A Phase 1, Open-label, Non-comparative, Multicenter Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Ceftolozane/Tazobactam (MK-7625A) in Pediatric Participants With Nosocomial Pneumonia
Phase: PHASE1
Conditions: Nosocomial Pneumonia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 1, open-label, non-comparative, multicenter 
clinical study to evaluate the safety, tolerability, and 
pharmacokinetics of ceftolozane/tazobactam 
(MK-7625A) in pediatric participants with nosocomial 
pneumonia
NCT04223752
12-Dec-2022

PRODUCT: MK-7625A
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 1, open-label, non-comparative, multicenter clinical study to 
evaluate the safety, tolerability, and pharmacokinetics of ceftolozane/tazobactam 
(MK-7625A) in pediatric participants with nosocomial pneumonia
Protocol Number: 036-02
Compound Number: MK-7625A
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT04223752
EU CT
2022-501110-56-00
EudraCT
2018-004704-19
JAPIC-CT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
104,490
Approval Date: 12 December 2022
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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
Amendment 2
12-DEC-2022
The end-of-study definition was changed from 
LPLV to LDA to allow for the data collection and 
evaluation needed to fulfill regulatory 
requirements.
Amendment 1
05-MAY-2020
Guidance regarding contraceptive use was 
updated to remove the option of “acceptable 
contraceptive methods” in order to align protocol 
language with recommendations outlined by 
Clinical Trial Facilitation Group (CTFG) 
guidance for contraception and pregnancy testing 
in clinical trials in which the investigational 
product has the designation of possible risk of 
human teratogenicity/fetotoxicity in early 
pregnancy. The definition of overdose was 
updated to align with the definition of overdose 
across the ceftolozane/tazobactam program.
Original Protocol
02-APR-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendment:
The end-of-study definition was changed from LPLV to LDA to allow for the data collection and evaluation needed to fulfill 
regulatory requirements.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
4.4 Beginning and End-of-Study 
Definition
1.1 Synopsis
Text defining the end of the study as the LPLV
or contact was updated to clarify that this 
corresponds to when the last data are available to 
the Sponsor.
This change was made to address strategy.
The rationale is further supported by the 
fact that data related to the primary and 
secondary endpoint, PK, and/or laboratory 
data may not be available to the Sponsor 
until after the date of the LPLV or contact. 
Section Number and Name
Description of Change
Brief Rationale
Other Changes in Amendment
Title Page
10.1.1 Code of Conduct for 
Interventional Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent 
an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, 
USA. This conversion resulted only in an 
entity name change and update to the 
address.
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Section Number and Name
Description of Change
Brief Rationale
Title Page
Updated NCT and EU CT identifying numbers.
To update new regulatory agency 
identifying numbers.
1.1 Synopsis
Revised estimated duration of study from 40 
months to 70 months in overall design table.
To update study timelines to reflect delays 
in study completion caused by the 
Sponsor's voluntary global recall of 
ZERBAXA® following a sterility 
manufacturing issue, loss of study sites due 
to the conflict in Ukraine and Russia, and 
the ongoing COVID-19 public health 
emergency.
2.1 Study Rationale
2.2.2 Preclinical and Clinical 
Studies
Updated background information for the 
completed pediatric clinical studies for cUTI and 
cIAI.
To reflect new safety and efficacy 
information for completed clinical studies 
in the ZERBAXA® clinical development 
program.
5 Study Population
Updated text for specific populations as 
applicable to the study.
To clarify the collection, use, and 
confidentiality of demographic data 
provided by the participants.
6 Study Intervention
6.1 Study Intervention(s) 
Administered
8.1.8 Study Intervention 
Administration
Updated text to clarify that 
ceftolozane/tazobactam will be provided 
centrally or sourced locally.
To clarify the allowance of locally sourced 
ceftolozane/tazobactam in markets where 
ZERBAXA® is authorized and 
commercially marketed.
6.1 Study Intervention(s) 
Administered
Updated column headers and abbreviations in 
Table 3.
To align with the EU CTR.
8.1.6 Assignment of Screening 
Number
Screening logs will have identifying information
removed before being reviewed by Sponsor.
To allow collection of participant screening 
logs.
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Section Number and Name
Description of Change
Brief Rationale
8.4 Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
Added that investigators need to document if an
SAE was associated with a medication error, 
misuse, or abuse. Clarified that collection is 
related to SUSARs and the collection of SAEs 
only.
To align with the EU CTR.
8.4.7 Events of Clinical Interest
Clarified definition of potential DILI.
To improve clarity and consistency.
10.3 Appendix 3: Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, 
and Reporting
10.3.2 Definition of AE
Updated “sponsor product” to “study 
intervention” to be consistent with the rest of the 
protocol (ie, Study Intervention Table).
To improve consistency.
10.3.1 Definitions of Medication 
Error, Misuse, and Abuse
Added definitions of medication error, misuse,
and abuse.
To align with the EU CTR.
Throughout Document
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document
To ensure clarity and accurate 
interpretation of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.........................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................22
2.2.1
Pharmaceutical and Therapeutic Background .............................................22
2.2.2
Preclinical and Clinical Studies ...................................................................23
2.3
Benefit/Risk Assessment......................................................................................24
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................25
4
STUDY DESIGN............................................................................................................26
4.1
Overall Design......................................................................................................26
4.2
Scientific Rationale for Study Design.................................................................27
4.2.1
Rationale for Endpoints ...............................................................................27
4.2.1.1
Safety Endpoints................................................................................27
4.2.1.2
Pharmacokinetic Endpoints ...............................................................27
4.2.2
Rationale for Sample Size............................................................................28
4.3
Justification for Dose...........................................................................................28
4.3.1
Starting Dose for This Study........................................................................28
4.3.2
Maximum Dose Exposure for This Study ...................................................31
4.3.3
Rationale for Dose Interval and Study Design ............................................31
4.3.4
Rationale for Treatment Duration................................................................31
4.4
Beginning and End-of-Study Definition ............................................................31
4.4.1
Clinical Criteria for Early Study Termination .............................................32
5
STUDY POPULATION ................................................................................................33
5.1
Inclusion Criteria.................................................................................................33
5.2
Exclusion Criteria................................................................................................35
5.3
Lifestyle Considerations......................................................................................36
5.4
Screen Failures.....................................................................................................36
5.5
Participant Replacement Strategy......................................................................37
6
STUDY INTERVENTION............................................................................................38
6.1
Study Intervention(s) Administered...................................................................38
6.2
Preparation/Handling/Storage/Accountability .................................................40
6.2.1
Dose Preparation..........................................................................................40
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6.2.2
Handling, Storage, and Accountability........................................................40
6.3
Measures to Minimize Bias: Randomization and Blinding..............................41
6.3.1
Intervention Assignment..............................................................................41
6.3.2
Stratification.................................................................................................41
6.3.3
Blinding........................................................................................................41
6.4
Study Intervention Compliance..........................................................................41
6.5
Concomitant Therapy..........................................................................................41
6.5.1
Rescue Medications and Supportive Care ...................................................42
6.6
Dose Modification (Escalation/Titration/Other)...............................................42
6.7
Intervention After the End of the Study............................................................42
6.8
Clinical Supplies Disclosure................................................................................42
6.9
Standard Policies..................................................................................................42
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................43
7.1
Discontinuation of Study Intervention...............................................................43
7.2
Participant Withdrawal From the Study...........................................................44
7.3
Lost to Follow-up .................................................................................................44
8
STUDY ASSESSMENTS AND PROCEDURES........................................................45
8.1
Administrative and General Procedures ...........................................................45
8.1.1
Informed Consent/Assent.............................................................................45
8.1.1.1
General Informed Consent/Assent.....................................................46
8.1.2
Inclusion/Exclusion Criteria ........................................................................46
8.1.3
Participant Identification Card.....................................................................46
8.1.4
Medical History ...........................................................................................47
8.1.5
Prior and Concomitant Medications Review ...............................................47
8.1.5.1
Prior Medications...............................................................................47
8.1.5.2
Concomitant Medications..................................................................47
8.1.6
Assignment of Screening Number...............................................................47
8.1.7
Assignment of Treatment/Randomization Number.....................................47
8.1.8
Study Intervention Administration ..............................................................48
8.1.8.1
Timing of Dose Administration.........................................................48
8.1.9
Discontinuation and Withdrawal .................................................................48
8.1.10
Participant Blinding/Unblinding..................................................................48
8.1.11
Calibration of Equipment.............................................................................48
8.2
Efficacy Assessments ...........................................................................................49
8.3
Safety Assessments...............................................................................................49
8.3.1
Physical Examinations.................................................................................49
8.3.2
Vital Signs....................................................................................................49
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8.3.3
Clinical Safety Laboratory Assessments .....................................................50
8.3.3.1
Assessment of Creatinine Clearance..................................................50
8.3.4
Pregnancy Testing (WOCBP only)..............................................................51
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................51
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................51
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......53
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...53
8.4.4
Regulatory Reporting Requirements for SAE .............................................53
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................54
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying
as AEs or SAEs............................................................................................54
8.4.7
Events of Clinical Interest............................................................................54
8.5
Treatment of Overdose........................................................................................55
8.6
Pharmacokinetics.................................................................................................55
8.6.1
Blood Collection for Plasma Concentrations of 
Ceftolozane/Tazobactam..............................................................................55
8.7
Pharmacodynamics..............................................................................................56
8.8
Biomarkers ...........................................................................................................56
8.8.1
Planned Genetic Analysis Sample Collection..............................................56
8.9
Future Biomedical Research Sample Collection...............................................56
8.10
Visit Requirements...............................................................................................56
8.10.1
Screening (Visit 1).......................................................................................56
8.10.2
Allocation Visit (Visit 2; Day 1)..................................................................56
8.10.3
Treatment Period Visits ...............................................................................56
8.10.4
Intervention Period Visits (Visits 3 through 15; Days 2 through 14)..........56
8.10.5
EOT Visit (Visit 16).....................................................................................57
8.10.6
LFU Visit (Visit 17).....................................................................................57
8.10.7
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................57
9
STATISTICAL ANALYSIS PLAN .............................................................................58
9.1
Statistical Analysis Plan Summary.....................................................................58
9.2
Responsibility for Analyses/In-house Blinding .................................................59
9.3
Hypotheses/Estimation ........................................................................................59
9.4
Analysis Endpoints...............................................................................................59
9.4.1
Safety Endpoints..........................................................................................59
9.4.2
PK Endpoints ...............................................................................................59
9.5
Analysis Populations............................................................................................60
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9.5.1
Safety Population.........................................................................................60
9.5.2
PK Population..............................................................................................60
9.6
Statistical Methods...............................................................................................60
9.6.1
Statistical Methods for Safety Analyses ......................................................60
9.6.2
Statistical Methods for PK Analyses ...........................................................61
9.7
Interim Analyses ..................................................................................................61
9.8
Multiplicity ...........................................................................................................62
9.9
Sample Size and Power Calculations .................................................................62
9.10
Subgroup Analyses...............................................................................................62
9.11
Compliance (Medication Adherence).................................................................62
9.12
Extent of Exposure...............................................................................................63
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................64
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........64
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................64
10.1.2
Financial Disclosure.....................................................................................67
10.1.3
Data Protection.............................................................................................67
10.1.3.1
Confidentiality of Data ......................................................................67
10.1.3.2
Confidentiality of Participant Records...............................................68
10.1.3.3
Confidentiality of IRB/IEC Information............................................68
10.1.4
Publication Policy........................................................................................68
10.1.5
Compliance with Study Registration and Results Posting Requirements ...68
10.1.6
Compliance with Law, Audit, and Debarment ............................................69
10.1.7
Data Quality Assurance ...............................................................................69
10.1.8
Source Documents .......................................................................................70
10.1.9
Study and Site Closure.................................................................................71
10.2
Appendix 2: Clinical Laboratory Tests..............................................................72
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................73
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................73
10.3.2
Definition of AE ..........................................................................................73
10.3.3
Definition of SAE ........................................................................................74
10.3.4
Additional Events Reported.........................................................................75
10.3.5
Recording AE and SAE ...............................................................................75
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................79
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................80
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10.5
Appendix 5: Contraceptive Guidance................................................................81
10.5.1
Definitions....................................................................................................81
10.5.2
Contraceptive Requirements........................................................................82
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................83
10.7
Appendix 7: Country-specific Requirements....................................................84
10.8
Appendix 8: Abbreviations .................................................................................85
11
REFERENCES...............................................................................................................89
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LIST OF TABLES
Table 1
Ceftolozane Exposure and Target Attainment Summary for Simulated 
Adult and Pediatric Subjects with NP..............................................................30
Table 2
Tazobactam Exposure and Target Attainment Summary for Simulated 
Adult and Pediatric Subjects with NP..............................................................30
Table 3
Study Interventions..........................................................................................39
Table 4
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................52
Table 5
Analysis Strategy for Safety Parameters..........................................................60
Table 6
Protocol-required Safety Laboratory Assessments..........................................72
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LIST OF FIGURES
Figure 1
Study Design................................................................................................18
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1, open-label, non-comparative, multicenter clinical study to 
evaluate the safety, tolerability, and pharmacokinetics of ceftolozane/tazobactam 
(MK-7625A) in pediatric participants with nosocomial pneumonia
Short Title: Safety and pharmacokinetics of ceftolozane/tazobactam in pediatric participants 
with nosocomial pneumonia
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses to be tested in this study.
