacteroides fragilis are major pathogens in IAIs necessitating the need for an 
antibacterial agent with activity against a range of anaerobic organisms. Metronidazole, a 
limited-spectrum, anaerobe-specific antibiotic, is commonly used in the treatment of cIAI in 
combination with a cephalosporin, and its use is recommended in the evidence-based 
guidelines for the treatment of cIAI at 500 mg every 8 hours[Solomkin, J. S., et al 2010]. 
Metronidazole is approved and marketed for the treatment of anaerobe infection in China and 
overseas. Taking into consideration this background, IV metronidazole will be used 
concomitantly in this study in order to appropriately treat the target pathogens associated 
with cIAIs. No changes to the metronidazole dose are required for renal insufficiency.
In China tertiary hospitals, carbapenems (e.g. imipenem/cilastatin, meropenem) are most 
widely used antibiotic for treating cIAI. Meropenem is indicated for the treatment of cIAI in 
the approved China label and was chosen as active comparator in the global pivotal studies
[Solomkin, J., et al 2015] as well. Meropenem will be used in this study as the active 
comparator. Meropenem will be administered intravenously 1000 mg every 8 hours when 
CrCL is > 50 mL/min and 1000 mg every 12 hours when CrCL is 30 to ≤ 50 mL/min 
according to the approved label in China.
Since Enterococcus is one of the common pathogens in cIAI, in case an infection with 
MRSA or Enterococcus is suspected, antibiotics with gram-positive coverage such as 
vancomycin, teicoplanin, linezolid and daptomycin are allowed in the study.
This study is a double-blinded design. In order to maintain the blind, a placebo will be used 
in this study. After randomization, all eligible participants will be randomized to Treatment 
Group 1 (ceftolozane/tazobactam plus metronidazole) or Treatment Group 2 (meropenem 
plus placebo). Metronidazole will be administered following ceftolozane/tazobactam and 
placebo will be administered following meropenem, respectively.
Considering increasing resistance rate of key pathogens in cIAI e.g. Escherichia coli., 
Klebsiella pneumoniae and Pseudomonas aeruginosa, especially ESBL producing strains, to 
widely used antibacterials in China including Carbapenems, ceftolozane/tazobactam will 
provide a new efficacious option in treating cIAI in clinical practice.
 
 
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4.3
Justification for Dose
Starting Dose for This Study
The dose selection of the ceftolozane component of ceftolozane/tazobactam was mainly 
based on the PK of ceftolozane and all known relevant pharmacokinetic/pharmacodynamics 
(PK/PD) principles for cephalosporins. Tazobactam, the other component of 
ceftolozane/tazobactam, is broadly used in China clinical practice (such as 
piperacillin/tazobactam). The dose of tazobactam is based on prior data which is known to be 
well-tolerated. 
Based on the combined plasma concentration-time data from Phase 1 and 2 studies, a 
population PK analysis was conducted to characterize the PK of ceftolozane, and using these 
data, Monte Carlo simulations were conducted to evaluate the expected efficacy of different 
dosing regimens of ceftolozane. Like other β-lactam antibiotics, the PK/PD parameter that 
most closely correlates with efficacy is the time, as a percentage of the dosing interval, that 
the plasma concentration of ceftolozane exceeds the minimum inhibitory concentration 
(MIC) of the infecting organism (%T>MIC). Monte Carlo simulation analysis of clinical PK 
data revealed that using 30% T>MIC, an IV 1-hour infusion of 1500 mg
ceftolozane/tazobactam administered every 8 hours would provide sufficient drug 
concentrations to cover target pathogens, with a probability of target attainment (PTA) of 
100% for pathogens with an MIC of up to 8 μg/mL. According to the results from a Phase 1
study (CXA-EB-13-05), the pharmacokinetics of ceftolozane/tazobactam is dose independent 
and similar between Japanese, Chinese and Caucasian healthy participants.
In Phase 3 studies (CXA-cIAI-10-08 and CXA-cIAI-10-09), IV ceftolozane/tazobactam 1500 
mg every 8 hours and 500 mg metronidazole demonstrated non-inferiority to IV meropenem 
1000 mg every 8 hours for the treatment of cIAIs. Additionally, in Phase 3 studies of 
complicated urinary tract infections (cUTI) including pyelonephritis (CXA-cUTI-10-04 and 
CXA-cUTI-10-05), IV ceftolozane/tazobactam 1500 mg every 8 hours demonstrated non-
inferiority to IV levofloxacin 750 mg once daily. In both indications, IV 
ceftolozane/tazobactam 1500 mg every 8 hours was generally well tolerated.
Relative to ceftolozane/tazobactam exposures in participants with normal renal function 
(CrCL ≥90 mL/min), no clinically relevant differences in exposure were observed in 
participants with mild renal impairment, whereas exposures increased approximately 2-fold 
in participants with moderate renal impairment.
Based on these results, no dose adjustment is recommended for participants with mild renal 
impairment (CrCL >50 to 89 mL/min). However, the ceftolozane/tazobactam dose in 
participants with moderate (CrCL 30 to ≤50 mL/min) is recommended to be reduced by 2-
fold (i.e., 750 mg ceftolozane/tazobactam every 8 hours). Based on Monte Carlo simulation 
analysis a 2-fold dose reduction in participants with moderate renal impairment was 
predicted to produce sufficient drug concentration to cover target pathogens.
 
 
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In this Chinese Phase 3 study (Protocol 015), participants with CrCL > 50 mL/min will 
receive ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg/ tazobactam 500 mg) every 8 
hours and participants with CrCL 30 to ≤50 mL/min will receive ceftolozane/tazobactam 750
mg (ceftolozane 500 mg/tazobactam 250 mg) every 8 hours. Participants with severe renal 
impairment (i.e., CrCL < 30 mL/min) will not be enrolled and any participant who develops 
severe renal impairment during the treatment phase must be discontinued from study drug 
administration if already enrolled.
Maximum Dose/Exposure for This Study
No dose modifications are planned for this study aside from dose reductions for renal 
insufficiency. Therefore, the maximum dose for this study will be 1500 mg 
ceftolozane/tazobactam every 8 hours.
Rationale for Dose Interval and Study Design
The treatment period for ceftolozane/tazobactam in this China Phase 3 study (Protocol 015) 
will be 4-14 days. This duration was determined based on 2 global phase 3 studies (CXA-
cIAI-10-08 and CXA-cIAI-10-09) and the US package insert [U.S. Prescribing Information 
2016].
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable.  In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male/Female Chinese participants with cIAI between the ages of 18 and 75 years (inclusive) 
will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
 
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5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Have one of the following diagnoses (in which there is evidence of intraperitoneal 
bacterial infection) including:
a.
Cholecystitis (including gangrenous cholecystitis) with rupture, perforation, or 
progression of the infection beyond the gallbladder wall;
b. Acute gastric or small intestine including duodenal perforation, only if operated on 
> 24 hours after perforation  occurs;
c.
Traumatic perforation of the intestine (including colon), only if operated on > 12 
hours after perforation  occurs;
d. Appendiceal perforation or periappendiceal abscess ;
e.
Diverticular disease with perforation or abscess;
f.
Peritonitis due to other perforated viscus or following a prior operative procedure;
•
Participants with inflammatory bowel disease or ischemic bowel disease are 
eligible provided there is bowel perforation(only if operated on > 24 hours 
after perforation  occurs)
g. Intraabdominal abscess (including liver or spleen).
2. Evidence of systemic infection including one or more of the following:
a.
Temperature (axillary) greater than 37.4°C or less than 35°C, other temperature 
method will be allowed based on the discussion between the sponsor and 
investigator (for subjects who only meet Inclusion Criterion 2a in systemic infection 
assessment, axillary temperature will be the required method);
b. Elevated white blood cells (WBC >10,000/mm3) or decreased WBC count (≤4,000 
/mm3);
c.
Abdominal pain, flank pain, or pain likely due to cIAI that is referred to another 
anatomic area such as back or hip; or
d. Nausea or vomiting.
3. Requires surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous
draining of an abscess) within 24 hours of (before or after) the first dose of study drug.
 
 
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4. If participant is to be enrolled preoperatively, the participant should have radiographic 
evidence of gastric or bowel perforation or intra-abdominal abscess or other radiographic 
evidence for cIAI.
5. Subjects who failed prior antibacterial treatment for the current cIAI can be enrolled but 
must: (a) have a positive culture (from an intraabdominal site or blood sample) and (b) 
require surgical intervention. Such subjects can be enrolled before the results of the 
culture are known; however, if the culture is negative, study drug administration may be 
discontinued.
† Participants considered to have failed a previous antibiotic regimen
Should meet all of the following criteria
1)
The systemic antibacterial treatment was given for at least 48 hours;
2)
There are clinical plus operative findings OR clinical plus radiographic findings clearly 
indicating ongoing infection or worsening infection;
3)
Operative intervention or re-intervention (if previous surgical procedure) is intended within 24 
hours of (before or after) the first dose of study drug;
Note: Specimens for bacterial culture and susceptibility testing are to be taken at operative 
intervention.Culture results do not need to be known before randomization(citing Section 8.3.12 
for details). 
Demographics
6. Participant is male or female.
7. Chinese participant is from 18 years to 75 years of age inclusive, at the time of signing 
the informed consent.
Note: Chinese participant is defined as a person of Chinese descent, A potential 
participant who is of ex-China descent (e.g., Western European) descent living in China 
will be excluded.
Male Participants
8. Agree to use a contraception as detailed in Appendix 5 of this protocol during the 
treatment period and for at least 30 days (a spermatogenesis cycle) after the last dose of 
study medication and refrain from donating sperm during this period.
Female Participants
9.
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
•
Is not a WOCBP
 
 
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OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), or be abstinent from heterosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix 5 
during the intervention period and for at least 30 days after the last dose of study 
intervention. The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test (serum) within 48 hours 
before the first dose of study intervention.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 5.
•
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.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
10. The participant (or legally acceptable representative if applicable) provides written 
informed consent/assent for the study.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has any of the following diagnoses :
a.
Simple appendicitis;
b. Abdominal wall abscess; 
c.
Small bowel obstruction or ischemic bowel disease without perforation;
d. Spontaneous (primary) bacterial peritonitis associated with cirrhosis and chronic 
ascites; or
e.
Pelvic infections.
 
 
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2. Has any of the following diseases:
a.
Acute suppurative cholangitis; 
b. Infected necrotizing pancreatitis; 
c.
Pancreatic abscess.  
3. Participant who has complicated intra-abdominal infection managed by staged abdominal 
repair (STAR), open abdomen technique (ie, fascia not closed) including temporary 
closure of the abdomen, or any situation where infection source control was not likely to 
be achieved. 
4. Participant who has abscess that is confirmed on imaging test but has not been or cannot 
be managed by surgical intervention including drainage.
5. Participant who is expected to be cured by only surgical intervention (e.g., drainage) 
without use of systemic antibiotic therapy.
6. Participant who has the following underlying conditions or who are at following serious 
conditions:
a.
Considered unlikely to survive during the study period (predicted life expectancy is 
< 4 weeks after randomization);
b. Organic brain or spinal cord disease;
c.
Any rapidly-progressing disease or immediately life-threatening illness (including 
respiratory failure and septic shock);
d. Immunocompromising condition, including established acquired immune 
deficiency syndrome (AIDS), hematological malignancy, or bone marrow 
transplantation, or immunosuppressive therapy including cancer chemotherapy, 
medications for prevention of organ transplantation rejection, or the administration 
of corticosteroids equivalent to or greater than 40 mg of prednisone per day 
administered continuously for more than 14 days immediately preceding 
randomization.
7. Participant who have a history of any hypersensitivity or allergic reaction to any beta-
lactam (β-lactam) antibacterial, including cephalosporins, carbapenems, penicillins, or 
tazobactam, or metronidazole, or nitroimidazole derivatives;
OR if a skin test is required by local clinical regulations, the participant has a positive 
skin test result if no prior history of an allergic reaction to β-lactam antibacterials.
8. Has a history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that, in the opinion of the investigator, might confound the results of 
the study, interfere with the participant’s participation for the full duration of the study, or 
pose additional risk in administering the study drugs to the participant.
 
 
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9. A WOCBP who has a positive serum pregnancy test within 24 hours before the first dose 
of study intervention (see SoA and Appendix 5). 
Prior/Concomitant Therapy
10. Use of systemic antibiotic therapy with known coverage of pathogens that cause IAI for 
more than 24 hours (e.g >1 course of a once daily antibiotic or >2 courses of q12h 
antibiotic) during the previous 72 hours prior to the first dose of study drug, unless there 
is a documented treatment failure† with such therapy. 
11. For participants that are enrolled postoperatively, more than 1 dose of an active non-study 
antibacterial regimen administered postoperatively. For participants enrolled 
preoperatively, no postoperative non-study antibacterial therapy is allowed.
12. Participants who needs additional non-study systemic antibacterial therapy with gram-
negative activity in addition to study drug therapy 

Drugs with only gram-positive activity (eg, IV vancomycin, teicoplanin, linezolid 
and daptomycin) are allowed.
13. Participant is anticipated to be treated with Traditional Chinese Medicine or Herbal 
Medicine during study period.
14. Participant who received disulfiram, valproic acid or divalproex sodium within 14 days 
before the proposed first day of study drug or who are currently receiving probenecid.
Prior/Concurrent Clinical Study Experience
15. Is currently participating in, or has participated in, any other clinical study involving the 
administration of investigational or experimental medication (not licensed by regulatory 
agencies) at the time of the presentation or during the previous 90 days prior to screening 
or is anticipated to participate in such a clinical study during the course of this study.
16. Participant who has participated in a ceftolozane/tazobactam clinical study at any time in 
the past.
Diagnostic Assessments
17. Severe impairment of renal function (estimated CrCL <30 mL/min), or requirement for 
peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (<20 mL/h urine output 
over 24 hours).
18. Has hepatic disease in the period of screening as defined by any of the following:
a.
ALT (SGPT) or AST (SGOT) > 4 x upper limit of normal (ULN);
b. Total bilirubin > 2 x ULN, unrelated to cholecystitis;
 
 
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c.
Alkaline phosphatase > 4 x ULN. Participants with a value > 4 x ULN and < 5 x 
ULN are eligible if this value is historically stable at discretion of the investigator;
d. Acute or chronic hepatitis, liver cirrhosis, acute hepatic failure, acute 
decompensation of chronic hepatic failure.
19. Participant who has any of the following value in the period of screening period:
a.
Hematocrit <25%;
b. Hemoglobin <8 g/dL;
c.
Neutropenia with absolute neutrophil count <1,000/mm3; OR
d. Platelet count <75,000/mm3.
Other Exclusions
20. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
There are no dietary or activity restrictions in this study, except as medically indicated.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
Participants who have been screened but have not been previously randomized to this study 
may be rescreened for participation if their eligibility characteristics have changed and (a) 
they have not received any antibacterial therapy for the current cIAI or (b) their previous 
cIAI has been successfully treated and they present with signs and symptoms of a new cIAI.
 