The following objectives and endpoints will be evaluated in hospitalized male and female 
pediatric participants from birth (>32 weeks gestational age and ≥7 days postnatal) to <18 
years of age with nosocomial pneumonia (NP).
Primary Objective
Primary Endpoint
•
To evaluate the safety and tolerability of 
ceftolozane/tazobactam for all 
participants
•
Adverse events (AEs), including any 
AEs, any serious AEs, any drug-related 
AEs and any serious drug-related AEs
•
AEs leading to discontinuation of study 
intervention
Secondary Objectives
Secondary Endpoints
•
To evaluate the pharmacokinetics (PK) 
of multiple doses of 
ceftolozane/tazobactam for each age 
group and/or dose level
•
Plasma concentrations at each time 
point for ceftolozane and tazobactam
•
Steady state plasma area under the 
concentration-time curve of an 8-hour 
dosing interval, maximum observed 
concentration during a dosage interval 
(Cmax), elimination half-life (t1/2), 
volume of distribution (Vd), and 
clearance (CL) for ceftolozane and 
tazobactam
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
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Indication
Nosocomial infection, Pneumonia
Population
Pediatric participants from birth (>32 weeks 
gestational age and ≥7 days postnatal) to 
<18 years of age
Study Type
Interventional
Intervention Model
Single Group
This is a multi site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 70 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent/assent until 
the last participant’s last study-related 
contact. For this study, the overall study 
ends when the last data are available to the 
Sponsor. 
Number of Participants:
Approximately 40 participants will be enrolled.
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Intervention Groups and Duration:
Arm 
Name
Intervention Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Use
Group 1 
(12 to <18 
years of 
age [n=>6]) Ceftolozane/ tazobactam
Ceftolozane 2 g 
and tazobactam 
1 g
Ceftolozane 
2 g and 
tazobactam 
1 g
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test 
Product
Group 2 (7 
to <12 
years of 
age [n=>6]) Ceftolozane/ tazobactam
Ceftolozane 2 g 
and tazobactam 
1 g
Ceftolozane 
40 mg/kg 
and 
tazobactam 
20 mg/kg
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test 
Product
Group 3 (2 
to <7 years 
of age 
[n=>6])
Ceftolozane/ tazobactam
Ceftolozane 2 g 
and tazobactam 
1 g
Ceftolozane 
40 mg/kg 
and 
tazobactam 
20 mg/kg
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test 
Product
Group 4 (3 
months to 
<2 years of 
age [n=>6]) Ceftolozane/ tazobactam
Ceftolozane 2 g 
and tazobactam 
1 g
Ceftolozane 
40 mg/kg 
and 
tazobactam 
20 mg/kg
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test 
Product
Group 5 
(birth [>32 
weeks 
gestational 
age and ≥7 
days 
postnatal] 
to <3 
months of 
age [n=>6]) Ceftolozane/ tazobactam
Ceftolozane 2 g 
and tazobactam 
1 g
Ceftolozane 
40 mg/kg 
and 
tazobactam 
20 mg/kg
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test 
Product
IV=intravenous; NP=nosocomial pneumonia; q8h=every 8 hours. The proposed initial doses may be modified based on interim data as 
described in Section 6.6. Single IV doses for all cohorts will not exceed the adult maximum dose of 3 g (2 g ceftolozane and 1 g 
tazobactam) for NP.
Other current or former name(s) or alias(es) for study intervention(s) are as follows:
ZERBAXA®, MK-7625A, CXA-201, CXA-101/tazobactam.
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Total Number of Intervention Groups/Arms
1 intervention with different doses across 5 
age groups.
Duration of Participation
Each participant will participate in the study 
for approximately 30 days from the time the 
participant provides documented informed 
consent through the final contact. After a 
screening phase of up to 2 days, each 
participant will receive assigned 
intervention for approximately 8 to 14 days. 
After the end of treatment, each participant 
will be followed for 14 days.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Steering Committee
No
There are no governance committees in this study.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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1.3
Schedule of Activities
Study Period
Screening
Intervention
Follow-up
Notes
Visit Number/Title
1
Screening
2
Allocation
3
4
PK Visit
5-15
16
EOT Visit
17
LFU Visit
Visits 1 and 2 can be on 
the same day. Visit 17 
can be by telephone; in-
person visit required for 
AE or abnormal 
laboratory follow-up.
Scheduled Day:
≤48 hours 
prior to first 
dose of 
ceftolozane/ 
tazobactam
Day 1
Day 2
Day 3
Day 
4-14
≤48 hours 
after last 
dose of 
ceftolozane/ 
tazobactam
14 days after 
last dose of 
ceftolozane/ 
tazobactam
Scheduled Window:
--
--
--
+2 days
--
--
+3 days
Administrative Procedures
Informed Consent/Assent
X
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
X
Medical History 
X
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
Study Intervention Allocation
X
Ceftolozane/tazobactam 
should be initiated as 
soon as possible and 
within 24 hours of 
allocation.
Administration of 
Ceftolozane/tazobactam IV q8h
X
X
X
X
Each participant is 
anticipated to receive 
ceftolozane/tazobactam 
for 8-14 days.
Administration of Concomitant 
Standard-of-Care Antibiotics for NP 
X
X
X
X
X
X
Standard-of-care
antibiotic administration 
as applicable (may or 
may not be ongoing at 
screening and/or after 
stopping ceftolozane/
tazobactam).
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Study Period
Screening
Intervention
Follow-up
Notes
Visit Number/Title
1
Screening
2
Allocation
3
4
PK Visit
5-15
16
EOT Visit
17
LFU Visit
Visits 1 and 2 can be on 
the same day. Visit 17 
can be by telephone; in-
person visit required for 
AE or abnormal 
laboratory follow-up.
Scheduled Day:
≤48 hours 
prior to first 
dose of 
ceftolozane/ 
tazobactam
Day 1
Day 2
Day 3
Day 
4-14
≤48 hours 
after last 
dose of 
ceftolozane/ 
tazobactam
14 days after 
last dose of 
ceftolozane/ 
tazobactam
Scheduled Window:
--
--
--
+2 days
--
--
+3 days
Safety Procedures
Full Physical Examination 
X
Height
X
Weight
X
Directed Physical Examination
X
X
X
X
X
Can also be performed 
whenever medically 
necessary.
Vital Signs 
X
X
X
X
X
X
Heart rate, blood 
pressure, respiratory 
rate, and temperature. If 
Visit 1 and 2 occur on 
the same day, does not 
need to be performed 
twice.
Urine or Serum Pregnancy Test 
(WOCBP only)
X
X
Collect per local 
guidance.
Blood for Hematology and Chemistry 
Safety Evaluations
X
X
X
X
X
X
X
Required for Visits 1, 4, 
and 16. Only collect if 
clinically indicated at 
Visits 2, 3, 5-15, and 17.  
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Study Period
Screening
Intervention
Follow-up
Notes
Visit Number/Title
1
Screening
2
Allocation
3
4
PK Visit
5-15
16
EOT Visit
17
LFU Visit
Visits 1 and 2 can be on 
the same day. Visit 17 
can be by telephone; in-
person visit required for 
AE or abnormal 
laboratory follow-up.
Scheduled Day:
≤48 hours 
prior to first 
dose of 
ceftolozane/ 
tazobactam
Day 1
Day 2
Day 3
Day 
4-14
≤48 hours 
after last 
dose of 
ceftolozane/ 
tazobactam
14 days after 
last dose of 
ceftolozane/ 
tazobactam
Scheduled Window:
--
--
--
+2 days
--
--
+3 days
Assessment of CrCL
X
X
X
X
X
X
X
Required for Visit 1 and 
only if clinically 
indicated at all other 
visits. See Section 
8.3.3.1.
AE/SAE Monitoring
X
X
X
X
X
X
Pharmacokinetics 
Plasma PK Sampling
X
Number of samples and 
timing is described in 
Section 8.6.1.
AE=adverse event; CrCL=creatinine clearance; EOT=end of treatment; IV=intravenous; LFU=last follow-up; NP=nosocomial pneumonia; PK=pharmacokinetics; 
q8h=every 8 hours; SAE=serious adverse event; WOCBP=woman/women of childbearing potential.
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2
INTRODUCTION
Ceftolozane/tazobactam (ZERBAXA®, MK-7625A) is a fixed-dose combination of the 
antipseudomonal cephalosporin, ceftolozane, and the BLI, tazobactam, being evaluated for 
treatment of gram-negative infections, including NP in pediatric participants.
2.1
Study Rationale
The treatment of gram-negative infections is complicated by growing rates of antibiotic 
resistance [Nicasio, A. M., et al 2008] [Talbot, G. H. 2008]. Of the more than 2 million 
nosocomial infections occurring annually in the US, 50% to 60% are caused by antibiotic 
resistant strains. Multidrug resistance is increasing among common gram-negative bacteria 
such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. New 
antibiotics with improved activity against these organisms are needed.  
Ceftolozane/tazobactam is approved for use in adults and pediatric patients with cUTI, 
including pyelonephritis, and cIAI (in combination with metronidazole) [U.S. Prescribing 
Information 2022] in adults with NP.
The prevalence of antibiotic resistant gram-negative infections among children is increasing, 
particularly involving P. aeruginosa and Enterobacteriaceae [Medernach, R. L. 2018], which
are frequent causes of NP [Lake, J. G., et al 2018] [Carvalhaes, C. G., et al 2018]. Patients 
with NP caused by antibiotic resistant organisms have prolonged hospitalizations and worse 
outcomes, particularly among vulnerable pediatric patients with immature immune systems 
[Lake, J. G., et al 2018] [Gallagher, J. C., et al 2018]. Thus, an unmet medical need exists for 
treatment of resistant, gram-negative infections in children with NP.