 
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies study interventions provided by the Sponsor will be packaged to support 
enrollment . Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
 
 
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Group 
1
Experimental
Ceftolozane
/tazobactam
1500 mg
Drug
Vial
20 mL vial 
Lyophilized 
Powder for 
IV Infusion
1500 mg 
(ceftolozane 
1000 mg 
/tazobactam 
500 mg)
750 mg†
(ceftolozane 
500 mg 
/tazobactam 
250 mg)
IV 
Infusion
Q8h/60 min IV
infusion/4-14
days
Experimental
IMP
Provided
centrally by
the Sponsor
Group 
1
Experimental
Metronidazole
500 mg
Drug
IV bag
500 mg 
metronidazole 
and
800 mg 
sodium 
chloride in 
100 mL
500 mg
IV 
Infusion
Q8h/ 60 min IV 
infusion/4-14 
days
Concomitant 
drug
IMP
Provided
centrally by
the Sponsor
Group 
2
Comparator
Meropenem
1000 mg
Drug
Vial
500 mg vial 
lyophilized 
powder for IV 
infusion
1000 mg
IV 
Infusion
Q8h/ 60 min IV 
infusion/4-14 
days
OR
Q12h/60 min IV 
infusion/4-14 
days
†
Challenge 
Agent
IMP
Provided
centrally by
the Sponsor
 
 
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Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Group 
2
Comparator
Saline 
Placebo
IV bag
NA
NA
IV 
Infusion
Q8h/ 60 min IV 
infusion/4-14 
days
Placebo
IMP
Provided
centrally by 
the Sponsor
In order to maintain double dummy of the study, the placebo (saline) need to be administered in the participant with CrCL 30 to ≤50 mL/min in both arms.
Abbreviations: Q8h=every 8 hours; IV=intravenous; NA=not applicable.
† For participants with CrCL :30 to ≤ 50 mL/min.
 
 
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
Dose Preparation
All IV study therapy will be reconstituted and administered according to the details provided
in a separate Pharmacy Manual. An unblinded study staff (eg, pharmacist or qualified
designee) at the study site will be responsible for preparing the IV study therapy for this
study; this individual(s) must not be involved in any of the safety and efficacy evaluations of
the study participants. Due to a visual difference in the appearance of study treatment
solutions, the infusion bags will be covered with an opaque sleeve by the unblinded study
staff (e.g., pharmacist or qualified designee) to ensure that other study personnel and all
participants remain blinded to clinical material assignments.
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
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) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
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).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
 
 
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
Intervention Assignment
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS). There are 2 study intervention arms. 
Participants will be assigned randomly in a 1:1 ratio to ceftolozane/tazobactam + 
metronidazole (Treatment Group 1) and meropenem +  placebo (Treatment Group 2), 
respectively
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
•
Bowel [small or large] vs. other site of cIAI
Note:  Participants with appendix, stomach, or duodenum as the anatomic site of infection, 
will be stratified to the “other site” group during the randomization process. The number of 
participants with localized complicated appendicitis will be limited up to approximately 50% 
of the randomized population.
In addition, the randomization will also be controlled by quotas built into the IVRS/IWRS
such that the enrollment of the participants with CrCL (30 to ≤ 50 mL/min) will be limited up 
to approximately 15% of the randomized population.
Blinding
A double-blinding technique will be used. Study drug will be prepared and/or dispensed in a 
blinded fashion by an unblinded pharmacist or unblinded qualified study site personnel. Due 
to a visual difference in the appearance of study treatment solutions, the infusion bags will be 
covered with an opaque sleeve by the unblinded study staff (eg, pharmacist or qualified 
designee) to ensure that other study personnel and all participants remain blinded to clinical 
material assignments. The participant, the investigator, and Sponsor personnel or delegate(s) 
in this study are all blinded except for the few designated members of the unblinded study 
team.
In order to maintain the blind, placebo for metronidazole infusions must be given to those 
participants assigned to meropenem treatment. Placebo for meropenem must be administered 
to participants in the ceftolozane/tazobactam treatment group with CrCL 30 to ≤ 50mL/min 
due to a dose adjustment of meropenem to maintain the study blind. In addition, the infusion 
frequency of placebos will be adjusted according to CrCL value  to ensure double dummy 
nature of the study. Referring to section 8.1.8 for details.
 
 
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6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for ≥1 days (i.e. 3 doses if no dose 
adjustment made based on renal function) require consultation between the investigator and 
the Sponsor and written documentation of the collaborative decision on participant 
management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
Listed below are specific restrictions for concomitant therapy or vaccination:
1. Systemic antibacterials other than study drugs: From the timing of first study drug 
administration to TOC visit (allow for use of systemic antibiotic in failures).
NOTE: Vancomycin, teicoplanin, linezolid, and daptomycin are allowed if infection 
with MRSA or Enterococcus is suspected
2. Disulfiram, valproic acid or divalproex sodium: From 14 days before the first study 
drug administration to TOC visit
3. Probenecid: From the timing of first study drug administration to EOT visit
4. Systemic steroids: From the timing of first study drug administration to TOC visit. 
Short-term treatment with systemic (IV or oral) steroids of <1 week duration (eg, 
treatment for an acute asthma exacerbation or acute skin condition) is allowed. 
Topical steroids for the treatment of skin conditions are also allowed.
5. Systemic immunosuppressive agents: From the timing of first study drug 
administration to TOC visit.
6. Traditional Chinese Medicine or Herbal Medicine: From the timing of first study drug 
administration to EOT visit
7. Other investigational drugs: From 90 days prior to the proposed first day of study 
drug to TOC visit
8. Peritoneal irrigation with antibiotic-containing solutions
 
 
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All prescription and over-the-counter medications (including Traditional Chinese Medicine 
and Herbal Medicine) other than antibacterial agents that the participant received from 7 days 
before the first dose of study drug and throughout the study (up to the TOC evaluation) will 
be documented in the eCRF. 
All antibacterial agents that the participant received within 14 days before the first dose of 
study drug and throughout the study up to the TOC evaluation will be documented in the 
eCRF.
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
6.6
Dose Modification (Escalation/Titration/Other)
Ceftolozane/Tazobactam
In participants with impaired renal function, it is necessary to adjust the 
ceftolozane/tazobactam dosage based on the grade of a renal function (creatinine clearance: 
CrCL). Estimate the participant’s CrCL using the participant’s serum creatinine value, actual 
body weight, and the appropriate Cockroft-Gault formula below.  Careful monitoring of renal 
function is important, especially during the first few days following intra-abdominal surgery, 
as there are often fluctuations in CrCL following surgery. For participants with changing 
renal function (creatinine clearance is close to 50 mL/min or less), monitor CrCL at least 
daily and adjust the dosage of ceftolozane/ tazobactam accordingly. Elderly participants are 
also likely to have renal impairment, care should be taken in dose selection in this age group 
and it may be useful to monitor their renal function.
For serum creatinine reported in μmol/l:
CrCL (mL/min) = (140-age[yr])(body wt[kg])*(0.85 if female)
                             (72)(serum creatinine [mol/L] x 0.0113)
The dosage of ceftolozane/tazobactam for each creatinine clearance category is shown in
Table 3.
Table 3
Administration Dosage of Ceftolozane/Tazobactam According to Renal Function
Creatinine clearance (mL/min)
Dosage of ceftolozane/tazobactam 
>50
1500 mg (1000 mg ceftolozane and 500 mg tazobactam) 
intravenously every 8 hours a
30 to ≤50
750 mg (500 mg ceftolozane and 250 mg tazobactam) 
intravenously every 8 hours a
a. 2 hours window is allowed.
 
 
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Metronidazole
The dosage of metronidazole IV is administered 500 mg every 8 hours based on the package 
insert in China regardless of the calculation of creatinine clearance. 
In order to maintain the blind, placebo for metronidazole infusions must be given at 8 and 16 
hours following the first infusion (the second and fourth infusion of four times a day), to 
those participants assigned to meropenem treatment in order to avoid the observation that 
only one infusion is given.
Meropenem
Dose adjustment of meropenem in moderate renal insufficiency will require a change to q12h 
dosing, two 60-min dummy infusions (saline) 12 hours (± 2 hours) apart following the first 
infusion of the day must be administered to participants in the ceftolozane/tazobactam 
treatment group with CrCL 30 to ≤ 50 mL/min to maintain the study blind.
The infusion frequency of placebos will be adjusted (see examples in 8.1.8.1) according to 
different calculation of creatinine clearance, to ensure double dummy of the study.
The dosage of meropenem for each creatinine clearance category is shown in Table 4.
Table 4
Administration Dosage of Meropenem According to Renal Function
Creatinine clearance (mL/min)
Dosage of meropenem
>50
No dose adjustment required
30 to ≤ 50
Decrease meropenem frequency to 1000 mg IV every 12 
hours a
a. 2 hours window is allowed.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind participants and to unmask treatment identity. In the event that the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order 
to unblind participants and to unmask treatment identity.  The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
 
 
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6.9
Standard Policies
For studies using Controlled Substances, all Federal, State, Province, Country, etc. 
regulations must be adhered to in regard to the shipping, storage, handling and dispensing of 
controlled substances. Additionally, the investigator should have the appropriate controlled 
drug license(s) as mandated by Federal, State, Province, Country, etc. laws in which the 
study is being conducted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and Section 
8.12.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Severe impairment of renal function (estimated CrCL <30 mL/min), oliguria (<20 mL/h 
urine output over 24 hours) or requirement for hemodialysis/hemofiltration.
•
Lack of efficacy: the primary or sub-investigator judges that study treatment is not 
efficacious (defined as lack of improvement or worsening of the baseline clinical signs 
and symptoms after 48 hours of study therapy).
•
The index cIAI was clinically confirmed to be due to tuberculosis or of fungal, parasitic,
or viral origin.
 
 
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•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
The participant’s treatment assignment has been unblinded by the investigator, Merck 
subsidiary or through the emergency unblinding call center.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
 
 
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•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
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 ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 100 mL (Appendix 2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study .If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
 
 
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The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
(all antibacterial medications taken within 14 days and other medications within 7 days 
before first dose of study medication.
 
 
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study (from the first dose of study medication to TOC visit).
Since the study will enroll participants without confirmed microbiological (culture) evidence 
of the cIAI pathogen from intra-abdominal specimen at study entry, drugs with only gram-
positive activity [e.g., daptomycin, vancomycin, linezolid] are allowed.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization OR intervention
allocation. Each participant will be assigned only 1 screening number. Screening numbers 
must not be re-used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.12.1.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Study Intervention Administration
Administration of study medication will be witnessed by the investigator and/or study staff.
The first dose of study intervention will be administered at the Day 1 Visit.
8.1.8.1
Timing of Dose Administration
Participants with creatinine clearance > 50 mL/min 
After randomization, ceftolozane/tazobactam 1500 mg followed by metronidazole 500 mg, or 
meropenem 1000 mg followed by placebo will be administered intravenously every 8 hours 
(± 2 hours) starting on Day 1, respectively. Administration example for participants with 
creatinine clearance > 50 mL/min is shown as below.
 
 
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For Participants randomized to ceftolozane/tazobactam:
8am
4pm
12am
ceftolozane/tazobactam + 
metronidazole
ceftolozane/tazobactam + 
metronidazole
ceftolozane/tazobactam + 
metronidazole
For Participants randomized to meropenem:
8am
4pm
12am
meropenem + placebo
meropenem + placebo
meropenem + placebo
Participants with creatinine clearance 30 to ≤50 mL/min 
After randomization, the dosage of ceftolozane/ tazobactam and meropenem will be adjusted 
to ceftolozane/tazobactam 750 mg intravenously every 8 hours (± 2 hours) and meropenem 
1000 mg intravenously every 12 hours (± 2 hours). Administration example for participants 
with creatinine clearance 30 to ≤50 mL/min is shown as below. 
For Participants randomized to ceftolozane/tazobactam:
8am
4pm
8pm
12am
ceftolozane/tazobactam
+ metronidazole
ceftolozane/tazobactam
+ metronidazole
placebo + 
placebo
ceftolozane/tazobactam
+ metronidazole
For Participants randomized to meropenem:
8am
4pm
8pm
12am
meropenem + placebo
placebo + placebo
meropenem + 
placebo
placebo + placebo
Treatment duration for all participants and decision of treatment completion
Participants should receive study drug for a minimum of 4 days (unless clinical failure occurs 
earlier or an AE necessitating early discontinuation occurs), and end the treatment of study 
drug within 14 days. 
After 4 days and at the discretion of the Investigator, study drug administration may be 
discontinued if the participant has shown signs and symptoms of clinical improvement such 
as:

WBC count is 4,000 to < 10,000/mm3;

Maximum axillary temperature has been < 37.4 °C, for > 24 hours, without the 
influence of antipyretic agents, such as aspirin, acetaminophen, non-steroidal anti-
inflammatory drugs, or corticosteroids; other body temperature measurements
 
 
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method will be allowed as long as the same method is used for a participant 
throughout the study;

Improvement of abdominal signs and symptoms manifested at study entry;

Return of bowel function and restoration of oral/enteral intake; and

No further antibiotic therapy is required.
Metronidazole and the saline placebo should be given for the same duration as the study drug.
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the 14 days treatment 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND THE PARTICIPANT UNLESS 
NECESSARY.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
 
 
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Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this study, IVRS/IWRS should be used for 
emergency unblinding in the event that this is required for participant safety.
Domiciling
This study will only enroll participants who are expected to be hospitalized during the period 
of study therapy and is consistent with the clinical management of cIAI infection in China. 
Study medications will not be admistered as outpatients.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
The primary efficacy endpoint in this study is clinical response (i.e. clinical cure rate) at TOC 
visit in CE population.  In order to assess the efficacy at the end of treatment of 
ceftolozane/tazobactam, EOT is set as secondary time point for efficacy. 
Different study populations have been pre-specified and to be analyzed to have better 
understanding the robustness of efficacy. The analysis populations in the study objectives are 
comparable to those of global cIAI study (CXA-cIAI-10-08 and CXA-cIAI-10-09). 
Clinical Response
Clinical outcome assessments will be made at the EOT and TOC visits. Clinical response 
will be classified by the investigator as cure, failure, or indeterminate. A favorable clinical 
response is “clinical cure”.
Failure will be carried forward; participants who are assessed as a failure prior to the TOC 
visit should have “failure” recorded on the TOC outcome visit eCRF, regardless of their final 
outcome at that time. Participants who are assessed as a failure prior to the TOC should 
attend the TOC visit but will not have a clinical outcome assessment at the TOC visit. 
 
 
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Clinical cure, clinical failure, and indeterminate responses are defined in Table 5.
Table 5
Clinical Response Categories at the EOT and TOC Visits
Outcome
Definition
Clinical Cure
Complete resolution or significant improvement in signs and symptoms of the 
index infection, such that no additional antibacterial therapy or surgical or 
drainage procedure is required for the index infection.
Clinical Failure

Death related to IAI at any time point prior to the TOC 

Persisting or recurrent infection within the abdomen requiring additional 
intervention to cure the infection* 

Need for treatment with additional antibiotics for ongoing symptoms of IAI 
prior to each assessment point (EOT or TOC), or 

Post-surgical wound infection, defined as an open wound with signs of local 
infection, such as purulent exudate, erythema, or warmth that requires 
additional antimicrobial therapy and/or non-routine wound care (such as 
incision and drainage or re-opening of the wound).** 
Note: Closure of a colostomy or an enterocutaneous fistula is not considered a 
failure. Wherever possible, failures should be documented microbiologically by 
obtaining an appropriate deep wound or intraabdominal site culture. Blood 
cultures should also be obtained. 
* Repeat percutaneous aspiration of an abscess within 72 hours of the original 
aspiration, without worsening clinical signs and symptoms, is not considered a 
failure. However, the need to repeat any procedure after 72 hours of study therapy 
to cure the infection should be considered a failure. Exploratory or diagnostic 
procedures with no evidence of an ongoing infection are not considered a failure. 
** Use of vacuum-assisted wound closure following fascial closure is acceptable 
and such procedure must be reported on the abdominal intervention page. Daily 
wound assessments must be conducted according to schedule of events.
Indeterminate

Study data are not available for evaluation of efficacy for any reason, 
including death during the study period unrelated to the index infection, or 

Extenuating circumstances that preclude classification as cure or failure 
(e.g., participant lost to follow-up).
Microbiological Response
Per Subject Microbiological Outcomes 
An overall microbiological response will be determined by the Sponsor for each participant
based on individual microbiological responses for each baseline bacterial pathogen. In order 
for the participant to have a favorable overall microbiological response (i.e., eradication or 
presumed eradication), each baseline bacterial pathogen must have a favorable 
microbiological outcome. If the outcome for any baseline bacterial pathogen is unfavorable, 
the participant will be considered an overall microbiological failure. Per participant
microbiological response is assessed at both the EOT and TOC visits.
 