This study is being conducted to evaluate the safety and tolerability and the PK of 
ceftolozane and tazobactam after administration of ceftolozane/tazobactam in pediatric 
participants with NP.
2.2
Background
Refer to the IB/approved labeling for detailed background information on 
ceftolozane/tazobactam.
2.2.1
Pharmaceutical and Therapeutic Background
Ceftolozane/Tazobactam
Ceftolozane is a member of the cephalosporin class of antibiotics, which is well characterized 
in terms of safety, efficacy, and general antimicrobial profile. Ceftolozane is structurally 
similar to ceftazidime, but is less affected by common bacterial resistance mechanisms (ie, 
porin loss, hydrolysis by AmpC β-lactamases) [Duin, D. V. 2016]. While ceftolozane alone 
represents an important therapeutic option for the treatment of infections caused by P. 
aeruginosa, the efficacy of ceftolozane for the treatment of suspected gram-negative 
infections could be compromised by the spread of ESBL-producing bacteria. The addition of 
tazobactam improves the coverage of ceftolozane against select ESBL-producing 
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Enterobacteriaceae [Duin, D. V. 2016]. Combining ceftolozane with a BLI such as 
tazobactam broadens its in vitro spectrum of activity to include many drug-resistant 
Enterobacteriaceae and is, thereby, likely to improve its clinical utility as a therapy for 
serious bacterial infections caused by resistant gram-negative bacteria.
Nosocomial Pneumonia
Nosocomial pneumonia, including HABP and VABP, is one of the most frequent 
complications of hospital care and is associated with high cost, morbidity, and mortality 
[Kalil, A. C., et al 2016]. The US FDA guidance defines HABP as an acute infection of the 
pulmonary parenchyma that is associated with clinical signs and symptoms such as fever or 
hypothermia, chills, rigors, cough, purulent sputum production, chest pain, or dyspnea, 
accompanied by the presence of a new or progressive infiltrate on a chest radiograph in a 
patient hospitalized for >48 hours or developing within 7 days after discharge from a hospital
[Center for Drug Evaluation and Research 2014]. Similarly, VABP is defined as an acute 
infection of the pulmonary parenchyma that is associated with clinical signs and symptoms 
such as fever or hypothermia, chills, rigors, purulent respiratory secretions, and increased 
oxygen requirements accompanied by the presence of a new or progressive infiltrate on a 
chest radiograph in a patient receiving mechanical ventilation via an endotracheal or 
nasotracheal tube for >48 hours [Center for Drug Evaluation and Research 2014].
In comparison, the diagnostic criteria and clinical manifestations of NP in neonates, infants, 
and children varies considerably due to multiple factors such as distinctive underlying 
comorbidities, microbiology, risk factors, and outcomes of NP among different pediatric age 
groups and adults [Bradley, J. S. 2010]. However, the resource expenditure and associated 
adverse outcomes with pediatric NP remain high, particularly among those children with 
VABP, who are almost 3 times more likely to die in comparison to mechanically ventilated 
children without VABP [Bradley, J. S. 2010] [Gupta, S., et al 2015].
Aside from Staphylococcus aureus, the most common pathogens responsible for pediatric NP 
are P. aeruginosa and Enterobacteriaceae [Lake, J. G., et al 2018]. Antibacterial resistance 
among these organisms is becoming increasingly common in children, and results in serious 
consequences such as prolonged length of hospital stay and higher morbidity/mortality 
[Medernach, R. L. 2018] [Logan, L. K., et al 2017] [Kehl, S. C. 2015] [Lake, J. G., et al 
2018]. Therefore, there is an unmet medical need for treatment of antibacterial-resistant 
gram-negative infections in children with NP.
2.2.2
Preclinical and Clinical Studies
The safety and efficacy of ceftolozane/tazobactam was demonstrated in adult Phase 3 and 
cUTI, cIAI, and NP studies. In addition, the safety and efficacy of ceftolozane/tazobactam 
has also been demonstrated in pediatric studies of cUTI and cIAI, where 
ceftolozane/tazobactam was well tolerated with a safety profile consistent with the known 
safety profile of ceftolozane/tazobactam in adults. 
The safety and efficacy of ceftolozane/tazobactam for use in adults with NP (including 
VABP and HABP) are derived from a large, multinational, multicenter, randomized, double-
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blind, active comparator-controlled Phase 3 study (MK-7625A-008) (ClinicalTrials.gov 
Identifier: NCT02070757). Ceftolozane/tazobactam 3 g (2 g ceftolozane and 1 g 
tazobactam), which is 2 times the dose used for cUTI or cIAI, administered q8h as an IV 
infusion (60 ±10 minutes) for up to 14 days demonstrated noninferiority versus meropenem 
based on the treatment difference in Day 28 all-cause mortality rate and clinical cure rate at 
the test-of-cure visit. Ceftolozane/tazobactam was generally well tolerated in this critically ill 
population with no notable or unexpected safety signals that would preclude its general use in 
adults with NP. The doses for the present study were selected to match adult exposures in NP 
and do not exceed the adult dose.
The toxicological profile of ceftolozane, both alone and in combination with tazobactam, has 
been well characterized in a comprehensive series of nonclinical studies (both in vitro and in 
vivo safety and efficacy studies) and supports the continued clinical investigation of NP in 
the pediatric population.
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.
This study will include hospitalized pediatric participants who require antibiotic therapy for 
NP due to either gram-positive or gram-negative pathogens. Participants will receive an 
antibiotic regimen that is active against gram-negative pathogens frequently isolated from 
pediatric patients with NP and that has proven to be effective in a large-scale clinical study 
for the treatment of NP in adults (Section 2.2). While no obvious benefit may be derived 
from participation in the study, those participants receiving narrow-spectrum antibiotics may 
potentially benefit from additional broad-spectrum gram-negative coverage.
Although study procedures may potentially occur more frequently than the standard-of-care, 
the planned study procedures are generally typical procedures performed for this patient 
population. Study procedures, including the number of blood draws for PK sampling, are 
limited to minimize risk. Additional burden may be incurred due to visits after release from 
the hospital; however, the procedures performed at these visits will not likely lead to 
significant harm (eg, blood draws, physical examinations, and vital signs) and are necessary 
to support a robust evaluation of the safety of the study intervention
In vitro synergy studies with ceftolozane/tazobactam demonstrated no antagonism with a 
variety of other classes of antibiotics; thus, ceftolozane/tazobactam is not expected to 
interfere with the PK or safety of other standard-of-care antibiotics. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the IB and informed consent/assent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses to be tested in this study.
The following objectives and endpoints will be evaluated in hospitalized male and female 
pediatric participants from birth (>32 weeks gestational age and ≥7 days postnatal) to <18 
years of age with nosocomial pneumonia (NP).
Primary Objective
Primary Endpoint
•
To evaluate the safety and tolerability of 
ceftolozane/tazobactam for all 
participants
•
Adverse events (AEs), including any 
AEs, any serious AEs, any drug-related 
AEs and any serious drug-related AEs
•
AEs leading to discontinuation of study 
intervention
Secondary Objectives
Secondary Endpoints
•
To evaluate the pharmacokinetics (PK) 
of multiple doses of 
ceftolozane/tazobactam for each age 
group and/or dose level
•
Plasma concentrations at each time 
point for ceftolozane and tazobactam
•
Steady state plasma area under the 
concentration-time curve of an 8-hour 
dosing interval, maximum observed 
concentration during a dosage interval 
(Cmax), elimination half-life (t1/2), 
volume of distribution (Vd), and 
clearance (CL) for ceftolozane and 
tazobactam
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 1, open-label, non-comparative, multicenter clinical study of 
ceftolozane/tazobactam in hospitalized pediatric participants (ages from birth to <18 years) 
receiving concomitant standard-of-care antibiotics for NP (including VABP and HABP).  
Approximately 40 participants will be enrolled into 5 age groups (12 to <18 years, 7 to 
<12 years, 2 to <7 years, 3 months to <2 years, and birth [>32 weeks gestational age and 
≥7 days postnatal] to <3 months). Enrollment to all groups will open in parallel (see 
Section 4.2). After a minimum enrollment target of 6 participants for each age group is met, 
at least 10 additional participants will be enrolled across any of the 5 age groups. No more 
than 4 additional participants (for a total of 10 participants in any given age group) will be 
enrolled in any given age group. Proposed initial doses of ceftolozane/tazobactam for each 
age group were selected based on PK modeling and simulation analyses (see Section 4.3.1).  
After the first 3 participants are enrolled into a given age group, enrollment will be paused in 
that age group for an interim PK analysis to confirm or modify the proposed pediatric dose 
for the remaining participants in that group and/or other age groups. Enrollment will continue 
in the other age groups during each interim PK analysis. The proposed initial pediatric doses 
may be modified based on whether the dose evaluated in the interim PK analysis 
demonstrates an acceptable safety profile in the exposed age group and is suitable based on 
adequate PK plasma exposures (see Section 9.7). PK samples will be collected in all pediatric 
participants according to the sampling scheme in Section 8.6.1. After the first 3 participants 
have been enrolled into a given age group, at least 3 additional participants will be enrolled
in that age group after the interim PK analysis.
Each participant will participate in the study for approximately 30 days from the time the 
participant provides documented informed consent through the final contact. After a 
screening phase of up to 2 days, each participant will receive ceftolozane/tazobactam 
administered as a 60-minute IV infusion (±10 minutes) q8h as add-on therapy in addition to a 
concomitant standard-of-care antibiotic regimen. The diagnosis of NP does not require a 
pathogen to be isolated from a diagnostic test and will be based on the judgment of the 
investigator.  
The duration of ceftolozane/tazobactam administration will be a minimum of 8 days and up 
to a maximum of 14 days to match the treatment duration in the adult NP study 
(MK-7625A 008) (see Section 4.3.4). Participants who discontinue or complete concomitant 
standard-of-care antibiotic therapy in less than 8 days may also discontinue 
ceftolozane/tazobactam before the minimum duration of 8 days at the investigator’s 
discretion. However, participants are strongly encouraged to receive a minimum of 8 days of 
ceftolozane/tazobactam. Participants must remain in the hospital for the duration of the 
intervention period; outpatient therapy is not permitted. After the end-of-study treatment, 
each participant will be followed for 14 days.
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Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is designed to assess the safety and PK of ceftolozane/tazobactam in pediatric 
participants with NP. The PK of a drug in the pediatric population usually cannot be 
precisely predicted from that in adults, and safety must also be evaluated. Therefore, safety 
and PK studies are needed to identify safe and appropriate pediatric doses.  
The proposed initial pediatric doses of ceftolozane/tazobactam were chosen based on a 
pediatric population PK approach leveraging Phase 1 pediatric PK data and PK models in 
adults. As ceftolozane/tazobactam is primarily renally eliminated, the proposed initial doses 
for each age group were based on renal function and body weight. Participants will be 
enrolled into 1 of 5 age groups, which were chosen to ensure that adequate safety and PK 
data would be available for participants at each stage of pediatric development and for 
consistency with the pediatric cUTI and cIAI studies of ceftolozane/tazobactam. The age 
groups in the present study are based on the age groups assessed in MK-7625A-010. 
Parallel enrollment of all age groups is considered appropriate as ceftolozane/tazobactam was 
well tolerated in the Phase 1 single-dose PK and safety study of pediatric participants with 
proven or suspected gram-negative infection (MK-7625A-010). As ceftolozane/tazobactam, 
much like other β-lactam antibiotics, has a well-defined safety profile with robust 
PK modeling, the simultaneous enrollment of all age groups will help to mitigate delays
often encountered when stepwise enrollment (ie, older children first, then younger children) 
is implemented.
No efficacy endpoints are evaluated in this study, as efficacy will be extrapolated from adults 
to the pediatric population using population PK modeling.
4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
The safety and tolerability of ceftolozane/tazobactam in pediatric participants will be 
assessed by a clinical evaluation of AEs (any AEs, any SAEs, any drug-related AEs, any 
serious and drug-related AEs, and AEs leading to discontinuation of study intervention) and 
inspection of other study parameters including clinical laboratory tests and vital signs 
measurements at appropriate time points as specified in the SoA. AEs are assessed and 
recorded according to Section 10.3. Participants may be asked to return for unscheduled 
visits to perform additional safety monitoring.
4.2.1.2
Pharmacokinetic Endpoints
Whole blood samples will be collected at the time points specified in Section 8.6.1 for 
determination of plasma concentrations of ceftolozane and tazobactam. Plasma 
concentrations of ceftolozane and tazobactam at each time point will be summarized. In 
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addition, plasma concentrations of ceftolozane and tazobactam will be used to update 
pediatric population PK models on completion of this study using the existing pediatric PK 
models as a starting point. The updated pediatric population PK models will be used to 
characterize plasma PK of both drugs. Primary plasma PK parameters for ceftolozane and
tazobactam, such as steady state plasma AUC0-8, Cmax, t1/2, Vd, and CL, will be estimated 
through population PK modeling and provided in a separate population PK modeling report. 
Additional steady state plasma PK parameters may also be estimated, as appropriate, through 
modeling and provided in the same population PK modeling report.
4.2.2
Rationale for Sample Size
The cumulative sample size of 40 participants for this study is based on obtaining sufficient 
data to evaluate the safety and PK of ceftolozane/tazobactam in pediatric participants, in 
addition to feasibility considerations. This study is not powered to test formal hypotheses. 
See Section 9.9 for additional details.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
The recommended dosing regimen for adult patients with NP is 3 g ceftolozane/tazobactam 
(2 g ceftolozane and 1 g tazobactam or adjusted based on renal function) administered as a 
60-minute (±10 minutes) IV infusion q8h. This dose is 2 times the dose recommended for 
adult patients with cUTI or cIAI. The NP dose of 3 g was chosen, in part, based on the lung 
penetration data obtained in healthy adult subjects receiving a 1.5 g dose administered as a 
60-minute IV infusion q8h, which showed approximately 50% to 60% penetration into lung 
relative to plasma exposure for both ceftolozane and tazobactam, suggesting that doubling 
the dose would result in lung exposures needed to achieve ceftolozane and tazobactam 
PK/PD targets at the site of infection [Xiao, A. J., et al 2016]. The 3 g dose was tested in a 
large Phase 3 study in adult participants with NP (MK-7625A-008) and is supported by the 
favorable efficacy and safety profiles in NP participants, as well as attainment of >90% PTA 
in lung, the site of action, using Monte Carlo simulations. 
The proposed ceftolozane/tazobactam pediatric doses for participants with NP were projected 
using a similar modeling approach as described above. Pediatric population PK models for 
ceftolozane and tazobactam were developed using PK data from the Phase 1 PK study in 
pediatric participants (MK-7625A-010) informed by the adult NP models, including the 
effect of NP on ceftolozane and tazobactam PK. As in adults, renal function was a covariate 
on CL and body weight was a covariate on Vc and Vp for ceftolozane and tazobactam. 
Model fit for both drugs was improved by inclusion of allometric scaling on CL.  
The final PK models for ceftolozane and tazobactam were used to simulate plasma and lung 
ELF concentration-time profiles in pediatric subjects with NP. To provide a benchmark for 
evaluating the safety of ceftolozane and tazobactam in simulated pediatric subjects, steady 
state plasma AUC0-8 and Cmax were simulated. For ensuring efficacy of the doses, PTA 
simulations were conducted. The PK targets for the selected pediatric doses were assumed to 
be the same as those for adults, which are 30% fT>MIC of 4 μg/mL for ceftolozane and 20% 
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fT>Ct of 1 μg/mL for tazobactam because the pathogenesis and microbiology of NP are 
similar in adult and pediatric populations. Using these PK/PD targets, steady state plasma 
and lung PTA for adult subjects with NP and 5 pediatric age groups was evaluated for 
ceftolozane and tazobactam.  
The criteria for evaluating the appropriateness of the proposed initial doses included the 
following:
•
Projected distributions of pediatric plasma exposures of ceftolozane and tazobactam (ie, 
steady state plasma AUC0-8 and Cmax) comparable to the corresponding projected 
distributions of exposures in adult patients with NP. 
•
Steady state ceftolozane lung PTA >90% at the tazobactam-potentiated ceftolozane MIC 
of 4 μg/mL and steady state tazobactam lung PTA >90% at the threshold concentration of 
1 μg/mL.
Based on plasma exposure and PTA criteria described above, simulations in pediatric 
subjects indicated that the following doses are appropriate for evaluation in the current study:
•
12 to <18 years of age: ceftolozane 2 g with tazobactam 1 g via a 60-minute (±10 
minutes) IV infusion q8h
•
<12 years of age: ceftolozane 40 mg/kg with tazobactam 20 mg/kg via a 60-minute (±10 
minutes) IV infusion q8h (not to exceed a dose of ceftolozane 2 g and tazobactam 1 g)
Like the adult NP 3 g dose, these doses for pediatric subjects with NP are 2 times the doses 
that were evaluated in pediatric participants with cUTI and cIAI in the MK-7625A-034 and 
MK-7625A-035 studies. Per age group plasma ceftolozane and tazobactam exposures and 
lung ELF PTA for adult and pediatric subjects are summarized in Table 1 and Table 2, 
respectively. As shown in these tables, the selected doses provide exposures for the age 
groups that are constrained within the corresponding adult steady state AUC0-8 and Cmax
ranges and achieve PTAs >90%.  
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Table 1
Ceftolozane Exposure and Target Attainment Summary for Simulated Adult 
and Pediatric Subjects with NP
Adult NP 
Subjects
(n=1000)
Pediatric Age Groupa,b
1
(n=1000)
2
(n=1000)
3
(n=1000)
4
(n=1000)
5
(n=1200)
Dose
2 g
q8h
2 g
q8h
40 mg/kg
q8h
40 mg/kg
q8h
40 mg/kg
q8h
40 mg/kg
q8h
Ceftolozane Exposure
Steady state
AUC0-8
(µg×h/mL)
5th, 95th
165, 787
173, 661
172, 713
163, 570
154, 565
204, 827
Steady state
Cmax
(µg /mL)
5th, 95th
51.2, 202
65.3, 187
78.7, 180
74.6, 162
71.7, 145
77.4, 164
ELF Target 
attainment
N
(%)
995 
(99.5)
1000
(100.0)
999
(99.9)
1000 
(100.0)
999
(99.9)
1200 
(100.0)
5th, 95th=5th, 95th percentiles; AUC0-8=steady state plasma area under the concentration-time curve of an 8-hour dosing interval; 
Cmax=maximum observed concentration during a dosage interval; eGFR=estimated glomerular filtration rate; ELF= epithelial lining 
fluid; h=hours; N=number of subjects achieving target attainment; n=number of subjects; NP=nosocomial pneumonia; q8h=every 8 
hours.
a Age Group 1, 12 years ≤ age <18 years; Age Group 2, 7 years ≤ age < 12 years; Age Group 3, 2 years ≤ age <7 years; Age Group 4, 
3 months ≤age <2 years; Age Group 5, >32 gestational week age, 7 days postnatal ≤ age <3 months.
b eGFR ≥ 20 mL/min/1.73 m2
Table 2
Tazobactam Exposure and Target Attainment Summary for Simulated Adult 
and Pediatric Subjects with NP
Adult NP 
Subjects
(n=1000)
Pediatric Age Groupa,b
1
(n=1000)
2
(n=1000)
3
(n=1000)
4
(n=1000)
5
(n=1200)
Dose
1 g
q8h
1 g
q8h
20 mg/kg
q8h
20 mg/kg
q8h
20 mg/kg
q8h
20 mg/kg
q8h
Tazobactam Exposure
Steady state
AUC0-8
(µg×h/mL)
5th, 95th
21.9, 172
23.3, 111
25.7, 123
24.8, 107
24.3, 116
35.7, 175
Steady state
Cmax
(µg /mL)
5th, 95th
12.9, 47.0
14.7, 51.9
21.2, 53.4
20.4, 50.8
19.5, 46.7
21.5, 47.4
ELF Target 
attainment
N
(%)
995 
(99.5)
982 
(98.2)
987 
(98.7)
981 
(98.1)
983 
(98.3)
1197 
(99.8)
5th, 95th=5th, 95th percentiles; AUC0-8=steady state plasma area under the concentration-time curve of an 8-hour 
dosing interval; Cmax=maximum observed concentration during a dosage interval; eGFR=estimated glomerular filtration 
rate; ELF= epithelial lining fluid; h=hours; N=number of subjects achieving target attainment; n=number of subjects; 
NP=nosocomial pneumonia; q8h=every 8 hours.
a Age Group 1, 12 years ≤ age <18 years; Age Group 2, 7 years ≤ age < 12 years; Age Group 3, 2 years ≤ age <7 years; 
Age Group 4, 3 months ≤ age <2 years; Age Group 5, >32 gestational week age, 7 days postnatal ≤ age <3 months.
b eGFR ≥ 20 mL/min/1.73 m2
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4.3.2
Maximum Dose Exposure for This Study
The maximum dose for this study will be 3 g ceftolozane/tazobactam administered as a 
60-minute ±10 minutes IV infusion q8h for up to 14 days, which was the dose and duration 
that was evaluated in adults with NP (MK-7625A-008).
4.3.3
Rationale for Dose Interval and Study Design
A dosing interval of q8h was chosen to be consistent with the proposed 8-hour dosing 
interval for pediatric participants with cUTI and cIAI and is supported by model-projected 
exposures of ceftolozane and tazobactam that meet their respective PK targets during the 
proposed dosing interval.
4.3.4
Rationale for Treatment Duration
For all participants, the duration of ceftolozane/tazobactam administration will be a minimum 
of 8 days and up to a maximum of 14 days. The standard treatment duration for NP is 
variable, with no clear consensus; treatment durations ranging from 8 to 15 days have been 
evaluated with similar mortality rates, although shorter durations are often recommended 
[Kalil, A. C., et al 2016] [Foglia, E., et al 2007]. Therefore, the ceftolozane/tazobactam 
treatment duration of 8 to 14 days is consistent with the standard-of-care for treatment of 
pediatric NP and was selected to evaluate safety at the duration used to treat this patient 
population. In addition, this treatment duration is consistent with the adult NP study 
(MK-7625A-008). 
Likewise, participants are anticipated to receive a minimum of 8 days of concomitant 
standard-of-care antibiotic therapy; however, concomitant standard-of-care antibiotics may 
be stopped before the 8-day minimum at the discretion of the investigator. Participants who 
discontinue or complete concomitant standard-of-care antibiotic therapy in less than 8 days 
may also discontinue ceftolozane/tazobactam prior to the minimum duration of 8 days at the 
investigator’s discretion. However, participants are strongly encouraged to receive a 
minimum of 8 days of ceftolozane/tazobactam.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent/assent. The overall study ends when the last 
participant completes the last study-related contact, withdraws consent/assent, or is lost to 
follow-up (ie, the participant is unable to be contacted by the investigator). For purposes of 
analysis and reporting, the overall study ends when the Sponsor receives the last laboratory 
result or at the time of final contact with the last participant, whichever comes last. For this 
study, this corresponds to when the last data are available to the Sponsor.  