 
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Per Pathogen Microbiological Outcomes 
A microbiological response will be determined for each bacterial pathogen isolated at 
baseline by the Sponsor. Microbiological response categories are eradication, presumed 
eradication, persistence, persistence acquiring resistance, presumed persistence, and 
indeterminate, as defined below in Table 6. Favorable microbiological responses include 
“eradication” or “presumed eradication.” “Persistence,” “persistence acquiring resistance,” 
and “presumed persistence” are considered unfavorable responses. Per pathogen 
microbiological response is assessed at both the EOT and TOC visits.
Table 6
Microbiological Outcome Categories
Outcome
Definition
Eradication
Absence of the baseline bacterial pathogen in a specimen appropriately obtained 
from the original site of infection
Presumed eradication
Absence of material to culture in a participant who is assessed as a clinical cure
Persistence
Presence of the baseline bacterial pathogen in a culture of an appropriately 
obtained specimen from the site of infection or surgical wound. Cultures from 
indwelling drains are not considered appropriate.
Persistence acquiring 
resistance
As above, and the baseline bacterial pathogen that was susceptible to study drug 
pretreatment is resistant to study drug post-treatment.
Presumed persistence
Absence of material to culture in a participant who is assessed as a clinical failure
Indeterminate
Baseline culture either not obtained or has no growth
Assessment not possible
Any other circumstance that makes it impossible to define the microbiological 
response (e.g., participant lost to follow-up)
Pathogens isolated after baseline will be assessed for the outcome of superinfection or new 
infection, as defined in Table 7. 
The percentage of participants with superinfection or new infection will be determined.
Table 7
Emergent Infection
Outcome
Definition
Superinfection
Isolation of a pathogen, other than the original baseline pathogen(s), from an 
intraabdominal specimen taken from a participant with signs or symptoms of 
infection while on study drug
New infection
Isolation of a pathogen, other than the original baseline pathogen(s), from an 
intraabdominal specimen in a participant with signs or symptoms of infection 
after treatment with study drug
 
 
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn/collected by visit 
and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard 
systems/evaluations.Citing the SoA and the visit requirements (Section 8.12) for details.
A full physical examination, performed at randomization includes the following assessments: 
general appearance, head, eyes, ears/nose/ throat, neck, lymph nodes, skin, lungs, heart, 
abdomen, musculoskeletal, and neurologic evaluations. Breast, rectal, and 
genitourinary/pelvic exams should be performed when clinically indicated. If a physical 
examination was performed within 72 hours prior to screening, those results can be recorded 
and a repeat physical examination is not required.  Any abnormal or clinically significant 
findings from the physical examinations must be recorded on the appropriate eCRF.
A brief directed physical examination targeted to the participant’s illness and complaints will 
be conducted by an investigator or medically qualified designee (consistent with local 
requirements) in the period of study therapy at the discretion of the investigator and at TOC
visit as specified in Section 1.3–SoA.
Investigators should pay special attention to clinical signs related to cIAI.
Vital Signs
•
Axillary temperature, pulse rate, respiratory rate, and blood pressure will be assessed
(other body temperature measurement methods will be allowed as long as the same 
measurement method is used for a participant throughout the study).
•
Blood pressure and pulse measurements are recommended tobe assessed in a supine or 
semi-recumbent position with a completely automated device. Manual techniques will be 
used only if an automated device is not available.
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions.
•
Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse and respiratory rate.
 
 
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Height and Weight
The participant’s height and weight should be measured prior to initiation of IV study 
therapy during the screening.  
Surgical wound examination
Conduct surgical wound examination at the visits specified in SoA to assess signs of 
infection such as skin erythema, induration, tenderness, swelling, and wound pain
(superficial). If signs of infection are present, findings will be recorded and graded as mild, 
moderate, or severe according to the definitions provided in section 8.3.6. Warmth and 
fluctuance will be assessed as absent or present. The nature of any discharge (non-purulent or 
purulent) will also be assessed. Surgical wound examination should be conducted at the
baseline visit if participant already had surgical intervention before the allocation. On each 
study day, surgical wound examination will be conducted by the Investigator. It is preferred
that this assessment should be performed approximately at the same time each day (e.g.,
every morning).
APACHE II Score
Severity of illness in this study will be determined by APACHE II score at screening . See 
Appendix 8 for details regarding the calculation of this score. Results of APACHE II score 
calculations must be entered on the appropriate eCRF(s).
Abdominal symptoms and signs
Abdominal symptoms and signs will be assessed at screening and collected daily during the 
period of IV study therapy, end of IV study therapy (EOT) and post-treatment visit (TOC).
Thorough clinical examinations of the abdomen will be conducted. Specific findings such as 
abdominal pain, tenderness to palpation, rebound tenderness, guarding, or presence of ascites, 
will be assessed and grades as none, mild, moderate or severe according to the following 
definitions:

None: sign or symptom absent

Mild: awareness of sign or symptom, but easily tolerated

Moderate: sign or symptom of enough intensity to cause interference with usual 
activity

Severe: sign or symptom of enough intensity to incapacitate
On each study day thereafter, each cIAI symptom will be assessed by the Investigator as 
unchanged, worse, or improved compared to the baseline symptom assessment.
Other pertinent findings should be recorded, including ability to tolerate oral or enteral intake and 
presence of ileus.
 
 
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Radiographic examination (Ultrasound, X-ray or CT etc)
Specific radiographic examinations are not required for this study unless the participant is 
enrolled pre-operatively or clinically indicated. Bowel perforation or intra-abdominal abscess 
must be observed. Radiological examinations should only be performed as required for 
routine participant management. Radiologic evaluations might include plain abdominal 
radiograph, computerized tomography (CT) scan, ultrasound, and/or magnetic resonance 
imaging (MRI) scan, with or without contrast. The results of any such studies should be 
recorded.
Retain copies of all interventional radiological reports and diagnostic study reports for 
collection during monitoring visits.
Any abnormal or clinically significant findings must be recorded on the appropriate eCRF.
Diagnosis of target disease and site of infection
Participant must have at least one clear diagnosis of target disease as listed in the section 5.1, 
and also the corresponding site of infection before the randomization.
Assess and record the diagnosis of target disease, anatomic site of infection, the presence and
extent of abscesses (i.e. presence or absence of a abscess, single or multiple abscess), the
presence and extent of peritonitis (i.e. presence or absence of peritonitis, local or diffuse), the
etiological mechanism (i.e., postoperative/hospital acquired infection, trauma, spontaneous
rupture, malignancy or other) and infection history (i.e. new infection or failure of prior
antibiotic therapy) at screening.
Record any blood or blood product transfusions 
Participants with surgical intervention, record any blood or blood product transfusions in the 
previous 48 hours during the screen period. For the rest visits of the study, record any 
transfusions of blood or blood products.
Record summary of operative procedures and operative notes
During the trial, record summary of initial and any subsequent interventional operative 
procedure and operative note for complicated intra-abdominal infection (e.g laparotomy, 
laparoscopic surgery, or percutaneous draining of an abscess) in the eCRF and retain source 
records of all operative procedure notes for collection during monitoring visits. The initial 
interventional procedure must intend to achieve adequate source control, (i.e., all 
communications between the GI tract and the peritoneal cavity are closed), no necrotic 
intestine (or other tissue) is left, and all infected collections are drained).
 
 
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Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Local Laboratory Monitoring for Renal Function
During this study period, serum creatinine value to determine dose adjustment will be
collected in local laboratory. Obtain serum creatinine value and estimate the participant’s
CrCL using the participant’s serum creatinine value, actual body weight, and the appropriate 
Cockroft-Gault formula described in section 6.6 at the visit specified in SoA.
For participants with renal insufficiency or whose creatinine clearance changes during 
treatment with study therapy (refer to Table 3 and Table 4 in Section 6.6), the dose of 
study drug must be adjusted based upon the degree of renal function impairment as 
determined by the estimated or actual creatinine clearance. 
Results of these local laboratory tests must be documented in the appropriate eCRF.  
Laboratory abnormalities resulting in an adverse event or dose adjustment should also be 
collected on the appropriate eCRF. Any clinically relevant laboratory test abnormality 
that emerged during study therapy and was considered by the investigator to be an 
adverse event or event of clinical interest should be repeated until the abnormal value has 
normalized, stabilized, or returned to baseline.
 
 
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Criteria for Baseline Culture
The Investigator will collect intraabdominal specimens for culture of both aerobes and 
anaerobes at the time of the initial procedure. Specimens should be collected at the beginning 
of the interventional procedure prior to debridement, removal or disinfection of the primary 
site of infection. Aspirates (collected with a needle or syringe) or tissue or biopsy samples are 
recommended, swabs of purulent material are discouraged.
Sample collection should be done at initial operative intervention. For subjects who are 
enrolled after surgery, collection of an intrabdominal specimen is a mandatory requirement 
only for participants who failed prior antibacterial therapy .
Participants who are not failures of prior treatment (i.e., have not received prior antibacterial 
treatment for the current cIAI) with negative culture results from intraabdominal specimens 
should continue with study drug treatment and have all study procedures performed as 
outlined in the protocol. 
Participants enrolled with failure of a prior regimen with negative culture results from 
intraabdominal specimens and blood sample are considered to have undocumented evidence 
of prior treatment failure and may discontinue study drug treatment and completed study 
procedures as outlined in the protocol. 
Blood samples for culture will be drawn in participants with hospital-acquired infections, 
those who have failed prior antibacterial therapy, or who have signs of severe sepsis.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
 
 
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Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before intervention allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event causes the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
From the time of intervention allocation/randomization through TOC visit, all AEs, SAEs, 
and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered drug-related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 8.
 
 
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Table 8
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Nonserious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious 
Adverse Event 
(SAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported 
– Follow to 
completion/terminat
ion; report outcome
Within 24 hours 
of learning of 
event
Event of 
Clinical Interest 
(require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of 
Clinical Interest 
(do not require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days of 
learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days of 
learning of 
event
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 5 
calendar days of 
learning of 
event
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
 
 
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Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of 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 wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
 
 
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Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Treatment failure or relapse will be captured on the clinical response pages, and only needs 
to be reported as an SAE if the SAE criteria are met (such as prolongation of existing 
hospitalization). Treatment failure includes progression, relapse, or recurrence of new 
symptoms or complications attributable to cIAI or a lack of resolution (persistence) or 
insufficient improvement in signs and symptoms of cIAI which were present at baseline.
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
•
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study site guidance 
for assessment and follow-up of these criteria can be found in the Investigator Study 
File Binder (or equivalent).
8.5
Treatment of Overdose
In this study, an overdose is defined as any dose that is more than 2 times higher than the 
protocol-specified dose for the patient’s renal function.
No specific information is available on the treatment of overdose. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Not applicable.
 
 
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8.9
Planned Genetic Analysis Sample Collection
Not applicable.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
8.11
Health Economics Medical Resource Utilization and Health Economics
Health Economics OR Medical Resource Utilization and Health Economics are not evaluated 
in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
Screening (Visit 1)
Baseline (screening) assessments are to be performed as close as possible to the start of study 
therapy and at most within 24 hours before randomization. If a participant is enrolled and 
dosed pre-operatively, it is acceptable that the sample from the site of infection be obtained 
following the start of administration of the first dose of study drug. All potential study 
participants will undergo the same screening evaluations, which will include obtaining a 
medical history and performing clinical examinations and laboratory tests. All baseline 
assessment results except the results of the culture must be available before randomization 
and study drug administration..
Treatment Period (Visit 2 to Visit 6)
The treatment period for ceftolozane/tazobactam in this study should be a minimum of 4 full 
days to up to a maximum of 14 days. All study assessments are recommended to be 
performed at an approximately consistent time of day for the participant (e.g. every morning) 
for each calendar day.
Assessments and procedures during the study therapy will be completed at the indicated 
times and intervals as per Section 1.3 – SoA. The EOT visit for participants will be 
completed within 24 hours after the last dose of study therapy.
Follow-up Period (Visit 7)
Participants will be required to return to clinic at Day28+/-2days ( TOC visit). If the TOC
visit occurs less than 14 days after the last dose of study intervention, a subsequent follow-up 
telephone call should be made at 14 days post the last dose of study intervention to determine 
if any AEs have occurred since the poststudy clinic visit.
 
 
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes are made to primary and/or 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design Overview
A randomized, active-controlled, parallel-group, multicenter, double-blind 
study of ceftolozane/tazobactam IV infusion (1500 mg q8h) plus 
metronidazole (500 mg q8h) IV infusion vs. meropenem IV (1000 mg
q8h) plus placebo in Chinese participants with cIAI.
Treatment Assignment
Randomization method: Participants will be randomized in a 1: 1 ratio to 
two treatment arms of the study, Treatment 1 (ceftolozane/tazobactam + 
metronidazole) group or Treatment 2 (meropenem + placebo) group. Both 
treatments will be administered IV q8h. 
Stratification method: Randomization will be stratified by anatomic site of 
infection (bowel [small or large] vs. other site of cIAI). Participants with 
appendix, stomach, or duodenum as the anatomic site of infection, will be 
stratified to the “other site” group during the randomization process.
Double-dummy double-blind method: A double-blinding technique will be 
used. Study drug will be prepared and/or dispensed in a blinded fashion 
by an unblinded pharmacist or unblinded qualified study site personnel.
The participant, the investigator and Sponsor personnel or delegate(s) who 
are involved in the treatment administration or clinical evaluation of the 
participants are unaware of the group assignments
Analysis Populations
Primary Efficacy Analysis: Clinical evaluable (CE) population.
Secondary Efficacy Analysis: Intent-to-treat (ITT) population, 
microbiological intent-to-treat (MITT) population, microbiologically
evaluable (ME) population and expanded microbiologically evaluable 
(EME) population.
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Clinical response at the TOC visit
Secondary Endpoints
Clinical response at the EOT visit
Microbiological response (Per-subject and per-pathogen microbiological 
response) at the TOC visit
 