For studies conducted in the European Economic Area (EEA), the local start of the study is 
defined as First Site Ready (FSR) in any Member State.
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4.4.1
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.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1) this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Male and female pediatric participants from birth (>32 weeks gestational age and ≥7 days 
postnatal) to <18 years of age with NP 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.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
Type of Participant and Disease Characteristics
1. Has a diagnosis of proven or suspected NP (including HABP or VABP), as determined 
by the investigator.
Note:  The diagnosis of NP does not require a pathogen to be isolated from a 
diagnostic test. 
2. Is hospitalized and anticipated to receive a minimum of 8 days of concomitant standard 
of-care antibiotic therapy for proven or suspected NP. The concomitant standard-of-care 
antibiotic therapy can have coverage for either gram-positive and/or gram-negative 
respiratory pathogen(s).
Note:  Concomitant standard-of-care antibiotics may be stopped before the 8-day 
minimum at the discretion of the investigator. Participants who discontinue or 
complete concomitant standard-of-care antibiotic therapy in less than 8 days may also 
discontinue ceftolozane/tazobactam prior to the minimum duration of 8 days at the 
investigator’s discretion. However, participants are strongly encouraged to receive a 
minimum of 8 days of ceftolozane/tazobactam.  
Demographics
3. Is male or female (not pregnant or nursing) from birth (defined as >32 weeks gestational
age and ≥7 days postnatal) to <18 years of age inclusive, at the time of providing
informed consent/assent.
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Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 30 days after the last dose of study intervention:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause) (Appendix 5) as detailed below:

Agree to 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. 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-vaginal penetration.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
•
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
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 (urine or serum 
as required by local regulations) within 48 hours before the first dose of study 
intervention.

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
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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.
Informed Consent/Assent
4. The participant (or legally acceptable representative(s), if applicable) provides 
documented informed consent/assent for the study.
Additional Categories
5. Is able to comply with all study procedures and restrictions for the duration of the study.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has a documented history of any moderate or severe hypersensitivity (or allergic) 
reaction to any β-lactam antibacterial. 
Note: A history of a rash while on a β-lactam antibiotic does not automatically exclude a 
participant (eg, a participant with history of a mild rash followed by uneventful re-
exposure may be considered for enrollment).
2. For Groups 1 through 4, has moderate to severe impairment of renal function, defined as 
an estimated CrCL <50 mL/min/1.73 m2 based on the revised Schwartz equation or 
requirement for peritoneal dialysis, hemodialysis, or hemofiltration.
For Group 5, has CrCL <20 mL/min/1.73 m2 based on the revised Schwartz equation or 
requirement for peritoneal dialysis, hemodialysis, or hemofiltration.
Prior/Concomitant Therapy
3. Is receiving or is anticipated to receive piperacillin/tazobactam while receiving 
ceftolozane/tazobactam or has received piperacillin/tazobactam within 24 hours prior to 
the first dose of ceftolozane/tazobactam.
Prior/Concurrent Clinical Study Experience
4. Participation in any clinical study of a therapeutic investigational product within 30 days 
prior to the first dose of ceftolozane/tazobactam.
5. Previous participation in any study of ceftolozane or ceftolozane/tazobactam.
Diagnostic Assessments
Not applicable.
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Other Exclusions
6. Has one or more of the following laboratory abnormalities in a specimen obtained at 
screening:
•
ANC <1000/mm3
•
AST or ALT ≥3 × the ULN
•
Total bilirubin ≥2 × the ULN (if 7 to ≤28 days of age and breastfeeding, total 
bilirubin >10 mg/dL OR ≥2 × ULN). 
7. Any condition or circumstance that, in the opinion of the investigator, would compromise 
the safety of the participant or the quality of study data.
8. Has any rapidly progressing disease or immediately life-threatening illness including 
acute hepatic failure or septic shock.
9. Has active immunosuppression, including any of the following:
•
HIV infection, with a known CD4 percentage of <15% in pediatric participants ≤5 
years of age, or CD4 count of <200 cells/mm3 in pediatric participants >5 years of 
age 
•
active hematological malignancy 
•
recipient of solid organ or bone marrow transplants
•
currently on immunosuppressive therapy, including cancer chemotherapy 
•
currently on medications for prevention of transplant rejection 
•
chronic administration of systemic corticosteroids (defined as the systemic equivalent 
of ≥2 mg/kg total daily dose of prednisone for participants ≤20 kg, or >40 mg of 
prednisone per day for participants >20 kg, administered continuously for more than 
14 days in the 30 days prior to the first dose of ceftolozane/tazobactam).
10. 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
No restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently entered in the study. A minimal set of screen-failure 
information is required to ensure transparent reporting of screen-failure participants to meet 
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen-failure details, eligibility 
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criteria, and any AEs or SAEs meeting reporting requirements as outlined in the data entry 
guidelines.
5.5
Participant Replacement Strategy
Replacement participants will be assigned a unique allocation number. The participant 
replacement strategy is as follows:
•
If a participant withdraws from the study prior to receiving any study treatment (ie,
participant enrolled, not treated), a replacement participant will be enrolled.  
•
If a participant discontinues from ceftolozane/tazobactam OR withdraws from the 
study prior to the PK collection, a replacement participant may be enrolled if deemed 
appropriate by the Sponsor based on the number of other participants in that age 
group meeting the PK and safety interim analysis criteria (see Section 9.7).
•
If a participant discontinues from ceftolozane/tazobactam OR withdraws from the 
study after PK collection after having received 6 doses of ceftolozane/tazobactam, a 
replacement participant may be enrolled if deemed appropriate by the Sponsor based 
on the average treatment duration of ceftolozane/tazobactam among all participants 
enrolled in the study.
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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 of ceftolozane/tazobactam will either be provided centrally by the Sponsor 
or sourced locally. When provided centrally by the Sponsor, clinical supplies will be 
packaged to support enrollment and replacement participants as required. When a 
replacement participant is required, the Sponsor or designee needs to be contacted prior to 
dosing the replacement supplies. Ceftolozane/tazobactam will be distributed using an IVRS. 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Clinical supplies sourced locally will be distributed and labeled in accordance 
with local regulatory requirements. 
6.1
Study Intervention(s) Administered
The ceftolozane/tazobactam to be used in this study is outlined in Table 3. 
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Table 3
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Test 
Product/ 
Comparator
IMP 
or 
NIMP/
AxMP
Sourcing
Group 1 (12 to 
<18 years of age 
[n=>6])
Experimental Ceftolozane/ 
tazobactam
Drug
Powder
Ceftolozane 
2 g and 
tazobactam 
1 g
Ceftolozane 
2 g and 
tazobactam 
1 g
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test Product
IMP
Centrally 
or locally 
Group 2 (7 to 
<12 years of age 
[n=>6])
Experimental Ceftolozane/ 
tazobactam
Drug
Powder
Ceftolozane 
2 g and 
tazobactam 
1 g
Ceftolozane 
40 mg/kg 
and 
tazobactam 
20 mg/kg
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test Product
IMP
Centrally 
or locally
Group 3 (2 to <7 
years of age 
[n=>6])
Experimental Ceftolozane/ 
tazobactam
Drug
Powder
Ceftolozane 
2 g and 
tazobactam 
1 g
Ceftolozane 
40 mg/kg 
and 
tazobactam 
20 mg/kg
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test Product
IMP
Centrally 
or locally
Group 4 (3 
months to <2 
years of age 
[n=>6])
Experimental Ceftolozane/ 
tazobactam
Drug
Powder
Ceftolozane 
2 g and 
tazobactam 
1 g
Ceftolozane 
40 mg/kg 
and 
tazobactam 
20 mg/kg
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test Product
IMP
Centrally 
or locally
Group 5 (birth 
[>32 weeks 
gestational age 
and ≥7 days 
postnatal] to <3 
months of age 
[n=>6])
Experimental Ceftolozane/ 
tazobactam
Drug
Powder
Ceftolozane 
2 g and 
tazobactam 
1 g
Ceftolozane 
40 mg/kg 
and 
tazobactam 
20 mg/kg
IV Infusion
60-minute IV 
infusion (±10 
minutes) q8h 
for 8-14 days
Test Product
IMP
Centrally 
or locally
EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational/auxiliary medicinal product; NP=nosocomial pneumonia; q8h=every 8 
hours.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
The proposed initial doses may be modified based on interim data as described in Section 6.6 and Section 9.7. Single IV doses for all cohorts will not exceed the adult maximum dose of 3 g (2 g 
ceftolozane and 1 g tazobactam) for NP.
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All supplies indicated in Table 3 will be provided per the “Sourcing” column depending on 
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.
The same formulation and concentration of ceftolozane/tazobactam as is used for adults will 
be used in pediatric participants, whereby the dose will be determined by the volume of 
product administered rather than reformulating the product at a decreased dose.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Refer to the Pharmacy Manual for step-by step directions for ceftolozane/tazobactam dosing 
calculations and preparation.
The rationale for selection of doses to be used in this study is provided in Section 4.3.
6.2.2
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
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
6.3.2
Stratification
The design of this study is a single arm intervention with age cohorts. A stratification will be 
applied prior to allocation to a dose level based on the age cohort. Study intervention
allocation will be distributed across 5 age groups as defined in Section 4.1. After the 
minimum enrollment target of 6 participants for each age group are met, at least 10 additional 
participants will be enrolled across any of the 5 age groups. No more than 4 additional 
participants (for a total of 10 participants in any given age group) will be enrolled in any 
given age group.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the study intervention administered.  
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medications 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 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:
a.
Piperacillin/tazobactam
b.
Probenecid
c.
Immunosuppressive agents
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Note:  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.
All other concomitant medications necessary for the health and well-being of the participant 
are permitted.  
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
After the first 3 participants are enrolled into a given age group, enrollment will be paused in 
that age group for an interim PK analysis to confirm or modify the proposed pediatric dose 
for the remaining participants in that group and/or other age groups. The proposed initial 
pediatric doses may be modified based on whether the dose evaluated in the interim PK 
analysis demonstrates an acceptable safety profile in the exposed age group and is suitable 
based on adequate PK plasma exposures (see Section 9.7).
Dose modifications, if required, will be communicated to investigators and sites via Protocol 
Clarification Letters.
No dose adjustment for renal insufficiency is allowed in this study (see Section 7.1).
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not applicable.
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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 before completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.10.7 unless the participant has 
withdrawn from the study (Section 7.2).
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.
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.
•
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.
•
For Groups 1 through 4, the participant develops moderate to severe impairment of renal 
function, defined as an estimated CrCL <50 mL/min/1.73 m2 based on the revised 
Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration. 
For Group 5, the participant develops CrCL <20 mL/min/1.73 m2 based on the revised 
Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration.
Specific details regarding procedures to be performed at study intervention discontinuation 
are provided in Section 8.1.9 and Section 8.10.6. Participants are anticipated to receive a 
minimum of 8 days of concomitant standard-of-care antibiotic therapy; however, 
concomitant standard-of-care antibiotics may be stopped before the 8-day minimum at the 
discretion of the investigator. Participants who discontinue or complete concomitant 
standard-of-care antibiotic therapy in less than 8 days may also discontinue 
ceftolozane/tazobactam prior to the minimum duration of 8 days at the investigator’s 
discretion. However, participants are strongly encouraged to receive a minimum of 8 days of 
ceftolozane/tazobactam.
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For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
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.
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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.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) 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 used for screening or baseline purposes 
provided the procedures meet 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/assent 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 18 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this 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 documented 
informed consent/assent is in place.
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8.1.1.1
General Informed Consent/Assent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent/assent form. The form must include the study protocol 
number, study protocol title, dated signature, and agreement of the participant (or his/her 
legally acceptable representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the 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/assent form or addendum to the original consent/assent
form that captures the participant’s or the participant’s legally acceptable representative’s 
dated signature.
Specifics about the study and the study population are to be included in the study informed 
consent/assent form.
Informed consent/assent will adhere to IRB/IEC requirements, applicable laws and 
regulations, and Sponsor requirements.
Participants unable to provide assent at enrollment due to incapacitation will be assented per 
local regulations/requirements.
8.1.2
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.
8.1.3
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 documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
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8.1.4
Medical History
The participant’s medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
At Screening, the investigator or qualified designee will review prior medication use and 
record prior medication taken by the participant within 7 days before the first dose of study 
intervention (or within 14 days before the first dose of study intervention for all antibacterial 
agents, and within 30 days before the first dose of study intervention for any other
investigational drug). For participants who are breastfeeding, prior medication use by the 
participant’s mother will be recorded similarly.
Any blood or blood product transfusions in the previous 48 hours before first dose of study 
intervention will be recorded.
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 the last study evaluation). For 
participants who are breastfeeding, concomitant medication use by the participant’s mother 
will be recorded similarly.
8.1.6
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 before intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
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 8.10.1. Pretrial screening logs may be collected for 
review by the Sponsor. If applicable, any information that would make the participant
identifiable will be removed.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. 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.
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8.1.8
Study Intervention Administration
The ceftolozane/tazobactam to be used in this study is outlined in Table 3.
Ceftolozane/tazobactam should begin as soon as possible after allocation and at the latest 
within 24 hours of allocation. There should be no medically inappropriate delay in allocation 
and subsequent treatment with ceftolozane/tazobactam. All supplies indicated in Table 3 will 
either be provided centrally by the Sponsor or sourced locally.
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 
ceftolozane/tazobactam in accordance with the protocol and any applicable laws and 
regulations.
8.1.8.1
Timing of Dose Administration
Ceftolozane/tazobactam will be dosed q8h (±1 hour) after the previous infusion. The second 
IV dose has a ±4-hour window for dosing to facilitate adjustment of the dosing schedule 
(once q8h) to be carried out throughout the IV dosing period.
If the first administration of ceftolozane/tazobactam occurs later on Day 1 (Visit 2) such that 
the second or third dose is not given on Day 1 (Visit 2), the final day of study treatment may 
extend to Day 15 to allow for up to 14 consecutive 24-hour periods of 
ceftolozane/tazobactam treatment.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.7.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit 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.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
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 are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy Assessments
There are no efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A full physical examination will be conducted at Screening (Visit 1) by an investigator or 
medically qualified designee (consistent with local requirements) as per institutional 
standard. Height (cm) and weight (kg) will also be measured and recorded. Body weight will 
be measured without shoes, jacket, or diaper (in participants using diapers). The full physical 
examination will include examination of body systems (including, but not limited to, general 
appearance, skin, neck, eyes, ears, nose, throat, breast, lungs, heart, abdomen, back, lymph 
nodes, extremities, and nervous system).
The investigator or qualified designee will also perform a directed physical examination at 
other times at the investigator’s discretion, if an AE or abnormality is suspected. A brief 
directed physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. The directed physical 
examination should be based on the participant’s condition and circumstances, at the 
investigator’s discretion. The directed physical examination should note any changes in the 
participant’s condition (body systems) since the last examination and does not preclude 
examination of any of the body systems as clinically indicated. Investigators should pay 
special attention to clinical signs related to previous serious illnesses.
Changes in physical examination findings (abnormalities) that the investigator considers 
clinically significant will be recorded on the medical history eCRF page if observed prior to 
administration of the first dose of ceftolozane/tazobactam. Changes in physical examination 
findings (abnormalities) that the investigator considers clinically significant must be recorded 
as AEs if observed after the start of the first dose of ceftolozane/tazobactam.
8.3.2
Vital Signs
The investigator or qualified designee will record vital signs (heart rate, blood pressure, 
respiratory rate, and temperature [oral, tympanic, rectal, axillary, or temporal]). Systolic and 
diastolic blood pressure will be measured on the same arm. Heart rate and blood pressure will 
be measured simultaneously. If Screening (Visit 1) and Allocation (Visit 2) occur on the 
same day, vital signs do not need to be performed twice.
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8.3.3
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 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.
8.3.3.1
Assessment of Creatinine Clearance
Blood samples for serum creatinine will be obtained as indicated in the SoA and evaluated by 
the local laboratory. The participant’s CrCL will be estimated using the serum creatinine 
value, height, and the revised Schwartz equation [Schwartz, G. J., et al 2009], as follows:
GFR (mL/min per 1.73 m2) = 0.413 * H/SCr, where
•
GFR = mL/min per 1.73 m2
•
H = cm
•
SCr = mg/dL
For participants with unstable renal function (CrCL is close to 50 mL/min/1.73 m2) while 
receiving ceftolozane/tazobactam, obtain serum creatinine value and monitor CrCL at least 
daily. For Groups 1 through 4, a participant who develops moderate to severe impairment of 
renal function, defined as an estimated CrCL <50 mL/min/1.73 m2 based on the revised 
Schwartz equation, or requires peritoneal dialysis, hemodialysis, or hemofiltration, must be 
discontinued from ceftolozane/tazobactam. For Group 5, a participant who develops CrCL 
<20 mL/min/1.73 m2 based on the revised Schwartz equation or requires peritoneal dialysis, 
hemodialysis, or hemofiltration, must be discontinued from ceftolozane/tazobactam.
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8.3.4
Pregnancy Testing (WOCBP only)
Pregnancy testing will be performed by the local laboratory on female participants of 
childbearing potential. Prior to allocation, the investigator will ensure serum pregnancy tests 
are negative in female participants of childbearing potential. A urine pregnancy test instead 
of a serum pregnancy test may be performed by the local laboratory, if deemed clinically 
appropriate by the investigator. An additional pregnancy test will be performed on female 
participants of childbearing potential at the EOT Visit at the end of relevant systemic 
exposure.
8.4
Adverse Events, Serious Adverse Events, 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 need to document if an SAE was associated with a medication error, misuse, or 
abuse. 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.
8.4.1
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 participant provides 
documented informed consent, but before intervention allocation 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 through 14 days after cessation of treatment, 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 the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
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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 the investigator 
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 4.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 4
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
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
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:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
ECI (require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– require regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (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 (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
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, 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 allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
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 toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
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The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
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) 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.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3X the ULN and an elevated total bilirubin laboratory value that is 
greater than or equal to 2X the ULN and, at the same time, an alkaline phosphatase 
laboratory value that is less than 2X the ULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based on 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).
2. An overdose of the Sponsor's product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory result.
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8.5
Treatment of Overdose
For this study, an overdose of ceftolozane/tazobactam is considered to be any dose that is 
greater than 1.5 times higher than the protocol-specified dose for the participant’s age group. 
Any overdose must be reported to the Sponsor as described in Appendix 3.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma Concentrations of Ceftolozane/Tazobactam
Blood samples for ceftolozane and tazobactam concentration assays and plasma PK 
parameters will be collected from all participants over one 8-hour dosing period on Day 3 
(Visit 4) of the treatment period after administration of at least 6 doses of 
ceftolozane/tazobactam. These blood samples will be collected at the following times: at the 
end of infusion (1 hour after start of infusion of ceftolozane/tazobactam, collect within 
10 minutes after the end of total dose administration); between 4 and 5 hours after start of 
infusion; and between 7 and 8 hours after start of infusion, but prior to the start of the next 
dose of ceftolozane/tazobactam.
PK sample collection may occur on Day 4 (Visit 5) if the last dosing period of Day 3 
(Visit 4) is selected for PK sample collection. Additionally, if sampling on Day 3 (Visit 4) is 
logistically difficult, sampling may be performed at comparable time points after Day 3 
(Visit 4) in participants who are continuing to receive IV study treatment.
Approximately 0.25 mL blood for assay of ceftolozane/tazobactam in plasma will be 
collected for each PK timepoint over the 8-hour dosing interval. Approximately 0.75 mL of 
blood will be drawn from each participant for PK analyses. The actual time of collection of 
each PK sample should be documented.  
Plasma will be separated from blood and sent to the central laboratory for PK testing. Details 
of the procedures for collection, processing, storage, and shipment of PK samples from blood 
(plasma) will be provided separately in a laboratory manual. Actual whole blood sample 
collection dates and times must be recorded on the appropriate eCRF.
The method of sampling for PK blood draws is at the discretion of the Investigator (eg, PICC 
line, indwelling catheter access, individual peripheral phlebotomies, peri-operatively placed 
arterial line). Samples taken via an IV line (or comparable means of access) are preferred; 
however, in instances where samples are unable to be obtained from a second line, alternative 
methods (such as heel sticks or finger sticks) are allowed. In circumstances in which the 
blood draw and study intervention infusion must occur in the same limb, the blood must be 
drawn more distally in the vein (approximately 3 to 5 inches) from the infusion site.
In cases where obtaining a second IV line (or comparable means of access) is unsuccessful, a 
single IV line (or comparable means of access) is acceptable for both study intervention 
administration and sample collection at the required time points. Prior to obtaining PK 
samples, the line must be flushed per site standard-of-care to ensure the total dose is 
administered.
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8.7
Pharmacodynamics
PD parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.8.1
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.9
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening (Visit 1)
Screening assessments are performed within 48 hours prior to the start of administration of 
the first dose of ceftolozane/tazobactam. Potential participants are evaluated at the Screening 
Visit to determine if they fulfill the entry requirements in Section 5. All Screening results 
must be available prior to allocation. Screening, allocation, and first dose of 
ceftolozane/tazobactam may all occur on the same day.
8.10.2
Allocation Visit (Visit 2; Day 1)
The Allocation Visit is the date participants are allocated to treatment and may then receive 
the first dose of ceftolozane/tazobactam. Screening, allocation, and first dose of 
ceftolozane/tazobactam may all occur on the same day.
8.10.3
Treatment Period Visits
8.10.4
Intervention Period Visits (Visits 3 through 15; Days 2 through 14)
Intervention Period Visits on ceftolozane/tazobactam occur daily beginning on Day 2 
(Visit 3) and continuing through the last dose of ceftolozane/tazobactam. Assessments at 
these visits (concomitant medication review, directed physical examinations, vital signs, and 
AE/SAE monitoring) should be performed at a consistent time each day (eg, every morning), 
as much as possible. Safety laboratory tests should be completed on Day 3 (Visit 4) and only 
if clinically indicated at the other visits while receiving ceftolozane/tazobactam.
Blood is collected for PK analyses on Day 3 (Visit 4) (after ≥6 doses of 
ceftolozane/tazobactam). PK sample collection may occur on Day 4 (Visit 5) if the last 
dosing period of Day 3 (Visit 4) is selected for PK sample collection. Additionally, if 
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sampling on Day 3 (Visit 4) is logistically difficult, sampling may be performed at 
comparable time points after Day 3 (Visit 4) in subjects who are continuing to receive 
ceftolozane/tazobactam.
8.10.5
EOT Visit (Visit 16)
The EOT Visit will occur within 48 hours after the last dose of ceftolozane/tazobactam. 