 
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Statistical Methods for Key 
Efficacy
For the primary hypothesis (clinical response rate at the TOC visit in the 
CE population), Treatment 1 (ceftolozane/tazobactam + metronidazole)
will be considered non-inferior to Treatment 2 (meropenem + placebo) if 
the lower bound of the 2-sided 95% confidence interval for the between-
treatment difference in the clinical response rate (Treatment 1 minus 
Treatment 2) is larger than -12.5%.  The two-sided 95% confidence 
intervals for between-treatment differences in the clinical response rate 
will be calculated using the stratified Miettinen and Nurminen method
with the Cochran-Mantel-Haenszel (CMH) weighting. 
For secondary objectives, point estimates and two-sided 95% confidence 
intervals will be calculated using the same stratified Miettinen and 
Nurminen method as described above.
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and Tier 2) 
will be provided for between-treatment differences in the percentage of 
participants with events; these analyses will be performed using the 
unstratified Miettinen and Nurminen method.
Interim Analyses
A blinded review of the clinical response rate will be ongoing during the 
study. The impact of the blinded clinical response rate on the assumptions 
underlying the power/sample size calculation will be formally assessed by 
the Sponsor when approximately 75% of the planned sample size (N=201) 
have completed TOC visits or sooner if enrollment or event rates are 
occurring faster than anticipated. If the clinical response rate at the TOC 
visit is lower than the 90% assumed in the power calculation, consideration 
will be given to increasing the sample size.
There are no plans to conduct a formal interim analysis of unblinded 
efficacy data in the study.
Multiplicity
No multiplicity adjustment is planned as there is a single comparison of 2 
treatments using 1 endpoint in the primary hypothesis. Other efficacy 
analyses will be considered supportive and/or explanatory.
Sample Size and Power 
The planned sample size is 268 participants (134 per arm). Assuming a
75% evaluability rate in the CE population, it is expected that 200 CE 
participants (100 participants per arm) will be included. For the clinical 
response rate at the TOC visit in the CE population, the study has 80% 
power to demonstrate that Treatment 1 (ceftolozane/tazobactam + 
metronidazole) is non-inferior to Treatment 2 (meropenem + placebo) 
using a 1-tailed alpha of 2.5%, if there is no underlying treatment 
difference. The power and sample size are based on the following 
assumptions: 1) a non-inferiority margin of -12.5%, and 2) an underlying 
clinical response rate of 90% in the CE population for both treatments.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study. Unblinded Sponsor personnel [ie. 
unblinded CRA (uCRA), unblinded data manager (uDM), unblinded clinical scientist (uCS)], 
will be assigned to support the oversight and monitoring of study conduct. The uCRA will 
ensure that unblinded monitoring activities are conducted in compliance with protocol and 
 
 
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regulatory requirements and the Trial Specific Site Monitoring Plan. The uDM will perform 
data review and reconciliation for unblinded eCRF data. The uCS will provide support and 
guidance on study-specific unblinded procedure-related questions, in particular, questions 
related to the blinded clinical supplies as well as support for the uDM on data review issues 
requiring consultation.
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an interactive voice/web
response system (IVRS/IWRS).
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
Non-Inferiority Margin Justification:
A conservative method for estimating the treatment difference is adopted by comparison of 
the lower bound of the 95% CI for the antibacterial drug therapy and the upper bound of the 
95% CI for placebo/no treatment. The source data were obtained from the previous pivotal 
studies or medical literature. An upper bound of the 95% CI of 64.9% for placebo/no 
treatment was directly obtained from 2015 FDA Guidance for Industry Complicated Intra-
Abdominal Infections: Developing Drugs for Treatment. For antibacterial drug therapy, a 
meta-analysis for the clinical response rates was applied using study results from the two 
most commonly used cIAI drugs; meropenem and imipenem/cilastatin (Table 9). In this 
meta-analysis, a point estimate of 87.8% with a two-sided 95% CI of 84.9% and 90.8% was 
calculated. For consistency of analyses, the DerSimonian and Laird method using random 
effects was applied to both the above mentioned FDA guidance and the antibacterial drug 
results in Table 9.
Given an estimated treatment difference of 20.0% (84.9% minus 64.9%) and consideration of 
a 12.5% NI margin suggested by EMA guidance Addendum to the note for guidance on 
evaluation of medicinal products indicated for treatment of bacterial infections 
(CPMP/EWP/558/95 REV 2) to address indication-specific clinical data, the non-inferiority 
margin is selected to be 12.5%, which represents preserving about 40% of the estimated 
treatment difference of 20%, as shown above.
 
 
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Table 9
Clinical response rate at TOC visit
Drug
Clinical response rate at TOC 
n/N(%[95%CI])
Source
Note
Meropenem
364/417
87.3%[83.75, 90.15]
CXA-cIAI-10-08-09
Global 
study
Imipenem/cilastatin
50/55
90.9%[80.0, 97.0]
Chen et al. BMC Infectious 
Diseases 2010, 10:217
Chinese 
participants
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
Efficacy Endpoints
A full description of the efficacy measures is provided in Section 4.2.1.1. 
The primary efficacy endpoint is clinical response at the TOC visit in the CE population. 
The secondary efficacy endpoints are: 
(1) Clinical response at the TOC visit in the ITT population.
(2) Clinical response at the EOT visit in the ITT and CE population.
(3) Percentage of participants achieving a favorable microbiological response at the 
TOC visit in the EME population.
(4) Per-pathogen percentage of baseline intra-abdominal pathogens achieving a 
favorable microbiological response at the TOC visit in the EME population. 
The exploratory efficacy endpoints are:
(1) Clinical response at the TOC visit in the MITT population and ME population.
(2) Clinical response at the EOT visit in the MITT population.
(3) Percentage of participants achieving a favorable microbiological response at the 
TOC visit in the ME and MITT population.
(4) Percentage of participants achieving a favorable microbiological response at the 
EOT visit in the ME, EME and MITT population.
(5) Per-pathogen percentage of baseline intra-abdominal pathogens achieving a 
favorable microbiological response at the TOC visit in the ME and MITT 
population. 
 
 
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(6) Per-pathogen percentage of baseline intra-abdominal pathogens achieving a 
favorable microbiological response at the EOT visit in the ME, EME and MITT 
population.
Safety Endpoints
The descriptions of safety measurements are provided in Section 4.2.1.2. 
Based upon a review of adult and pediatric trial safety data, no Tier 1 AEs of clinical interest 
have been identified. The broad clinical and laboratory adverse event (AE) categories, 
consisting of the percentage of participants with any AE, a drug-related AE, a serious AE, an 
AE which is both drug related and serious, discontinuation of IV study therapy due to an AE, 
discontinuation of IV study therapy due to a drug-related AE, and an AE leading to death 
will be considered Tier 2 endpoints.
9.5
Analysis Populations
Efficacy Analysis Populations
The Clinically Evaluable (CE) population will serve as the primary population for the 
analysis of efficacy data in this study. The Intent-to-Treat (ITT), Microbiological Intent-to-
treat (MITT), Microbiologically Evaluable (ME) and Expanded Microbiologically Evaluable
(EME) populations will serve as secondary populations for efficacy analyses.
The ITT population will consist of all randomized participants. Participants in the ITT 
population will be analyzed based on the treatment they were randomized to, irrespective of 
what they actually received.
The MITT population will consist of all randomized participants who have a baseline 
bacterial pathogen known to cause cIAI, regardless of susceptibility to study drug. 
Participants in the MITT population will be analyzed based on the treatment they were 
randomized to, irrespective of what they actually received.
The CE population consists of subjects who meet the protocol definition of cIAI, who 
adhere to study procedures and have a clinical outcome at the TOC visit. Further specific 
details defining this population will be provided in the sSAP.
The CE population does not require a bacterial pathogen identified as the cause of cIAI.
The ME population is the subset of CE participants who have at least one baseline 
intraabdominal pathogen identified that is susceptible to study drug.
The EME population consists of all randomized participants who have cIAI as evidenced 
by identification of at least 1 baseline intra-abdominal pathogen, regardless of susceptibility 
to study drug and meet all CE population criteria.
The CE, ME, and EME populations will serve as the per-protocol analysis populations for the 
analysis of efficacy data in this study.
 
 
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Safety Analysis Population
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study.  The APaT population consists of all randomized participants who received any 
amount of study treatment (i.e. at least one dose, including only a partial dose). Participants
will be included in the treatment group corresponding to the study treatment they actually 
received for the analysis of safety data using the APaT population.  For most participants this 
will be the treatment group to which they are randomized.  Participants who take incorrect 
study treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
For the analysis of pre-specified events of interest (Tier 1 events) described above in Section
9.4.2, participants will be excluded from specific analyses if the conditions defining the event 
were present at randomization (Day 1).
Details on the approach to handling missing data for safety analyses are provided in Section 
9.6 Statistical Methods.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8, Multiplicity. Nominal p-values may be 
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size limitations, etc.  Unless otherwise stated, all statistical tests 
will be conducted at α=0.025 (1-sided) level.
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the supplemental 
SAP.
Primary Efficacy Analysis
The primary objective is to establish non-inferiority of Treatment 1 (ceftolozane/tazobactam 
+ metronidazole) to Treatment 2 (meropenem + placebo) with respect to clinical response
rate in the CE population at TOC visit. 95% confidence intervals for between-treatment 
differences in the clinical response rate will be calculated using the stratified Miettinen and 
Nurminen (M&N) method (1985) with the Cochran-Mantel-Haenszel (CMH) weighting. The 
analyses will be stratified by anatomic site of infection (bowel [small or large] vs. other site 
of cIAI). Treatment 1 (ceftolozane/tazobactam + metronidazole) will be considered non-
inferior to Treatment 2 (meropenem + placebo) if the lower bound of the 2-sided 95% 
 
 
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confidence interval of the between-treatment difference in clinical response rate (Treatment 1
minus Treatment 2) at TOC in the CE population is larger than -12.5%.
Secondary Efficacy Analysis
The secondary efficacy analysis will follow the same stratified M&N method described 
above for the primary efficacy analysis. The estimates and their two-sided 95% confidence 
intervals will be calculated for each secondary efficacy endpoint. The secondary efficacy 
objectives are estimation objectives only, so no NI testing will be applied on the secondary 
efficacy analysis.
Missing Values
Any participant missing an evaluation for a specific endpoint (clinical or microbiological) at 
any particular visit will be generally considered as being “indeterminate” for that endpoint in 
the ITT and MITT populations. Participants with an indeterminate clinical outcome will be 
considered as “Treatment Failure” in the ITT and MITT analysis populations. Participants
with an indeterminate clinical outcome will be excluded from per-protocol analysis 
populations (CE, ME and EME).  The following are exceptions to this rule:

Participants discontinuing IV study therapy due to lack of efficacy (i.e., withdrawals 
with subsequent non-study antibiotic therapy or participants requiring therapy beyond 
14 days) will be considered as “failures” with respect to clinical response at the time 
of discontinuation and all subsequent time points in all populations.

Participants discontinuing IV study therapy due to lack of efficacy will be presumed 
to have persistence for the microbiological response at the time of discontinuation and 
all subsequent time points.
The primary and secondary endpoints, primary and secondary analysis population, and 
statistical methods that will be employed for the efficacy analyses are presented in
Table 10. Since a favorable clinical response and favorable microbiological response requires 
a clear assessment, an assessment of “indeterminate” would be considered treatment failure 
in the ITT and MITT populations. 
 
 
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Table 10
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time point)
Statistical Method†
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis:
Clinical response at the TOC visit 
Stratified M&N‡
CE§
DAO††
Secondary Endpoints:
Clinical response at the TOC visit
Stratified M&N‡
ITT
M=F‡‡
Clinical response at the EOT visit
Stratified M&N‡
ITT
M=F‡‡
CE§
DAO††
Percentage of participants achieving a 
favorable microbiological response at
the TOC visit
Stratified M&N‡
EME#
DAO††
Per-pathogen percentage of baseline 
intra-abdominal pathogens achieving 
a favorable microbiological response 
at the TOC visit
Stratified M&N‡
EME#
DAO††
†  Statistical models are described in further detail below:
‡ M&N is Miettinen and Nurminen method stratified by anatomic site of infection (bowel [small or large] vs. other site of 
cIAI). 
§ The CE population consists of subjects who meet the protocol definition of cIAI, who adhere to study procedures and 
have a clinical outcome at the TOC visit. Further specific details defining the CE population will be provided in the 
sSAP.
  ITT population consists of all randomized participants.
¶ MITT population: consist of all randomized participants who have a baseline bacterial pathogen known to cause cIAI.
# ME population is the subset of CE participants who have at least one baseline intraabdominal pathogen identified that is 
susceptible to study drug. EME population is expanded ME population.
†† DAO is data as observed, that is, participants with missing values will be excluded from the analysis.  
‡‡ M=F is missing =failure
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and
multiple time points is described in Section 9.7, Interim Analyses and in Section 9.8, 
Multiplicity.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change (PDLCs) in 
laboratory and vital signs are either pre-specified as “Tier-1” endpoints, or will be classified 
as belonging to "Tier 2" or "Tier 3" based on the number of events observed.  
 
 
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Tier 1 Events
Safety parameters or adverse events of special interest that are identified a priori constitute 
“Tier 1” safety endpoints that will be subject to inferential testing for statistical significance. 
There are no Tier 1 events for this protocol based upon a review of adult and pediatric trial 
safety data.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the proportion of participants with events (also via the M&N 
method (1985)).Membership in Tier 2 requires that at least 4 participants in at least one
treatment group exhibit the event. The threshold of at least 4 events was chosen because the 
95% confidence interval for the between-group difference in percent incidence will always 
include zero when treatment groups of equal size each have less than 4 events and thus would 
add little to the interpretation of potentially meaningful differences.  Because many 95% 
confidence intervals may be provided without adjustment for multiplicity, the confidence 
intervals should be regarded as a helpful descriptive measure to be used in review, not a 
formal method for assessing the statistical significance of the between-group differences in 
adverse experiences and predefined limits of change.In addition to individual events that 
occur in 4 or more participants in any treatment group, the broad AE categories consisting of 
the proportion of participants with any AE, a drug related AE, a serious AE, an AE which is 
both drug-related and serious, and discontinuation due to an AE will be considered Tier 2 
endpoints.  
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
Continuous measures such as changes from baseline in laboratory and vital signs parameters, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format. 
 
 
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Table 11
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
None
X
X
X
Tier 2
Any AE‡
X
X
Any Serious AE
X
X
Any AE leading to death
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs† (incidence ≥4 
of participants in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs† (incidence <4 of 
participants in all of the treatment groups)
X
Change from Baseline Results (Labs, Vital 
Signs)
X
† Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
‡ Indicates broad AE category of the number of participants reporting any adverse event.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of descriptive statistics. No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of participants screened, randomized, the 
primary reasons for screening failure, and the primary reason for discontinuation will be 
displayed. Demographic variables, baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment using descriptive 
statistics for continuous or categorical variables, as appropriate.
9.7
Interim Analyses
An internal blinded sample size re-estimation will be conducted as described in the next 
paragraph. There are no plans to conduct a formal interim analysis of unblinded efficacy data 
in the study.
Blinded review of clinical response rate at TOC visits on the CE population will be ongoing 
during the study. The impact of the clinical response rate on the assumptions underlying the 
power/sample size calculation will be formally assessed when approximately 75% (N=201) 
of the planned sample size (N=268) have completed TOC visits or sooner if enrollment or 
 
 
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event rates are occurring faster than anticipated. In consideration of having enough time for 
blinded sample size re-estimation as well as a stable estimate for the clinical response rate, 
75% is selected as the time point for the blinded sample size assessment.
If the observed, blinded (pooled) clinical response rate is lower than the 90% assumed in the 
power calculation, consideration will be given to increasing the overall sample size as 
outlined in Table 12. If the observed clinical response rate is larger than 90%, the overall 
sample size will be maintained at the planned N=268 as the power for this 
endpoint/hypothesis will likely exceed 80%. The maximum sample size will not exceed 
N=408 (204 per group) regardless of the observed clinical response rate. 
Blinded review of clinical response is not a true interim analysis in that it will not require a 
dataset freeze, unblinding, and multiplicity adjustments. The accruing database will not be 
officially locked for this blinded sample size re-estimation; however, all data relating to the 
assessment of clinical response rate will be cleaned and all queries resolved before the formal 
assessment of the clinical response rate. As this sample size re-estimation will be done in a 
blinded fashion, there is no impact on type 1 error rates.
Table 12
Sample Size Adjustments based on Interim Blinded Review of Clinical Response 
Rate at TOC Visit
Observed 
Clinical 
Response Rate†
Power based on 
Original Sample Size 
(N=268) (%)
Revised 
Sample Size‡
Percent Increase from 
Original Sample Size (%)
89%
77.2
294
9.7
88%
74.6
310
15.7
87%
72.2
328
22.4
86%
70.0
344
28.4
85%
67.9
360
34.3
84%
66.0
376
40.3
83%
64.0
392
47.3
82%
62.2
408
52.2
†
This rate is expressed as a percent and rounded to the nearest integer value.
‡
Calculated to provide 80% power based on the observed clinical response rate and assumed evaluable 
rate of 75% in CE population in the power/sample size calculation.
Note:  The calculation is also based on the assumptions from the sample size section, i.e. one-sided 2.5% 
alpha-level, no underlying treatment difference, and NI margin of -12.5%.
 
 
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9.8
Multiplicity
As there is only a single primary efficacy hypothesis which is being conducted at the one -
sided α=0.025 level, no multiplicity adjustment is needed for the primary efficacy analysis.
The secondary efficacy objectives are estimation objectives, are supportive in nature and 
have no associated hypotheses. Therefore, no multiplicity adjustment is necessary for the 
secondary efficacy analysis.
There will be no multiplicity adjustments applied to the safety summaries.
9.9
Sample Size and Power Calculations
Sample Size and Power for Efficacy Analyses
This study will randomize 268 participants (134 per treatment arm) into the study and has 
80% power to establish that Treatment 1 (ceftolozane/tazobactam + metronidazole) is non-
inferior to Treatment 2 (meropenem + placebo)  in the clinical response rate at the TOC visit 
in CE population at an overall one-sided, 2.5% alpha-level, if there is no underlying 
treatment difference. The power and sample size are based on the following assumptions: 1) 
an approximately 75% evaluable rate in CE population 2) a non-inferiority margin of -12.5% 
(Treatment 1 minus Treatment 2), and 3) an underlying clinical response rate of 90% at the 
TOC visit. Above assumption is based on the pivotal study CXA-cIAI-10-08-09 CSR. The 
non-inferiority margin is regarded as the minimum difference of clinical interest between the 
2 treatments [rationale is described in Section 9.3]. The calculation is based on an asymptotic 
method proposed by Miettinen and Nurminen (1985) with 100 participants per group
expected to be included in the analysis in CE population and is carried out using PASS by 
selecting the test type of likelihood score (Miettinen & Nurminen) in the Non-inferiority & 
superiority tests for two proportions [differences] module. The minimum criterion for success 
is that the lower bound of the 95% CI on the treatment difference (Treatment 1 minus 
Treatment 2) > -12.5%. Table 13 summarizes power calculations for the primary comparison 
under various assumptions.
Table 13
Power (%) Under Various Assumptions (With 268 participants (134 per arm) into 
the study and NI margin of -12.5%)
Underlying clinical 
response rate of 
treatment 2 at TOC visit
Underlying Treatment Difference（%）
(Treatment 1 - Treatment 2)
2
1
0
-1
-2
-3
82%
76.9
69.9
62.2
54.3
46.4
38.7
84%
80.6
73.7
66.0
57.8
49.5
41.4
86%
84.4
77.7
70.0
61.6
52.9
44.4
88%
88.5
82.2
74.6
66.0
56.9
47.8
90%
92.6
87.2
80.0
71.4
61.9
52.0
92%
96.4
92.4
86.1
77.9
68.1
57.5
94%
99.0
96.9
92.5
85.5
76.1
65.0
Note:  The power is calculated based on 100 participants per each treatment group expected to be included in the analysis
in the CE population.
 
 
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Another way to assess the precision of a non-inferiority study is to consider the minimum
observed difference that would just meet the criterion for non-inferiority (in this case, a lower
bound of the 2-sided 95% CI for the difference in clinical response rate in CE population
[Treatment 1 minus Treatment 2] that is just larger than -12.5%). This minimum observed 
difference will decrease as the observed clinical response rate in the control group increases
(Table 14). An observed clinical response rate of 90% in the treatment 2 will just meet the 
criterion for non-inferiority given an observed difference (Treatment 1 – Treatment 2) is not 
less than -3.2%, that is the observed clinical response rate in the treatment 1 is not less than 
86.8%. An observed clinical response rate of 86% in the treatment 2 will just meet the 
criterion for non-inferiority given an observed difference (Treatment 1 – Treatment 2) is not 
less than -2.3%, that is the observed clinical response rate in the treatment 1 is not less than 
83.7%. Above calculation is carried out using PASS by selecting the test type of score 
(Miettinen & Nurminen) in the confidence intervals for two proportions [differences] module.
Table 14
Precision (Minimum Observed Difference and Two-sided 95% CI) Under Various 
Assumptions (With 268 participants (134 per arm) enrolled into the study)
Observed
Clinical 
Response 
Rate of 
Treatment 
2 at TOC 
visit
Minimum 
Observed 
Difference(%) 
required to 
achieve NI 
Margin of 
12.5%
Estimated Treatment Difference（%）
(Treatment 1 - Treatment 2)
0
-1
-2
-3
-4
-5
Two-sided 95% CI of Estimated Treatment Difference (%)
82%
-1.50
(-10.84, 
10.84)
(-11.94, 
9.94)
(-13.04, 
9.03)
(-14.13, 
8.13)
(-15.22, 
7.22)
(-16.30, 
6.31)
86%
-2.27
(-9.92, 
9.92)
(-11.06, 
9.03)
(-12.19, 
8.14)
(-13.31, 
7.24)
(-14.42, 
6.35)
(-15.53, 
5.45)
90%
-3.17
(-8.78, 
8.78)
(-9.96, 
7.90)
(-11.14, 
7.02)
(-12.30, 
6.14)
(-13.45, 
5.26)
(-14.60, 
4.38)
94%
-4.19
(-7.31, 
7.31)
(-8.58, 
6.44)
(-9.83, 
5.58)
(-11.05, 
4.71)
(-12.26, 
3.85)
(-13.46, 
2.98)
Note:  The 95% CI is calculated based on 100 participants per each treatment group expected to be included in the 
analysis in the CE population.
9.10
Subgroup Analyses and Effect of Baseline Factors
To assess the consistency of the treatment effect across various subgroups, the estimate of the 
between-group treatment effect (with a nominal 95% CI) for the primary endpoint will be 
estimated within each category of the following classification variables: 

Age category (≤65 vs. >65 years)

APACHE II Score (≤10 vs. >10)

Baseline renal CrCL (30 to ≤50 vs. >50 mL/min)
 
 
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
Procedure Type (percutaneous aspiration, laparoscopy, laparotomy, other)

Prior antibiotic use (yes or no)

Sex (female, male)

Primary Site of Infection Stratum: bowel [small or large] vs. other site of cIAI

Anatomic site of infection/diagnosis

Pathogens

Presence of baseline bacteremia

Number of baseline pathogens (polymicrobial, monomicrobial).

Number of Abscesses (single, multiple)

Peritonitis Type (local, diffuse)

Site of infection (appendix, non-appendix)

Pathogen MIC and Pathogen Classification
9.11
Compliance (Medication Adherence)
Considering this is an IV study conducted by investigators/nurses, it is expected to follow the 
protocol strictly without compliance issues. Any non-compliance dosage will be monitored 
and recorded.
9.12
Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics by 
treatment group.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
There are no governance committees in this study.
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally 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.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
 
 
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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
 
 
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Persons debarred from conducting or working on clinical studies by any court or regulatory
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
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 review and 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 ICF, 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.
 
 
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Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
Laboratory tests for hematology, coagulation, chemistry and urinalysis are specified in
Table 15.
Table 15
Laboratory Tests
Hematology
Coagulation
Chemistry
Urinalysis
Other
Hematocrit
Partial
Prothrombin 
time
Albumin
Blood
Follicle Stimulating 
Hormone (FSH)
Hemoglobin
Prothrombin 
time
Alkaline phosphatase
Glucose
Serum β-human 
chorionic 
gonadotropin (β-
hCG)
Platelet count
Alanine 
aminotransferase (ALT)
Protein
WBC 
(total and 
differential)
Aspartate 
aminotransferase (AST)
Specific gravity 
Lactic dehydrogenase 
(LDH)
Microscopic 
exam, if 
abnormal results 
are noted
Calcium
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated 
above the upper limit of 
normal
Total protein
Blood Urea Nitrogen or
Blood Urea
 
 
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All blood and urine samples for safety laboratory testing (hematology, coagulation,
chemistry and urinalysis) will be sent to local safety laboratory for testing.  Chemistry safety 
laboratory tests will be performed after at least an 8-hour fast. Non-fasting sample is 
acceptable for chemistry laboratory safety tests at screening.The timing for the collection of 
blood and urine samples for safety monitoring is provided in Section 1.3-SoA.
 
 
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Approximate Blood Volumes Drawn by Study Visit and Sample Types
Study Visit
Screening
IV Study Treatment
Post-Treatment
V1
Screening
V2
Randomization
V3
V 4 
V 5 
V 6 EOT
V7
TOC
Blood Parameter
Approximate Blood Volume (mL)
Hematology
2.0
2.0
2.0
2.0
Blood for Coagulation
4.0
4.0
4.0
4.0
Serum/Plasma 
Chemistry
3.5
3.5
3.5
3.5
Serum β-
HumanChorionic
Gonadotropin 
(β-hCG)
3.5
3.5
Blood For
LocalLaboratory
Assessment of 
Creatininea
2.0
2.0
2.0
2.0
2.0
2.0
2.0
Blood Specimen for 
Culture& 
Susceptibility
40
As clinically Indicated (40mL/assessment)
Expected Total (mL)bc
55.0
2.0 or 42.0 if 
culture
&
susceptibility 
testing clinically 
indicated
2.0 or 42.0 if 
culture
& 
susceptibility 
testing 
clinically 
indicated
11.5 or 51.5 if 
culture
&
susceptibility 
testing 
clinically 
indicated
2.0 or 42.0 if 
culture 
&
susceptibility 
testing 
clinically 
indicated
11.5 or 51.5 if 
culture
&
susceptibility 
testing clinically 
indicated
15.0 or 55.0 if 
culture 
&
susceptibility 
testing clinically 
indicated
a. 
On V1,V4,V6 and V7, perform if creatinine assessment not already done as part of ‘blood for chemistry’ assessment.
b. 
Additional blood samples may be collected in support of evaluation for an underlying etiology throughout the study. The trial site guidance 
for assessment and follow up of these criteria can 
be found in the Investigator Trial File Binder. Depending on the results of initial testing, 
additional blood volumes would be needed for further test such as HIV and/or viral hepatitis testing.
c. 
Culture for blood sample at screening is conducted as clinically indicated in participants with :1) hospital-acquired infections;2) for those who have failed prior antibacterial therapy; or 3) who 
have signs of severe sepsis as assessed by the investigator.
In addition, if signs of sepsis appear or the subject is assessed as a treatment failure at any time on study (including EOT, TOC visit), a blood 
culture should be taken. 
At each blood culture collection, approximately 40 mL, two sets (from two separate blood draws) of blood cultures (each set consisting of an 
aerobic and an anaerobic bottle) are collected: 2 
sets of blood cultures (10 mL x 2 = 20mL)/aerobic culture; (10 mL x 2 = 20 mL)/anaerobic 
culture. 
Blood culture is conducted at appropriate frequency until negative. Blood cultures will be performed at the local microbiology laboratory according to recognized methods and per each 
laboratory’s standard precedures and isolates sent to the central microbiology laboratory.
 
 
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Local Laboratory Monitoring for Renal Function
Specifically, for the purpose of monitoring an individual participant’s renal function in “real 
time”, a creatinine assessment should be performed at the local laboratory on the visit 
specified in SoA. 
For participants with renal insufficiency or whose creatinine clearance changes during 
treatment with study therapy (refer to Table 3 and Table 4 in Section 6.6), the dose of 
study drug must be adjusted based upon the degree of renal function impairment as 
determined by the estimated or actual creatinine clearance.
Results of these local laboratory tests must be documented in the appropriate eCRF.  
Laboratory abnormalities resulting in an adverse event or dose adjustment should also be 
collected on the appropriate eCRF. Any clinically relevant laboratory test abnormality that 
emerged during study therapy and was considered by the investigator to be an adverse event 
or event of clinical interest should be repeated until the abnormal value has normalized, 
stabilized, or returned to baseline.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a 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 a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing 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.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
•
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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
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.
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, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant 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, 
 
 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
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 1 
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.
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
 
 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
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.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) 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 (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
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 used for rating the intensity of an 
event; and both AE and SAE can be assessed as severe (for pediatric studies, extremely 
distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
 
 
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count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
-
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose drug study); or (3) Sponsor’s product(s) is/are used 
only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
 
 
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of the 
AE onset relative to the administration of the Sponsor’s product is reasonable. The 
AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the AE 
onset relative to administration of the Sponsor’s product is not reasonable OR the AE 
is more likely explained by another cause than the Sponsor’s product. (Also entered 
for a participant with overdose without an associated AE.)
•
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.
•
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 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 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 health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
 
 
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Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC 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 EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
•
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
 
 
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Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol defined time frame in Section 5.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
●
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
○
The following are not acceptable methods of contraception:
▪
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM).
▪
Male and female condom cannot be used together.
○
A combination of male condom with either cap, diaphragm or sponge with 
spermicide are considered acceptable, but not highly effective, birth control methods.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
 
 
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Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 16 consistently and correctly during the 
protocol-defined time frame in Section 5.1.
Table 16
Contraceptive Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantc,d
•
IUSc,e
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
- Oral
- Intravaginal
- Transdermal
- Injectable
•
Progestogen-only hormonal contraceptionc,d
- Oral
- Injectable
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.
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c Male condoms must be used in addition to hormonal contraception.
d If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
e IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
 
 
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Pregnancy Testing
WOCBP should only be included after a negative pregnancy test has been confirmed at 
screening. Prior documentation of a negative serum β-HCG within 2 days (48 hours) of 
enrollment is acceptable for women of reproductive potential.  If documentation is not 
available,  a serum pregnancy test will be required.. 
Additional serum pregnancy testing will be performed at the Day 28 post-randomization 
visit.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8:  APACHE II Severity of Disease Classification System – APACHE 
II Score Form
A. Acute Physiology Score:
HIGH ABNORMAL RANGE
LOW ABNORMAL 
RANGE
PHYSIOLOGIC VARIABLE
+4
+3
+2
+1
0
+1
+2
+3
+4
1
Temperature rectal (oC)
□
≥41
□
39-
40.9
□
38.5-
38.9
□
36.0-
38.4
□
34-
35.9
□
32-
33.9
□
30-
31.9
□
≤29.9
2
Mean arterial pressure (mmHg) =
(2 x diastolic + systolic)/3
□
≥160
□
130-
159
□
110-
129
□
70-
109
□
50-
69
□
≤49
3
Heart rate (ventricular response)a
□
≥180
□
140-
179
□
110-
139
□
70-
109
□
55-
69
□
40-
54
□
≤39
4
Respiratory rate (nonventilated 
or ventilated)
□
≥50
□
35-49
□
25-
34
□
12-
24
□
10-
11
□
6-9
□
≤5
5
Oxygenation
A-aDO2 or PaO2 (mm Hg)
a)FiO2≥0.5:record A-aDO2
□
≥500
□
350-
499
□
200-
349
□
<200
b)FiO2<0.5:record only PaO2
□
>70
□
61-
70
□
55-
60
□
<55
6
Arterial pH (*If no ABGs record 
Serum HCO3 below)
□
≥7.7
□
7.6-
7.69
□
7.5-
7.59
□
7.33-
7.49
□
7.25-
7.32
□
7.15-
7.24
□
<7.15
7
Serum Sodium (mMol/L)
□
≥180
□
160-
179
□
155-
159
□
150-
154
□
130-
149
□
120-
129
□
111-
119
□
≤110
8
Serum Potassium (mMol/L)
□
≥7
□
6-6.9
□
5.5-
5.9
□
3.5-
5.4
□
3-
3.4
□
2.5-
2.9
□
<2.5
9
Serum Creatinine (mg/dL) 
Double Point for acute renal 
failure
□
≥3.5
□
2-3.4
□
1.5-
1.9
□
0.6-
1.4
□
<0.6
10
Hematocrit (%)
□
≥60
□
50-
59.9
□
46-
49.9
□
30-
45.9
□
20-
29.9
□
<20
 