Concomitant medication review, administration of concomitant standard-of-care antibiotics 
for NP, directed physical examinations, vital signs, safety laboratory tests, pregnancy testing 
for WOCBP, and AE/SAE monitoring will be performed at this visit.
8.10.6
LFU Visit (Visit 17)
The LFU Visit occurs in all participants 14 days (+3 days) after the last dose of 
ceftolozane/tazobactam. The LFU Visit will be conducted by telephone; however, if the 
participant has abnormal laboratory values or AEs that require follow-up, an in-person visit is 
required.
8.10.7
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue from ceftolozane/tazobactam prior to completion of the study 
treatment regimen will continue to be monitored in the study according to the SoA.
For participants who prematurely withdraw from the study, see Section 7.2 and Section 7.3.
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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, changes are made to the objectives, or the statistical methods related to the 
objectives, 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 the conduct of any analysis, will be documented in the CSR for the study. Post 
hoc exploratory analyses will be clearly identified in the CSR.  
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.12.
9.1
Statistical Analysis Plan Summary 
Study Design Overview
A Phase 1, open-label, non-comparative, multicenter clinical study to 
evaluate the safety, tolerability, and pharmacokinetics of 
ceftolozane/tazobactam (MK-7625A) in pediatric participants with 
nosocomial pneumonia.
Treatment Assignment
All enrolled participants are to receive ceftolozane/tazobactam 
treatment.
Analysis Populations
Safety: ASaT Population
PK: PK Population
Primary Endpoints
The primary safety parameters will include the following safety 
evaluations:

Any AEs

Any SAEs

Any drug-related AEs

Any serious and drug-related AEs

AEs leading to discontinuation of study intervention
Secondary Endpoints
The secondary PK parameters will include the following ceftolozane 
and tazobactam PK parameters:
•
Plasma concentrations at each time point
•
Steady state plasma AUC0-8, Cmax, t1/2, Vd, and CL
Statistical Methods for
Key Efficacy Analyses
There are no efficacy analyses planned for this study.
Statistical Methods for 
Key Safety Analyses
The primary safety parameters will be evaluated by the number and 
percentage of all participants reporting these events with 95% CIs based 
on the Clopper and Pearson method. Primary safety parameters will also 
be evaluated separately using the same methods for participants with 
treatment exposure from 1 to <8 days versus treatment exposure for ≥8 
days. The number and percentage of all participants reporting specific 
AEs will be provided for all AEs by system organ class and PT. 
Summary statistics of clinical laboratory tests for baseline and all 
post-baseline evaluations including means, mean changes from baseline, 
standard deviations, minimum and maximum values over time will be 
provided. Summary statistics for vital signs will also be provided.
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Interim Analyses
Interim PK analyses will be conducted after enrollment of the first 
3 participants into a given age group.  
Multiplicity
There are no multiplicity adjustments planned for this study.
Sample Size and Power 
In this study, approximately 40 participants will be enrolled and treated. 
With this sample size, there will be at least 64% probability to observe 
any AEs that have an underlying true incidence rate of 2.5% or more, 
and there will be at least 87% probability to observe any AEs that have 
an underlying true incidence rate of 5% or more. If no AEs are 
observed, the upper bound of the 2-sided 95% CI for the 0% AE 
incidence rate will be 8.8%, based on the Clopper and Pearson method.  
9.2
Responsibility for Analyses/In-house Blinding 
There is no blinding required for this single arm study. The analysis of the safety data 
obtained from this study will be the responsibility of the Sponsor’s Clinical Biostatistics 
department.
The official, final database will not be locked until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The plasma concentrations at each time point and the primary PK parameters for ceftolozane 
and tazobactam will be summarized by the Sponsor’s Quantitative Pharmacology and 
Pharmacometrics department and the Early Clinical Development Statistics department.  
9.3
Hypotheses/Estimation 
Objectives of the study are stated in Section 3. There are no hypotheses to be tested in this 
study.
9.4
Analysis Endpoints 
9.4.1
Safety Endpoints
Safety endpoints include AEs (any AEs, any SAEs, any drug-related AEs, any serious and 
drug-related AEs, and AEs leading to discontinuation of study intervention), clinical 
laboratory tests, and vital sign measurements.
The rationale for safety endpoints is provided in Section 4.2.1.1, and ECIs are defined in 
Section 8.4.7. The proportion of subjects who experience AEs of elevated laboratory values 
that are reported as ECIs during the study treatment period will be estimated.
9.4.2
PK Endpoints
Plasma concentrations for ceftolozane and tazobactam at each time point will be determined 
and summarized in the CSR. Plasma concentration data will be used to update the existing 
ceftolozane and tazobactam pediatric population PK models. Due to the sparse PK sampling, 
the other PK endpoints, including steady state Cmax, AUC0-8, t1/2, Vd, and CL will be 
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characterized using a population PK modeling approach. These parameters will be 
summarized in a separate population PK modeling report. 
9.5
Analysis Populations 
9.5.1
Safety Population
The safety population will include participants who receive any dose (including partial doses) 
of ceftolozane/tazobactam (ASaT).
9.5.2
PK Population
The PK population will include participants who receive at least 6 doses of 
ceftolozane/tazobactam and have at least 1 quantifiable plasma concentration of ceftolozane 
or tazobactam.
9.6
Statistical Methods 
9.6.1
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of relevant parameters for all 
participants overall (ASaT), including AEs, clinical laboratory parameters, and vital sign 
measurements.  
The broad AE categories consisting of the percentage of participants with any AEs, any 
serious AEs, any drug-related AEs, any serious and drug-related AEs, and AEs leading to 
discontinuation of study intervention will be summarized for the ASaT population using 
point estimates with 95% CIs (Table 5). The calculation of 95% CIs is based on the exact 
binomial method proposed by Clopper and Pearson. These summaries will also be performed 
separately for participants with treatment exposure from 1 to <8 days versus treatment 
exposure for ≥8 days. 
For continuous measurements, such as changes from baseline in laboratory parameters and 
vital signs, summary statistics (including mean, mean change from baseline, standard 
deviation, minimum and maximum values over time) for baseline, on-treatment, and change 
from baseline values will be provided in table format. 
Table 5
Analysis Strategy for Safety Parameters
Safety Endpoint
Within Group 95% CI
Descriptive Statistics
Any AE
X
X
Any Serious AE
X
X
Any Drug-related AE
X
X
Any Serious and Drug-related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, System Organ Classes, or PTs 
X
Change from Baseline Results (Laboratory 
results, Vital Signs)
X
AE= adverse event; CI=confidence interval; PT=Preferred term.
Note: 95% CIs will be calculated using the Clopper Pearson method.
X=results will be provided
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9.6.2
Statistical Methods for PK Analyses
A PK Analysis Plan with further details will be prepared and finalized before database lock 
and analysis of the data.  
The primary PK parameters for ceftolozane and tazobactam (steady state plasma AUC0-8, 
Cmax, t1/2, Vd, and CL) will be characterized for each age group and/or dose level, as 
appropriate. Data will be presented in tables and listings. Listings may include but are not 
limited to: participant ID number, dose administered, body weight, plasma drug 
concentrations, time points, and individual derived PK parameters. Summary tables may 
include but are not limited to: the number of participants, arithmetic means, SD, %CV, 
minimum, median, and maximum values, and geometric mean for individual parameters.
Based on PK data obtained within this study and previous ceftolozane/tazobactam studies in 
adults, a separate pediatric population PK analysis will be performed for ceftolozane and 
tazobactam. The results of this analysis will be reported separately in a population PK 
modeling report.
9.7
Interim Analyses 
After the first 3 participants are enrolled into a given age group, enrollment will be paused in 
that age group for an interim PK analysis to confirm or modify the proposed pediatric dose 
for the remaining participants in that group and/or other age groups. Enrollment will continue 
in the other age groups during each interim PK analysis. The proposed initial pediatric doses 
may be modified based on whether the dose evaluated in the interim PK analysis 
demonstrates an acceptable safety profile in the exposed age group and is suitable based on 
adequate PK plasma exposures. 
All observed PK data will be entered into a population PK dataset on a rolling basis. 
Proposed initial doses will be considered suitable if the observed ceftolozane and tazobactam 
plasma exposures are similar to corresponding plasma exposures in adult participants with 
NP that have proved safe and efficacious. The criteria for demonstrating adequate PK plasma 
exposures and an acceptable safety profile of the proposed doses include the following:
•
Population PK model predicted pediatric plasma exposures of ceftolozane and 
tazobactam (ie, steady state plasma AUC0-8 and/or Cmax) within the ranges of the 5th 
and 95th percentile of the corresponding model-projected exposures in adult participants 
with NP.
•
Absence of a safety signal (eg, no SAEs related to study intervention).
Note:  If a safety signal is detected, additional analyses involving plasma PK exposure 
data will be evaluated to determine the appropriate course of action. 
After the first 3 participants have been enrolled into a given age group, at least 3 additional 
participants will be enrolled in that age group following the interim PK analysis. At least 
3 additional participants per age group, for a total of 6 participants per age group, is expected 
to provide sufficient data to inform pediatric population PK model development and for 
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determining the appropriate dose for a given age group. Dose modifications, if required, will 
be communicated to investigators and sites via Protocol Clarification Letters.  
9.8
Multiplicity 
There are no multiplicity adjustments planned for this study.
9.9
Sample Size and Power Calculations 
The cumulative sample size of 40 participants for this study is based on obtaining sufficient 
data to evaluate the safety and PK of ceftolozane/tazobactam in pediatric participants, in 
addition to feasibility considerations. This study is not powered to test formal hypotheses. 
With approximately 40 participants enrolled and treated, there will be at least 64% 
probability to observe any AEs that have an underlying true incidence rate of 2.5% or more, 
and there will be at least 87% probability to observe any AEs that have an underlying true 
incidence rate of 5% or more. If no AEs are observed, the upper bound of the 2-sided 95% CI 
for the 0% AE incidence rate will be 8.8%, based on Clopper and Pearson method.  
In addition, the sample size of 40 will provide for at least 6 participants per age group for the 
PK analysis, which is considered appropriate for the planned pediatric population PK 
analysis. The Phase 1 single-dose PK study (MK-7625A-010) had a similar PK sample size 
and enrolled approximately 6 participants per age group. Pediatric population PK models 
using MK-7625A-010 PK data adequately described the observed plasma concentration-time 
profiles of ceftolozane and tazobactam in all age groups, enabling PK target calculation and 
PTA simulation to support pediatric dose determination from the Phase 2 cUTI/cIAI studies 
[Modeling and Simulation Report: Population... 2017].
9.10
Subgroup Analyses 
No subgroup analysis will be performed for PK or safety; plasma concentrations of 
ceftolozane and tazobactam will be summarized by time point and by cohort, but this is not 
considered to be a subgroup analysis.
9.11
Compliance (Medication Adherence) 
Each participant will be scheduled to receive ceftolozane/tazobactam q8h (3 times daily) for 
approximately 8 to 14 days (maximum of fourteen 24-hour periods). Treatment compliance 
will be documented in the eCRF by recording the date, time, and length of infusion for each 
dose of ceftolozane/tazobactam. Study intervention adherence will be summarized as 
treatment exposure (number of days on study therapy and number of doses of study therapy 
received). As the study will only enroll hospitalized participants receiving IV therapy, high 
study intervention adherence among all participants is anticipated.