 
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HIGH ABNORMAL RANGE
LOW ABNORMAL 
RANGE
PHYSIOLOGIC VARIABLE
+4
+3
+2
+1
0
+1
+2
+3
+4
11
White Blood Count (total/mm3) 
(in 1000’s)
□
≥40
□
20-
39.9
□
15-
19.9
□
3-
14.9
□
1-2.9
□
<1
12
Glasgow Coma Scale 
Enter 15 minus actual GCS –see 
calculations in table below
15-GCS =
A
Total Acute Physiology Score 
(APS)
Sum of the 12 individual variable points =
*
Serum HCO3(venous-mMol/L)
(Not preferred, use if no ABGs)
□
≥52
□
41-
51.9
□
32-
40.9
□
22-
31.9
□
18-
21.9
□
15-
17.9
□
<15
APACHE II Severity of Disease Classification System
Glasgow Coma Score (GCS)
(circle appropriate response)
Eyes open (E)
4 - spontaneously
3 - to verbal command
2 - to painful stimul
1 - no response
Motor response (M)
6 - to verbal command
5 - localizes to pain
4 - withdraws to pain
3 - decorticate
2 - decerebrate
1 - no response
Verbal - Response (V)
5-oriented and 
controversed
4-confused and 
disoriented
3-inappropriate words
2-incomprehensible 
sounds
1-no response
GLASGOW COMA SCORE† = E + M + V
†Participants scoring 3 or 4 have an 85% chance of dying or remaining vegetative, while 
scores above 11 indicate 5 to 10% likelihood of death or vegetative state and 85% chance of 
moderate disability or good recovery.  Intermediate scores correlate with proportional 
chances of participants recovering.
B. Age Points
Age
Points
≤44
0
45-54
2
55-64
3
65-74
5
≥75
6
Age points = _________
 
 
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C. Chronic Health Points (CHE)
If any of the 5 CHE categories is answered with yes give +5 points for nonoperative or 
emergency postoperative participants, or +2 points for elective postoperative participants
Liver 
- Cirrhosis with Portal Hypertension (PHT) or encephalopathy
Cardiovascular - NYHA Class IV angina or at rest or with minimal self-care activities
Pulmonary 
- chronic hypoxemia or hypercapnia or polycythemia or pulmonary hypertension 
of PHT >40 mm Hg
Kidney 
- chronic peritoneal or hemodialysis
Immune
- immune compromised host
Chronic Health Points=________
APACHE-II Score is sum of A+B+C
APS points A _______
Age points +B _______
Chronic Health Points
+C _________
Total APACHE-II Score=________
a
Heart rate is recommended when determining the APACHE II score during screening. 
But if pulse rate is collected, it could be accepted.
Adapted from: [Knaus, W. A., et al 1985]
 
 
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ABG
Arterial Blood Gas
AE
Adverse Event 
AIDS
Acquired Immune Deficiency Syndrome
ALT
Alanine Aminotransferase (SGPT)
APACHE
Acute Physiology and Chronic Health Evaluation
APaT
All Participants as Treated
AST
Aspartate Aminotransferase (SGOT)
AUC
Area Under the Concentration-time Curve
β-hCG
β-Human Chorionic Gonadotropin
BLI
β-lactamase Inhibitor 
CE
Clinically Evaluable
CFR
Code of Federal Regulations 
CI
Confidence Interval
cIAI
Complicated Intraabdominal Infection
Cmax
Maximum Concentration
CNDA
China National Drug Administration
CrCL
Creatinine Clearance
CRF
Case Report Form 
CSR
Clinical Study Report
CT
Computerized Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
DILI
Drug-induced Liver Injury
ECG
Electrocardiogram 
ECI
Event of Clinical Interest
eCRF
Electronic Case Report Form
EDC
Electronic Data Collection 
EMA
European Medicines Agency
EOT
End-of-Therapy
ESBL
Extended-spectrum -lactamase
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FiO2
Fraction of inspired oxygen
FSH
Follicle Stimulating Hormone 
GCP
Good Clinical Practice 
GCS
Glasgow coma score
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure 
IAI
Intraabdominal infection
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IDSA
Infectious Diseases Society of America
IEC
Independent Ethics Committee
IRB
Institutional Review Board 
ITT
Intent-to-treat
IV
Intravenous(ly)
IVRS/IWRS
Interactive Voice Randomization System/Web Randomization System
LAM
Lactational Amenorrhea Method
LDH
Lactate Dehydrogenase
LFU
Late Follow-up
 
 
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Abbreviation
Expanded Term
ME
Microbiologically Evaluable
MIC
Minimum Inhibitory Concentration
MITT
Microbiological Intent-to Treat
MRI
Magnetic Resonance Imaging
MRSA
Methicillin-resistant Staphylococcus aureus
MSD
Merck & Co, Inc. (Merck Sharp & Dohme outside the US)
PaO2
Partial Pressure of Oxygen
PBP
Penicillin-binding proteins
Q8h
Every 8 hours
Q12h
Every 12 hours
PD
Pharmacodynamic
PDLC
Pre-Defined Limit of Change
PI
Principal Investigator
PK
Pharmacokinetic
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
STAR
Staged Abdominal Repair
SoA
Schedule of Activities
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TOC
Test-of-Cure
WOCBP
Woman/Women of Childbearing Potential 
 
 
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11
REFERENCES
[Knaus, W. A., et al 1985]
Knaus WA, Draper EA, Wagner DP, Zimmerman 
JE. Apache II:  A severity of disease 
classification system. Crit Care Med 
1985;13(10):818-29.
[03RRCS]
[Lee, Y. R., et al 2015]
Lee YR, McMahan D, McCall C, Perry GK. 
Complicated intra-abdominal infections: the old 
antimicrobials and the new players. Drugs. 
2015;75:2097-117.
[05020W]
[Qiao-juan, H., et al 2010]
Qiao-juan H, Zhi-dong H, Jin L, Bin T, Hai-ru X, 
Jing L. 2008 Mohnarin report: bacterial 
distribution and resistance in intra-abdominal 
infections [abstract]. Chinese Journal of 
Antibiotics. 2010;35(8):620-25.
[05025F]
[Sartelli, M., et al 2014]
Sartelli M, Catena F, Ansaloni L, Coccolini F, 
Corbella D, Moore EE, et al. Complicated intra-
abdominal infections worldwide: the definitive 
data of the CIAOW Study. World J Emerg Surg. 
2014 May 14;9:37.
[04483T]
[Solomkin, J. S., et al 
2010]
Solomkin JS, Mazuski JE, Bradley JS, Rodvold 
KA, Goldstein EJC, Baron EJ, et al. Diagnosis 
and management of complicated intra-abdominal 
infection in adults and children:  guidelines by the 
surgical infection society and the infectious 
diseases society of America. Clin Infect Dis 
2010;50:133-64.
[03RBW3]
[Solomkin, J., et al 2015]
Solomkin J, Hershberger E, Miller B, Popejoy M, 
Friedland I, Steenbergen J,et al. 
Ceftolozane/Tazobactam plus Metronidazole for 
complicated intra-abdominal infections in an era 
of multidrug resistance: Results from a 
randomized, double-blind, phase 3 trial 
(ASPECT-cIAI). Clin Infect Dis. 2015 May 
15;60(10):1462-71.
[04NRTL]
[U.S. Prescribing 
Information 2016]
U.S. Prescribing Information: ZERBAXA 
(ceftolozane and tazobactam) for injection, for 
intravenous use: 2016.
[04PH7J]
 
 
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[Yang, Q., et al 2010]
Yang Q, Wang H, Chen M, Ni Y, Yu Y, Hu B, et 
al. Surveillance of antimicrobial susceptibility of 
aerobic and facultative Gram-negative bacilli 
isolated from patients with intra-abdominal 
infections in China: the 2002-2009 Study for 
Monitoring Antimicrobial Resistance Trends 
(SMART). Int J Antimicrob Agents 2010;36:507-
12.
[03RBVL]
[Zhang, H., et al 2014]
Zhang H, Yang Q, Xiao M, Chen M, Badal RE, 
Xu Y. Antimicrobial susceptibility of Gram-
negative bacteria causing intra-abdominal 
infections in China: SMART China 2011. Chin 
Med J (Engl). 2014;127(13):2429-33.
[05023K]
 
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MK-7625A
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Supplemental SAP
24NOV2020 – AMENDMENT #02
Supplemental Statistical Analysis Plan (sSAP)
MK-7625A-015
A Phase 3, Multicenter, Double-blind, Randomized, Active-controlled Clinical Study to 
Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam (MK-7625A) plus 
Metronidazole Versus Meropenem in Chinese Participants with Complicated Intra-abdominal 
Infection
 
 
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24NOV2020 – AMENDMENT #02
TABLE OF CONTENTS
TABLE OF CONTENTS.......................................................................................................... 2
LIST OF TABLES.................................................................................................................... 3
1.
INTRODUCTION ........................................................................................................ 4
2.
SUMMARY OF CHANGES........................................................................................ 4
3.
ANALYTICAL AND METHODOLOGICAL DETAILS........................................... 6
Statistical Analysis Plan Summary......................................................... 6
Responsibility for Analyses/In-House Blinding..................................... 8
Hypotheses/Estimation........................................................................... 8
Analysis Endpoints................................................................................. 9
Efficacy Endpoints.................................................................................. 9
Safety Endpoints................................................................................... 10
Analysis Populations............................................................................ 10
Efficacy Analysis Populations.............................................................. 10
Safety Analysis Populations ................................................................. 11
Statistical Methods ............................................................................... 12
Statistical Methods for Efficacy Analyses............................................ 12
Statistical Methods for Safety Analyses ............................................... 15
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses ............................................................................................... 16
Interim Analyses................................................................................... 16
Multiplicity........................................................................................... 18
Sample Size and Power Calculations ................................................... 18
Sample Size and Power for Efficacy Analyses..................................... 18
Subgroup Analyses and Effect of Baseline Factors ............................. 20
Compliance (Medication Adherence) .................................................. 21
Extent of Exposure ............................................................................... 21
4.
SUPPORTING DOCUMENTATION AND REFERENCES.................................... 22
Appendix I............................................................................................ 22
References ............................................................................................ 22
 
 
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24NOV2020 – AMENDMENT #02
LIST OF TABLES
Table 1 Clinical response rate at TOC visit.............................................................................. 9
Table 2 Analysis Strategy for Key Efficacy Variables........................................................... 13
Table 3 Analysis Strategy for Safety Parameters ................................................................... 16
Table 4 Sample Size Adjustments based on Interim Blinded Review of Clinical Response Rate 
at TOC Visit................................................................................................................ 17
Table 5 Power (%) Under Various Assumptions (With 268 participants (134 per arm) into the 
study and NI margin of -12.5%) ................................................................................. 19
Table 6 Precision (Minimum Observed Difference and Two-sided 95% CI) Under Various 
Assumptions (With 268 participants (134 per arm) enrolled into the study) ............. 20
 
 
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Supplemental SAP
24NOV2020 – AMENDMENT #02
1.
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP provides additional statistical 
analysis details/data derivations and documents modifications or additions to the analysis 
plan that are not “principal” in nature and result from information that was not available at 
the time of protocol finalization.  
2.
SUMMARY OF CHANGES
Changes for Amendment 1:
Section 
Number(s)
Section Title(s)
Description of 
Change(s)
Rationale
3.5.1
Efficacy Analysis 
Populations
CE population inclusion 
criteria #3 was changed 
from 4 days to 3 days;
Changes are made to be
consistent with global 
pivotal studies. Details 
of exclusion criteria 
provided in the 
Appendix.
3.6.1
Statistical Methods 
for Efficacy Analyses
Add information for 
exploratory endpoints
Provide details in 
analysis method for 
exploratory endpoints
3.10
Subgroup Analyses 
and Effect of Baseline
Factors
Remove “Region” in the 
subgroup analyses and 
add statistical method for 
subgroup analyses.
Changes are made to be 
consistent with updated 
protocol (v01)
3.11
Compliance 
(Medication 
Adherence)
Add formula and details 
for calculation of 
compliance
Provide more details on 
compliance calculation
3.12
Extent of Exposure
Add analysis method
Provide details on the 
tabulation of extent of 
exposure
 
 
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Supplemental SAP
24NOV2020 – AMENDMENT #02
Changes for Amendment 2:
Section 
Number(s)
Section Title(s)
Description of 
Change(s)
Rationale
3.1
Statistical Analysis 
Plan Summary
Clarify data source of the 
stratification factor used
for efficacy and 
sensitivity analyses
where the stratified 
method is applied if 
≥10% of participants are 
mis-stratified.
The eCRF stratum will 
be primary for efficacy 
analyses; randomization 
stratum from 
IVRS/IWRS will be 
supportive for the 
sensitivity analysis.
3.4.1
Efficacy Endpoints
Add exploratory analysis 
for superinfection and 
new infection
Changes are made to be 
consistent with protocol 
8.2.2.
3.5.1
Efficacy Analysis 
Populations
Clarify the MITT 
population
Changes are made to 
clarify the inclusion 
criteria for the MITT 
population and to be 
consistent with the 
definition in the 
evaluability guideline.
3.6.1
Statistical Methods 
for Efficacy Analyses
Change the stratified 
M&N method to the 
unstratified M&N 
method for secondary 
efficacy analyses related 
to per-pathogen groups 
Due to reduced sample 
sizes at per-pathogen 
groups.
Add analysis for 
superinfection and new 
infection
Changes are made to be
consistent with protocol 
8.2.2.
3.6.2
Statistical Methods 
for Safety Analyses
PDLC analyses were 
removed from Tier 2 and 
Tier 3 analyses.
The PDLC analyses are 
not applicable for this 
study compound; 
change from baseline 
 
 
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Supplemental SAP
24NOV2020 – AMENDMENT #02
Section 
Number(s)
Section Title(s)
Description of 
Change(s)
Rationale
will also be evaluated 
based on DIVISION 
OF MICROBIOLOGY 
AND INFECTIOUS 
DISEASES (DMID)
criteria.
3.10
Subgroup Analyses 
and Effect of Baseline 
Factors
Update APACHE II 
categorization and 
provide details for 
pathogen MIC and 
pathogen classification;
Changes are made to be 
consistent with pivotal 
studies and efficacy 
analysis populations 
across this study 
compound program.
Clarify subgroup 
analyses for the CE 
population and add 
subgroup analyses for the 
MITT/ITT population.
3.12
Extent of Exposure
Adjust calculation of 
exposure (in days); add 
exposure summary for 
the CE population
Provide clarification on 
the tabulation of extent 
of exposure.
3.
ANALYTICAL AND METHODOLOGICAL DETAILS
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 3.1 through 3.12.
Study Design Overview
A randomized, active-controlled, parallel-group, multicenter, double-
blind study of ceftolozane/tazobactam IV infusion (1500 mg q8h) plus 
metronidazole (500 mg q8h) IV infusion vs. meropenem IV (1000 mg 
q8h) plus placebo in Chinese participants with cIAI.
Treatment Assignment
Randomization method: Participants will be randomized in a 1: 1 ratio to two 
treatment arms of the study, Treatment 1 (ceftolozane/tazobactam + 
metronidazole) group or Treatment 2 (meropenem + placebo) group. Both 
treatments will be administered IV q8h. 
Stratification method: Randomization will be stratified by anatomic site of 
infection (bowel [small or large] vs. other site of cIAI). Participants with 
appendix, stomach, or duodenum as the anatomic site of infection, will be 
stratified to the “other site” group during the randomization process.
 
 
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24NOV2020 – AMENDMENT #02
All efficacy analyses where the stratified method is applied will be 
performed based on eCRF stratum (actual stratum); the sensitivity 
analysis for the primary efficacy endpoint will be performed using the 
randomized stratum from the interactive voice/web response system 
(IVRS/IWRS), if any mis-stratification occurs. Double-dummy double-
blind method: A double-blinding technique will be used. Study drug will 
be prepared and/or dispensed in a blinded fashion by an unblinded 
pharmacist or unblinded qualified study site personnel. The participant, 
the investigator and Sponsor personnel or delegate(s) who are involved in 
the treatment administration or clinical evaluation of the participants are 
unaware of the group assignments
Analysis Populations
Primary Efficacy Analysis: Clinical evaluable (CE) population.
Secondary 
Efficacy 
Analysis: 
Intent-to-treat 
(ITT) 
population, 
microbiological intent-to-treat (MITT) population, microbiologically 
evaluable (ME) population and expanded microbiologically evaluable 
(EME) population.
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Clinical response at the TOC visit
Secondary Endpoints
Clinical response at the EOT visit
Microbiological response (Per-subject and per-pathogen microbiological 
response) at the TOC visit
Statistical Methods for Key 
Efficacy
For the primary hypothesis (clinical response rate at the TOC visit in the 
CE population), Treatment 1 (ceftolozane/tazobactam + metronidazole)
will be considered non-inferior to Treatment 2 (meropenem + placebo) if 
the lower bound of the 2-sided 95% confidence interval (CI) for the 
between-treatment difference in the clinical response rate (Treatment 1 
minus Treatment 2) is larger than -12.5%.  The two-sided 95% CIs for 
between-treatment differences in the clinical response rate will be 
calculated using the stratified Miettinen and Nurminen method with the 
Cochran-Mantel-Haenszel (CMH) weighting. 
For secondary objectives, point estimates and two-sided 95% CIs will be 
calculated using the same stratified Miettinen and Nurminen method as 
described above.
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 only) and 95% CIs (Tier 1 and Tier 2) will be provided 
for between-treatment differences in the percentage of participants with 
events; these analyses will be performed using the unstratified Miettinen 
and Nurminen method.
Interim Analyses
A blinded review of the clinical response rate will be ongoing during the 
study. The impact of the blinded clinical response rate on the assumptions 
underlying the power/sample size calculation will be formally assessed by 
the Sponsor when approximately 75% of the planned sample size (N=201) 
have completed TOC visits or sooner if enrollment or event rates are 
occurring faster than anticipated. If the clinical response rate at the TOC 
visit is lower than the 90% assumed in the power calculation, consideration 
will be given to increasing the sample size.
There are no plans to conduct a formal interim analysis of unblinded 
efficacy data in the study.
Multiplicity
No multiplicity adjustment is planned as there is a single comparison of 2 
treatments using 1 endpoint in the primary hypothesis. Other efficacy 
analyses will be considered supportive and/or explanatory.
Sample Size and Power 
The planned sample size is 268 participants (134 per arm). Assuming a 
75% evaluability rate in the CE population, it is expected that 200 CE 
 
 
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participants (100 participants per arm) will be included. For the clinical 
response rate at the TOC visit in the CE population, the study has 80% 
power to demonstrate that Treatment 1 (ceftolozane/tazobactam + 
metronidazole) is non-inferior to Treatment 2 (meropenem + placebo) 
using a 1-tailed alpha of 2.5%, if there is no underlying treatment 
difference. The power and sample size are based on the following 
assumptions: 1) a non-inferiority margin of -12.5%, and 2) an underlying 
clinical response rate of 90% in the CE population for both treatments.
Responsibility for Analyses/In-House Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study. Unblinded Sponsor personnel [ie. 
unblinded CRA (uCRA), unblinded data manager (uDM), unblinded clinical scientist (uCS)], 
will be assigned to support the oversight and monitoring of study conduct. The uCRA will 
ensure that unblinded monitoring activities are conducted in compliance with protocol and 
regulatory requirements and the Trial Specific Site Monitoring Plan. The uDM will perform 
data review and reconciliation for unblinded eCRF data. The uCS will provide support and 
guidance on study-specific unblinded procedure-related questions, in particular, questions 
related to the blinded clinical supplies as well as support for the uDM on data review issues 
requiring consultation. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an interactive voice/web 
response system (IVRS/IWRS).
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 of the protocol.
Non-Inferiority Margin Justification:
A conservative method for estimating the treatment difference is adopted by comparison of 
the lower bound of the 95% CI for the antibacterial drug therapy and the upper bound of the 
95% CI for placebo/no treatment. The source data were obtained from the previous pivotal 
studies or medical literature. An upper bound of the 95% CI of 64.9% for placebo/no 
treatment was directly obtained from 2015 FDA Guidance for Industry Complicated Intra-
Abdominal Infections: Developing Drugs for Treatment. For antibacterial drug therapy, a 
meta-analysis for the clinical response rates was applied using study results from the two 
most commonly used cIAI drugs; meropenem and imipenem/cilastatin [Table 1]. In this 
meta-analysis, a point estimate of 87.8% with a two-sided 95% CI of 84.9% and 90.8% was 
calculated. For consistency of analyses, the DerSimonian and Laird method using random 
 
 
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effects was applied to both the above mentioned FDA guidance and the antibacterial drug 
results in [Table 1].
Given an estimated treatment difference of 20.0% (84.9% minus 64.9%) and consideration of 
a 12.5% NI margin suggested by EMA guidance Addendum to the note for guidance on 
evaluation of medicinal products indicated for treatment of bacterial infections 
(CPMP/EWP/558/95 REV 2) to address indication-specific clinical data, the non-inferiority 
margin is selected to be 12.5%, which represents preserving about 40% of the estimated 
treatment difference of 20%, as shown above.
Table 1 Clinical response rate at TOC visit
Drug
Clinical response rate at TOC 
n/N(%[95%CI])
Source
Note
Meropenem
364/417
87.3% [83.75, 90.15]
CXA-cIAI-10-08-09
Global 
study
Imipenem/cilastatin
50/55
90.9% [80.0, 97.0]
Chen et al. BMC Infectious 
Diseases 2010, 10:217
Chinese 
participants
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
Efficacy Endpoints
A full description of the efficacy measures is provided in Section 4.2.1.1 of the protocol. 
The primary efficacy endpoint is the clinical response rate at the TOC visit in the CE 
population. 
The secondary efficacy endpoints are: 
(1) Clinical response at the TOC visit in the ITT population.
(2) Clinical response at the EOT visit in the ITT and CE population.
(3) Percentage of participants achieving a favorable microbiological response at the 
TOC visit in the EME population.
(4) Per-pathogen percentage of baseline intra-abdominal pathogens achieving a 
favorable microbiological response at the TOC visit in the EME population. 
The exploratory efficacy endpoints are:
(1) Clinical response at the TOC visit in the MITT and ME populations.
(2) Clinical response at the EOT visit in the MITT population.
 
 
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(3) Percentage of participants achieving a favorable microbiological response at the 
TOC visit in the ME and MITT populations.
(4) Percentage of participants achieving a favorable microbiological response at the 
EOT visit in the ME, EME and MITT populations.
(5) Per-pathogen percentage of baseline intra-abdominal pathogens achieving a 
favorable microbiological response at the TOC visit in the ME and MITT 
populations. 
(6) Per-pathogen percentage of baseline intra-abdominal pathogens achieving a 
favorable microbiological response at the EOT visit in the ME, EME and MITT 
populations.
(7) Percentage of participants with superinfection or new infection (defined in the 
protocol Table 7) in the MITT population.
Safety Endpoints
The descriptions of safety measurements are provided in Section 4.2.1.2 of the protocol. 
Based upon a review of adult and pediatric trial safety data, no Tier 1 AEs of clinical interest 
have been identified. The broad clinical and laboratory adverse event (AE) categories, 
consisting of the percentage of participants with any AE, a drug-related AE, a serious AE, an 
AE which is both drug related and serious, discontinuation of IV study therapy due to an AE, 
discontinuation of IV study therapy due to a drug-related AE, and an AE leading to death 
will be considered Tier 2 endpoints.
Analysis Populations
Efficacy Analysis Populations
The Clinically Evaluable (CE) population will serve as the primary population for the 
analysis of efficacy data in this study. The Intent-to-Treat (ITT), Microbiological Intent-to-
treat (MITT), Microbiologically Evaluable (ME) and Expanded Microbiologically Evaluable
(EME) populations will serve as secondary or exploratory populations for efficacy analyses.
The ITT population will consist of all randomized participants. Participants in the ITT 
population will be analyzed based on the treatment they were randomized to, irrespective of 
what they actually received.
The MITT population will consist of all randomized participants who have a baseline intra-
abdominal bacterial pathogen known to cause cIAI, regardless of susceptibility to study drug. 
Participants in the MITT population will be analyzed based on the treatment they were 
randomized to, irrespective of what they actually received.
 
 
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The CE population is a subset of the ITT population who also meet the following key
criteria:
1.
Meet the protocol definition of cIAI,
2.
Have no significant deviation from the protocol that could impact the 
assessment of efficacy,
3.
Receive the minimum duration of IV study therapy (3 days, unless a treatment 
failure prior to day 3) that participant was randomized to and
4.
Have an efficacy assessment of cure or failure at the TOC visit. 
The CE population does not require a bacterial pathogen identified as the cause of cIAI.
Details of exclusion criteria will be provided in Appendix I.
The ME population is the subset of CE participants who have at least one baseline 
intraabdominal pathogen identified that is susceptible to study drug.
The EME population consists of all randomized participants who have cIAI as evidenced 
by identification of at least 1 baseline intra-abdominal pathogen, regardless of susceptibility 
to study drug and meet all CE population criteria.
The CE, ME, and EME populations will serve as the per-protocol analysis populations for the 
analysis of efficacy data in this study.
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study.  The APaT population consists of all randomized participants who received at 
least one dose of study treatment. Participants will be included in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population.  For most participants this will be the treatment group to which 
they are randomized.  Participants who take incorrect study treatment for the entire treatment 
period will be included in the treatment group corresponding to the study treatment actually 
received.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
For the analysis of pre-specified events of interest described above in Section 3.4.2, 
participants will be excluded from specific analyses if the conditions defining the event were 
present at randomization (Day 1).
 
 
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Statistical Methods
Statistical testing and inference for safety analyses are described in Section 3.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 3.8, Multiplicity. Nominal p-values may be 
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size limitations, etc.  Unless otherwise stated, all statistical tests 
will be conducted at α=0.025 (1-sided) level.
Statistical Methods for Efficacy Analyses
Primary Efficacy Analysis
The primary objective is to establish non-inferiority of Treatment 1 (ceftolozane/tazobactam 
+ metronidazole) to Treatment 2 (meropenem + placebo) with respect to clinical response 
rate in the CE population at TOC visit. 95% CIs for between-treatment differences in the 
clinical response rate will be calculated using the stratified Miettinen and Nurminen (M&N) 
method (1985) with the Cochran-Mantel-Haenszel (CMH) weighting. The analyses will be 
stratified by anatomic site of infection (bowel [small or large] vs. other site of cIAI). 
Treatment 1 (ceftolozane/tazobactam + metronidazole) will be considered non-inferior to 
Treatment 2 (meropenem + placebo) if the lower bound of the 2-sided 95% CI of the 
between-treatment difference in clinical response rate (Treatment 1 minus Treatment 2) at 
TOC in the CE population is larger than -12.5%.
Secondary Efficacy Analysis
The secondary efficacy analyses will follow the same stratified M&N method described 
above for the primary efficacy analysis except the per-pathogen microbiological responses 
will be analyzed using the unstratified M&N method. The estimates and their two-sided 95% 
CIs will be calculated for each secondary efficacy endpoint. The secondary efficacy 
objectives are estimation objectives only, so no NI testing will be applied on the secondary 
efficacy analyses.
Exploratory Efficacy Analysis
The exploratory efficacy analyses will follow the M&N method, unless otherwise specified. 
Details of statistical method are provided in [Table 2]. The estimates and their two-sided 
95% CIs will be calculated for each exploratory efficacy endpoint. The exploratory efficacy 
objectives are estimation objectives only, and no hypothesis testing will be applied.
The percentage of participants with superinfection or new infection for the MITT population
will only be summarized.
Missing Values
Any participant missing an evaluation for a specific endpoint (clinical or microbiological) at 
any particular visit will be generally considered as being “indeterminate” for that endpoint in 
the ITT and MITT populations. Participants with an indeterminate clinical outcome will be 
 
 
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considered as “Treatment Failure” in the ITT and MITT analysis populations. Participants 
with an indeterminate clinical outcome will be excluded from per-protocol analysis 
populations (CE, ME and EME).  The following are exceptions to this rule:

Participants discontinuing IV study therapy due to lack of efficacy (i.e., withdrawals 
with subsequent non-study antibiotic therapy or participants requiring therapy beyond 
14 days) will be considered as “failures” with respect to clinical response at the time 
of discontinuation and all subsequent time points in all populations.