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9.12
Extent of Exposure 
The extent of exposure to ceftolozane/tazobactam will be summarized as both continuous and 
categorical variables alongside counts and percentages for the “Number of Days on Therapy” 
in the ASaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
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, 
planning, 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 and conduct of clinical trials. In all cases, MSD 
clinical trials will be conducted in compliance with MSD’s global standards, local 
and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice 
(ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, 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 (i.e., 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.
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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 (or individuals acting on behalf of MSD) 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 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-non-compliance is 
suspected, the issues 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 the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified 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. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations. Changes to the protocol that are required urgently to eliminate 
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an immediate hazard and to protect participant safety may be enacted in anticipation 
of ethics committee approval.  MSD will inform regulatory authorities of such new 
measures to protect participant safety, in compliance with local and/or national 
regulations.
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 individuals acting 
on behalf of MSD), 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 and medical evaluation to identify 
potentially eligible participants.
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.
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C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., 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.
10.1.2
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, frequently 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.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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.
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 
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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 before 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.
10.1.4
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.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the 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 
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review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials 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.
10.1.6
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, ICH 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 Trials.
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.
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.
10.1.7
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.
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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 participants’ documented informed consent, 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.
10.1.8
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.
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10.1.9
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 or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 6 will be performed by the local laboratory.
The timing for the collection of blood and urine samples for safety monitoring is provided in 
the SoA.
•
Pregnancy Testing:

Pregnancy testing requirements for study inclusion are described in Section 5.1

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant's participation in the study.
Table 6
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Hemoglobin
Hematocrit
WBC count with Differential:
Neutrophils
Band Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin, if total bilirubin is 
above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose
Calcium
Alkaline 
phosphatase
Pregnancy Testing

Serum or urine β hCG pregnancy test (as needed for WOCBP)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; β hCG=human chorionic gonadotropin; BUN=blood 
urea nitrogen; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; 
ULN=upper limit of normal; WOCBP=women of childbearing potential; WBC=white blood cell.
The investigator (or medically qualified designee) must document their review of each
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
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 includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, 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, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
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.
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
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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, 
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.
10.3.4
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.
10.3.5
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.
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•
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 
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 study intervention cause the AE?
•
The determination of the likelihood that the study intervention 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 on the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
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-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill 
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 study intervention? 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 study intervention 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 study intervention; 
(3) the study is a single-dose drug study; or (4) study intervention(s) is/are only used 1 
time.)
-
Rechallenge: Was the participant re-exposed to the study intervention 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) study intervention(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 STUDY INTERVENTION, OR IF RE-
EXPOSURE TO THE STUDY INTERVENTION 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 study intervention 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 study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
-
There is evidence of exposure to the study intervention. The temporal sequence of the AE 
onset relative to the administration of the study intervention is reasonable. The AE is 
more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
-
Participant did not receive the study intervention OR temporal sequence of the AE onset 
relative to administration of the study intervention is not reasonable OR the AE is more 
likely explained by another cause than the study intervention. (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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10.3.6
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 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 email 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: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
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
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 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 one 
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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10.5.2
Contraceptive Requirements
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 contraceptive implantc, d
IUSc, e
Nonhormonal 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 for a male participant 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.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Male or female condom with or without spermicide
Cervical cap, diaphragm, or sponge with spermicide
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)f
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 female participant 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.
f
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, 
but not highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
Male and female condom should not be used together (due to risk of failure with friction).
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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: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASaT
All Subjects as Treated
AST
aspartate aminotransferase 
AUC
area under the concentration-time curve
AUC0-8
Steady state plasma area under the concentration-time curve of an 8-
hour dosing interval
BLI
β-lactamase inhibitor
CD4
cluster of differentiation 4
CI
confidence interval
cIAI
complicated intraabdominal infection
Cmax
maximum observed concentration during a dosage interval
CL
clearance
CONSORT
Consolidated Standards of Reporting Trial
CrCL
creatinine clearance
CRF
Case Report Form 
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
cUTI
complicated urinary tract infection
CV
coefficient of variation
DILI
drug-induced liver injury
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
ELF
epithelial lining fluid
EMA
European Medicines Agency
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Abbreviation
Expanded Term
EOT
end of treatment
ESBL
extended spectrum β-lactamase
EU
European Union
EU CT
EU Clinical Trial
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
FSR
first site ready
ft>Ct
time that free plasma concentration exceeds the threshold concentration
fT>MIC
time that free plasma concentration exceeds the minimum inhibitory 
concentration
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
H
height
HABP
hospital-acquired bacterial pneumonia
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ID
identification
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
investigational new drug
IRB
Institutional Review Board 
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
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Abbreviation
Expanded Term
IVRS
interactive voice response system
JAPIC-CT
Japan Project-Industry Council for Clinical Trials
LAM
lactational amenorrhoea method
LDA
last data available
LFU
last follow-up
LPLV
last participant last visit
MIC
minimum inhibitory concentration
NCT
National Clinical Trial
NP
nosocomial pneumonia
PD
pharmacodynamic
PICC
peripherally inserted central catheter
PK
pharmacokinetic
PT
Preferred Term
PTA
probability of target attainment
q
every
q8h
every 8 hours
SAE
serious adverse event 
SCr
serum creatinine
SD
standard deviation
SLAB
supplemental laboratory test(s)
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reaction
t1/2
elimination half-life
ULN
upper limit of normal
US(A)
United States (of America)
VABP
ventilator-associated bacterial pneumonia
Vc
central volume of distribution
Vd
volume of distribution
Vp
peripheral compartment
WHO
World Health Organization
08WN8Y

PRODUCT: MK-7625A
88
PROTOCOL/AMENDMENT NO.: 036-02
MK-7625A-036-02 FINAL PROTOCOL
12-DEC-2022
Abbreviation
Expanded Term
WOCBP
woman/women of childbearing potential 
UTN
Universal Trial Number
08WN8Y

PRODUCT: MK-7625A
89
PROTOCOL/AMENDMENT NO.: 036-02
MK-7625A-036-02 FINAL PROTOCOL
12-DEC-2022
11
REFERENCES
[Bradley, J. S. 2010]
Bradley JS. Considerations unique to 
pediatrics for clinical trial design in 
hospital-acquired pneumonia and 
ventilator-associated pneumonia. Clin 
Infect Dis. 2010 Aug 1;51 Suppl 1:S136-
43.
[0446BJ]
[Carvalhaes, C. G., et al 
2018]
Carvalhaes CG, Castanheira M, Sader HS, 
Flamm RK, Shortridge D. Antimicrobial 
activity of ceftolozane-tazobactam tested 
against gram-negative contemporary 
(2015–2017) isolates from hospitalized 
patients with pneumonia in US medical 
centers [manuscript]. 2018. 47 p.
[054432]
[Center for Drug Evaluation 
and Research 2014]
Center for Drug Evaluation and Research. 
Guidance for industry hospital-acquired 
bacterial pneumonia and ventilator-
associated bacterial pneumonia: developing 
drugs for treatment. Rockville (MD): 
Center for Drug Evaluation and Research; 
May 2014. (Revision 2).
[04F6R8]
[Duin, D. V. 2016]
van Duin D, Bonomo RA. 
Ceftazidime/avibactam and 
ceftolozane/tazobactam: second-generation 
beta-Lactam/beta-Lactamase inhibitor 
combinations. Clin Infect Dis. 2016 Jul 
15;63(2):234-41.
[04TR9Q]
[Foglia, E., et al 2007]
Foglia E, Meier MD, Elward A. Ventilator-
associated pneumonia in neonatal and 
pediatric intensive care unit patients. Clin 
Microbiol Rev. 2007 Jul;20(3):409-25.
[044GPS]
[Gallagher, J. C., et al 2018]
Gallagher JC, Satlin MJ, Elabor A, Saraiya 
N, McCreary EK, Molnar E, et al. 
Ceftolozane-tazobactam for the treatment 
of multidrug-resistant Pseudomonas 
aeruginosa infections: a multicenter study. 
Open Forum Infect Dis. 
2018;5(11):ofy280.
[05443D]
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[Gupta, S., et al 2015]
Gupta S, Boville BM, Blanton R, 
Lukasiewicz G, Wincek J, Bai C, et al. A 
multicentered prospective analysis of 
diagnosis, risk factors, and outcomes 
associated with pediatric ventilator-
associated pneumonia. Pediatr Crit Care 
Med. 2015 Mar;16(3):e65-73.
[044NDX]
[Kalil, A. C., et al 2016]
Kalil AC, Metersky ML, Klompas M, 
Muscedere J, Sweeney DA, Palmer LB, et 
al. Management of adults with hospital-
acquired and ventilator-associated 
pneumonia: 2016 clinical practice 
guidelines by the Infectious Diseases 
Society of America and the American 
Thoracic Society. Clin Infect Dis. 2016 Sep 
1;63(5):e61-111.
[05442Y]
[Kehl, S. C. 2015]
Kehl SC, Dowzicky MJ. Global assessment 
of antimicrobial susceptibility among 
Gram-negative organisms collected from
pediatric patients between 2004 and 2012: 
results from the tigecycline evaluation and 
surveillance trial. J Clin Microbiol. 2015 
Apr;53(4):1286-93.
[053NMH]
[Lake, J. G., et al 2018]
Lake JG, Weiner LM, Milstone AM, 
Saiman L, Magill SS, See I. Pathogen 
distribution and antimicrobial resistance 
among pediatric healthcare-associated 
infections reported to the National 
Healthcare Safety Network, 2011-2014. 
Infect Control Hosp Epidemiol. 2018 
Jan;39(1):1-11.
[053NLZ]
[Logan, L. K., et al 2017]
Logan LK, Gandra S, Mandal S, Klein EY, 
Levinson J, Weinstein RA, et al. 
Multidrug- and carbapenem-resistant 
Pseudomonas aeruginosa in children, 
United States, 1999-2012. J Pediatric Infect 
Dis Soc. 2017 Dec;6(4):352-9.
[053NMF]
[Medernach, R. L. 2018]
Medernach RL, Logan LK. The growing 
threat of antibiotic resistance in children. 
Infect Dis Clin N Am. 2018;32:1-17.
[053NLW]
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[Modeling and Simulation 
Report: Population... 2017]
Modeling and Simulation Report: 
Population Pharmacokinetics of 
Ceftolozane/Tazobactam in pediatric 
patients, 2017.
[04KB9Q]
[Nicasio, A. M., et al 2008]
Nicasio AM, Kuti JL, Nicolau DP. The 
current state of multidrug-resistant gram-
negative bacilli in North America. 
Pharmacotherapy. 2008 Feb;28(2):235-49.
[047MQ6]
[Schwartz, G. J., et al 2009]
Schwartz GJ, Munoz A, Schneider MF, 
Mak RH, Kaskel F, Warady BA, et al. New 
equations to estimate GFR in children with 
CKD. J Am Soc Nephrol. 2009 
Mar;20(3):629-37.
[04FKFR]
[Talbot, G. H. 2008]
Talbot GH. What is in the pipeline for 
Gram-negative pathogens? Expert Rev Anti 
Infect Ther. 2008 Feb;6(1):39-49.
[047MY8]
[U.S. Prescribing Information 
2022]
U.S. Prescribing Information: ZERBAXA 
(ceftolozane and tazobactam) for injection, 
for intravenous use: May 2022.
[086MSK]
[Xiao, A. J., et al 2016]
Xiao AJ, Miller BW, Huntington JA, 
Nicolau DP. Ceftolozane/tazobactam 
pharmacokinetic/pharmacodynamic-
derived dose justification for phase 3 
studies in patients with nosocomial 
pneumonia. J Clin Pharmacol. 2016 
Jan;56(1):56-66.
[04DPZ3]
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