Participants discontinuing IV study therapy due to lack of efficacy will be presumed 
to have persistence for the microbiological response at the time of discontinuation and 
all subsequent time points.
The primary and secondary endpoints, primary and secondary analysis populations, and 
statistical methods that will be employed for the efficacy analyses are presented in [Table 2]. 
Since a favorable clinical response and a favorable microbiological response require a clear 
assessment, an assessment of “indeterminate” would be considered treatment failure in the 
ITT and MITT populations. 
Table 2 Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time point)
Statistical Method†
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis:
Clinical response at the TOC visit 
Stratified M&N‡
CE§
DAO††
Secondary Endpoints:
Clinical response at the TOC visit
Stratified M&N‡
ITT
M=F‡‡
Clinical response at the EOT visit
Stratified M&N‡
ITT
M=F‡‡
CE§
DAO††
Percentage of participants achieving a 
favorable microbiological response at 
the TOC visit
Stratified M&N‡
EME#
DAO††
Per-pathogen percentage of baseline 
intra-abdominal pathogens achieving a 
favorable microbiological response at 
the TOC visit
Unstratified M&N‡
EME#
DAO††
Exploratory Endpoints:
Clinical response at the TOC visit
Stratified M&N
MITT¶
M=F‡‡
ME#
DAO††
Clinical response at the EOT visit
Stratified M&N
MITT¶
M=F‡‡
 
 
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Endpoint/Variable
(Description, Time point)
Statistical Method†
Analysis 
Population
Missing Data 
Approach
Percentage of participants achieving a 
favorable microbiological response at 
the TOC visit
Stratified M&N
ME#
DAO††
MITT¶
M=F‡‡
Percentage of participants achieving a 
favorable microbiological response at 
the EOT visit
Stratified M&N
ME#
DAO††
EME#
DAO††
MITT¶
M=F‡‡
Per-pathogen percentage of baseline 
intra-abdominal pathogens achieving a 
favorable microbiological response at 
the TOC visit
Unstratified M&N
ME#
DAO††
MITT¶
M=F‡‡
Per-pathogen percentage of baseline 
intra-abdominal pathogens achieving a 
favorable microbiological response at 
the EOT visit
Unstratified M&N
ME#
DAO††
Per-pathogen percentage of baseline 
intra-abdominal pathogens achieving a 
favorable microbiological response at 
the EOT visit
Unstratified M&N
EME#
DAO††
MITT¶
M=F‡‡
† Statistical models are described in further detail below:
‡ M&N is Miettinen and Nurminen method stratified by anatomic site of infection (bowel [small or large] vs. other site of 
cIAI). 
§ CE population is a subset of the ITT population who also meet the following criteria:1) Meet the protocol definition of 
cIAI; 2) Have no significant deviation from the protocol that could impact the assessment of efficacy,3) Receive the 
minimum duration of IV study therapy (3 days unless treatment failure prior to Day 3), and 4) Have a efficacy assessment 
of Cure or Failure at the time point of interest.
ITT population consists of all randomized participants.
¶ MITT population: consist of all randomized participants who have a baseline intra-abdominal bacterial pathogen known 
to cause cIAI.
# ME population is the subset of CE participants who have at least one baseline intraabdominal pathogen identified that is 
susceptible to study drug. EME population is expanded ME population.
†† DAO is data as observed, that is, participants with missing values will be excluded from the analysis.  
‡‡ M=F is missing =failure
 
 
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The strategy to address multiplicity issues with regard to multiple efficacy endpoints and
multiple time points is described in Section 3.7, Interim Analyses and in Section 3.8, 
Multiplicity.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach [Table 3]. The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change (PDLCs) in 
laboratory and vital signs are either pre-specified as “Tier-1” endpoints or will be classified 
as belonging to "Tier 2" or "Tier 3" based on the number of events observed.  
Tier 1 Events
Safety parameters or adverse events of special interest that are identified a priori constitute 
“Tier 1” safety endpoints that will be subject to inferential testing for statistical significance. 
There are no Tier 1 events for this protocol based upon a review of adult and pediatric trial 
safety data. 
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (also via the M&N method (1985)). Membership 
in Tier 2 requires that at least 4 participants in at least one treatment group exhibit the event. 
The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include zero when treatment groups of equal size 
each have less than 4 events and thus would add little to the interpretation of potentially 
meaningful differences.  Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in 
review, not a formal method for assessing the statistical significance of the between-group 
differences in adverse experiences and predefined limits of change. In addition to individual 
events that occur in 4 or more participants in any treatment group, the broad AE categories 
consisting of the proportion of participants with any AE, a drug related AE, a serious AE, an 
AE which is both drug-related and serious, and discontinuation due to an AE will be 
considered Tier 2 endpoints.  
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
 
 
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Continuous Safety Measures
Continuous measures such as changes from baseline in laboratory and vital signs parameters, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format. 
Table 3 Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
None
X
X
X
Tier 2
Any AE‡
X
X
Any Serious AE
X
X
Any AE leading to death
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs or SOCs† (incidence ≥4 of 
participants in one of the treatment groups)
X
X
Tier 3
Specific AEs or SOCs† (incidence <4 of 
participants in all of the treatment groups)
X
Change from Baseline Results (Labs, Vital 
Signs)
X
† Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
‡ Indicates broad AE category of the number of participants reporting any adverse event.
Note: SOC=System Organ Class; X = results will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of descriptive statistics. No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of participants screened, randomized, the 
primary reasons for screening failure, and the primary reason for discontinuation will be 
displayed. Demographic variables, baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment using descriptive 
statistics for continuous or categorical variables, as appropriate.
Interim Analyses
An internal blinded sample size re-estimation will be conducted as described in the next 
paragraph. There are no plans to conduct a formal interim analysis of unblinded efficacy data 
in the study.
 
 
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Blinded review of clinical response rate at TOC visits on the CE population will be ongoing 
during the study. The impact of the clinical response rate on the assumptions underlying the 
power/sample size calculation will be formally assessed when approximately 75% (N=201) 
of the planned sample size (N=268) have completed TOC visits or sooner if enrollment or 
event rates are occurring faster than anticipated. In consideration of having enough time for 
blinded sample size re-estimation as well as a stable estimate for the clinical response rate, 
75% is selected as the time point for the blinded sample size assessment.
If the observed, blinded (pooled) clinical response rate is lower than the 90% assumed in the 
power calculation, consideration will be given to increasing the overall sample size as 
outlined in [Table 4]. If the observed clinical response rate is larger than 90%, the overall 
sample size will be maintained at the planned N=268 as the power for this 
endpoint/hypothesis will likely exceed 80%. The maximum sample size will not exceed 
N=408 (204 per group) regardless of the observed clinical response rate. 
Blinded review of clinical response is not a true interim analysis in that it will not require a 
dataset freeze, unblinding, and multiplicity adjustments. The accruing database will not be 
officially locked for this blinded sample size re-estimation; however, all data relating to the 
assessment of clinical response rate will be cleaned and all queries resolved before the formal 
assessment of the clinical response rate. As this sample size re-estimation will be done in a 
blinded fashion, there is no impact on type 1 error rates.
Table 4 Sample Size Adjustments based on Interim Blinded Review of Clinical Response 
Rate at TOC Visit
Observed 
Clinical 
Response Rate†
Power based on 
Original Sample Size 
(N=268) (%) 
Revised 
Sample Size‡
Percent Increase from 
Original Sample Size (%)
89%
77.2
294
9.7
88%
74.6
310
15.7
87%
72.2
328
22.4
86%
70.0
344
28.4
85%
67.9
360
34.3
84%
66.0
376
40.3
83%
64.0
392
47.3
82%
62.2
408
52.2
†
This rate is expressed as a percent and rounded to the nearest integer value.
‡
Calculated to provide 80% power based on the observed clinical response rate and assumed evaluable 
rate of 75% in CE population in the power/sample size calculation.
Note:  The calculation is also based on the assumptions from the sample size section, i.e. one-sided 2.5% 
alpha-level, no underlying treatment difference, and NI margin of -12.5%.
 
 
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Multiplicity
As there is only a single primary efficacy hypothesis which is being conducted at the one -
sided α=0.025 level, no multiplicity adjustment is needed for the primary efficacy analysis.
The secondary efficacy objectives are estimation objectives, are supportive in nature and 
have no associated hypotheses. Therefore, no multiplicity adjustment is necessary for the 
secondary efficacy analysis.
There will be no multiplicity adjustments applied to the safety summaries.
Sample Size and Power Calculations
Sample Size and Power for Efficacy Analyses
This study will randomize 268 participants (134 per treatment arm) into the study and has 
80% power to establish that Treatment 1 (ceftolozane/tazobactam + metronidazole) is non-
inferior to Treatment 2 (meropenem + placebo) in the clinical response rate at the TOC visit 
in CE population at an overall one-sided, 2.5% alpha-level, if there is no underlying 
treatment difference. The power and sample size are based on the following assumptions: 1) 
an approximately 75% evaluable rate in CE population 2) a non-inferiority margin of -12.5% 
(Treatment 1 minus Treatment 2), and 3) an underlying clinical response rate of 90% at the 
TOC visit. Above assumption is based on the pivotal study CXA-cIAI-10-08-09 CSR. The 
non-inferiority margin is regarded as the minimum difference of clinical interest between the 
2 treatments [rationale is described in Section 3.3]. The calculation is based on an asymptotic 
method proposed by Miettinen and Nurminen (1985) with 100 participants per group
expected to be included in the analysis in CE population and is carried out using PASS by 
selecting the test type of likelihood score (Miettinen & Nurminen) in the non-inferiority & 
superiority tests for two proportions [differences] module. The minimum criterion for success 
is that the lower bound of the 95% CI on the treatment difference (Treatment 1 minus 
Treatment 2) > -12.5%. [Table 5] summarizes power calculations for the primary comparison 
under various assumptions.
 
 
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Table 5 Power (%) Under Various Assumptions (With 268 participants (134 per arm) into the 
study and NI margin of -12.5%)
Underlying clinical 
response rate of 
treatment 2 at TOC visit
Underlying Treatment Difference˄%˅
(Treatment 1 - Treatment 2)
2
1
0
-1
-2
-3
82%
76.9
69.9
62.2
54.3
46.4
38.7
84%
80.6
73.7
66.0
57.8
49.5
41.4
86%
84.4
77.7
70.0
61.6
52.9
44.4
88%
88.5
82.2
74.6
66.0
56.9
47.8
90%
92.6
87.2
80.0
71.4
61.9
52.0
92%
96.4
92.4
86.1
77.9
68.1
57.5
94%
99.0
96.9
92.5
85.5
76.1
65.0
Note:  The power is calculated based on 100 participants per each treatment group expected to be included in 
the analysis in the CE population.
Another way to assess the precision of a non-inferiority study is to consider the minimum
observed difference that would just meet the criterion for non-inferiority (in this case, a lower
bound of the 2-sided 95% CI for the difference in clinical response rate in CE population
[Treatment 1 minus Treatment 2] that is just larger than -12.5%). This minimum observed 
difference will decrease as the observed clinical response rate in the control group increases
[Table 6]. An observed clinical response rate of 90% in the treatment 2 will just meet the 
criterion for non-inferiority given an observed difference (Treatment 1 – Treatment 2) is not 
less than -3.2%, that is the observed clinical response rate in the treatment 1 is not less than 
86.8%. An observed clinical response rate of 86% in the treatment 2 will just meet the 
criterion for non-inferiority given an observed difference (Treatment 1 – Treatment 2) is not 
less than -2.3%, that is the observed clinical response rate in the treatment 1 is not less than 
83.7%. Above calculation is carried out using PASS by selecting the test type of score 
(Miettinen & Nurminen) in the CIs for two proportions [differences] module.
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Table 6 Precision (Minimum Observed Difference and Two-sided 95% CI) Under Various 
Assumptions (With 268 participants (134 per arm) enrolled into the study)
Observed
Clinical 
Response 
Rate of 
Treatment 
2 at TOC 
visit
Minimum 
Observed 
Difference
(%) required 
to achieve NI 
Margin of 
12.5%
Estimated Treatment Difference˄%˅
(Treatment 1 - Treatment 2)
0
-1
-2
-3
-4
-5
Two-sided 95% CI of Estimated Treatment Difference (%)
82%
-1.50
(-10.84, 
10.84)
(-11.94, 
9.94)
(-13.04, 
9.03)
(-14.13, 
8.13)
(-15.22, 
7.22)
(-16.30, 
6.31)
86%
-2.27
(-9.92, 9.92)
(-11.06, 
9.03)
(-12.19, 
8.14)
(-13.31, 
7.24)
(-14.42, 
6.35)
(-15.53, 
5.45)
90%
-3.17
(-8.78, 8.78)
(-9.96, 
7.90)
(-11.14, 
7.02)
(-12.30, 
6.14)
(-13.45, 
5.26)
(-14.60, 
4.38)
94%
-4.19
(-7.31, 7.31)
(-8.58, 
6.44)
(-9.83, 
5.58)
(-11.05, 
4.71)
(-12.26, 
3.85)
(-13.46, 
2.98)
Note:  The 95% CI is calculated based on 100 participants per each treatment group expected to be included in the analysis
in the CE population.
Subgroup Analyses and Effect of Baseline Factors
To assess the consistency of the treatment effect across various subgroups, the estimate of the 
between-group treatment effect (with a nominal 95% CI except for baseline pathogen 
susceptibility) for the primary endpoint in the CE population will be estimated using the 
unstratified M&N method within each category of the following classification variables: 
•
Age category (≤65 vs. >65 years)
•
APACHE II Score (<10 vs. ≥10)
•
Baseline renal CrCL (30 to ≤50 vs. >50 mL/min)
•
Procedure Type (percutaneous aspiration, laparoscopy, laparotomy, other)
•
Prior antibiotic use (yes or no)
•
Sex (female, male)
•
Primary Site of Infection Stratum: bowel [small or large] vs. other site of cIAI
•
Anatomic site of infection/diagnosis
•
Baseline pathogens
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
Presence of baseline bacteremia

Number of baseline pathogens (polymicrobial, monomicrobial).

Number of Abscesses (single, multiple)

Peritonitis Type (local, diffuse)

Site of infection (appendix, non-appendix)

Baseline pathogen susceptibility to study treatment 

Baseline pathogen classification (ESBL status for baseline Enterobacteriaceae)
The baseline pathogen susceptibility to study treatment is categorized using the baseline 
pathogen MIC values. The subgroup analyses by baseline pathogen and by baseline pathogen 
susceptibility to study treatment will also be performed for the MITT population, and the rest 
of the subgroup analyses will also be performed for the ITT population.
Compliance (Medication Adherence)
Considering this is an IV study conducted by investigators/nurses, it is expected to follow the 
protocol strictly without compliance issues. Any non-compliance dosage will be monitored 
and recorded.
For each participant, percent compliance will be calculated using the following formula:
Compliance (%) = 100 times (Actual Number of Doses on Therapy) / (Total Number of 
Expected Doses on Therapy).
The “Total Number of Expected Doses on Therapy” is the total scheduled number of doses 
from the start of treatment administration to the last scheduled treatment administration for 
that participant based on Section 6.4 and 6.6 of the protocol. The “Actual Number of Doses 
on Therapy” is the total number of actual doses received from the start of treatment 
administration to the last treatment administration for that participant.
Compliance (%) will be categorized as: < 80%, ≥ 80% to ≤ 120%, > 120%.
Summaries of percent compliance and compliance (%) categories will be provided for the CE 
population.
Extent of Exposure
The treatment duration for patients will be calculated as follows:
The duration of study drug exposure is calculated as difference between the last study 
therapy date and time and the first study therapy date and time converted to days plus 1 day.
 
 
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The durations in days will be categorized into the following groups for the purpose of 
summaries: 1-3 days, 4-7 days, 8-10 days, 11-14 days, and > 14 days.
The extent of exposure (in days) to study treatment will be evaluated by summary statistics 
(n, mean, median, standard deviation, minimum, and maximum). Summaries will be 
tabulated by treatment group for the APaT and CE populations.
4.
SUPPORTING DOCUMENTATION AND REFERENCES
Appendix I
Exclusion Criteria of the CE Population
Population
Reason
CE
Does not meet ITT eligibility
CE
Clinical Diagnostic Definition Not Met
CE
No Clinical Efficacy Assessment or Only Indeterminate Clinical 
Assessments
CE
TOC Assessment Performed Out of 24-45 days in study visit
CE
Prior Antibacterial Violation
CE
Concomitant Antibacterial Violation 
CE
Confounding Antibacterial Post-treatment
CE
Participant with Previous Failure of Prior Antibiotic Therapy and Negative 
Intra-abdominal Specimen
CE
Participant Who Has Baseline Abscess Cannot Be Managed by Surgical 
Intervention Including Drainage
CE
Protocol Specified Minimum Duration of 3 Days of Study Therapy Not 
Received, unless treatment failure ≥ 48hours
CE
Maximum Protocol-Specified Duration of 14 Days of Study Therapy 
Exceeded
CE
Participant who missed 2 or more consecutive doses, or 3 or more non-
consecutive doses which resulted in receiving <80% of the expected study 
treatment course, or >120% of expected study treatment course
CE
Confounding Medical Condition or Procedure
CE
Met Significant Deviation Per ERT Decision, Not Mentioned Above
References
[1]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
 
 
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