Clinical trial NCT03969901
Conditions: Suspected or Documented Gram-negative Bacterial Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-10-08; Completion date: 2024-05-07
Enrollment: 115 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to evaluate the safety and tolerability of imipenem/cilastatin/relebactam (IMI/REL) in participants from birth to less than 18 years of age with confirmed or suspected gram-negative bacterial infection. Participants are expected to require hospitalization through completion of intravenous (IV) study intervention, and have at least one of the following primary infection types: hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP); complicated intra-abdominal infection (cIAI); or complicated urinary tract infection (cUTI). Participants will be randomized in a 3:1 ratio to receive IMI/REL or active control. This study will also evaluate the efficacy of IMI/REL by assessing all-cause mortality at Day 28 post-randomization, as well as clinical and microbiological response to treatment. It will also evaluate the pharmacokinetics of IMI/REL.

Detailed description:

Arms: arm 1: Participants with cIAI or cUTI will receive imipenem/cilastatin/relebactam (IMI/REL) via IV infusion for a minimum of 5 days (with optional investigator's choice of locally sourced oral switch medication after 3 days) up to a maximum of 14 days. Participants with HABP/VABP will receive IMI/REL via IV infusion for a minimum of 7 days up to a maximum of 14 days. Participants with bacteremia or Pseudomonas aeruginosa infection will receive IMI/REL via IV infusion for 14 days. All oral switch medications will be chosen from a list of acceptable approved agents and will be administered per authorized Package Insert (PI), Summary of Product Characteristics (SPC), or international treatment guidelines. arm 2: Participants with cIAI or cUTI will receive active control via IV infusion for a minimum of 5 days (with optional investigator's choice of locally sourced oral switch medication after 3 days) up to a maximum of 14 days. Participants with HABP/VABP will receive active control via IV infusion for a minimum of 7 days up to a maximum of 14 days. Participants with bacteremia or Pseudomonas aeruginosa infection will receive active control via IV infusion for 14 days. All active control and oral switch medications will be administered per authorized PI, SPC, or international treatment guidelines. All active control and oral switch medications will be chosen from a list of acceptable approved agents.
Interventions: intervention 1: IMI/REL intervention 2: Active Control intervention 3: Oral Switch
Intervention descriptions: intervention 1: Age-based dosing:

* 12 to \<18 years, IMI 500 and REL 250 mg, IV infusion every 6 hours
* 6 to \<12 years, IMI 15 and REL 7.5 mg/kg, IV infusion every 6 hours
* 2 to \<6 years, IMI 15 and REL 7.5 mg/kg, IV infusion every 6 hours
* 3 months to \<2 years, IMI 15 and REL 7.5 mg/kg, IV infusion every 6 hours
* Birth to \<3 months, IMI 15 and REL 7.5 mg/kg, IV infusion every 8 hours NOTE: Participants with cIAI or cUTI may be switched to oral therapy after at least 3 days of IV study intervention. intervention 2: All active control medications will be chosen from a list of acceptable approved agents for each infection type (HABP or VABP, cIAI, and UTI) and will be given via IV infusion, per authorized Package Insert (PI), Summary of Product Characteristics (SPC), or international treatment guidelines.

NOTE: Participants with cIAI or cUTI may be switched to oral therapy after at least 3 days of IV study intervention. All oral switch medications will be chosen from a list of acceptable approved agents. intervention 3: All oral switch medications will be investigator's choice from a list of acceptable approved agents for infection types cIAI, and cUTI and will be given per authorized Package Insert (PI), Summary of Product Characteristics (SPC), or international treatment guidelines. Participants with cIAI or cUTI may be switched to oral therapy after at least 3 days of IV study intervention.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                NCT03969901
Document Date:            20-JUL-2023
A Phase 2/3 Open-label, Randomized, Active-controlled 
Clinical Study to Evaluate the Safety, Tolerability, 
Efficacy and Pharmacokinetics of MK-7655A in Pediatric 
Participants From Birth to Less Than 18 Years of Age 
With Confirmed or Suspected Gramnegative Bacterial 
Infection


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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 2/3 Open-label, Randomized, Active-controlled Clinical Study to 
Evaluate the Safety, Tolerability, Efficacy and Pharmacokinetics of MK-7655A in Pediatric 
Participants From Birth to Less Than 18 Years of Age With Confirmed or Suspected Gram-
negative Bacterial Infection
Protocol Number: 021-05
Compound Number: MK-7655A
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
NCT03969901
EU CT
Not applicable
EudraCT
2019-000338-20
JAPIC-CT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
108754
Approval Date: 20 July 2023
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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 5
20-JUL-2023
The primary reason for this amendment is to 
clarify the infection types necessary for inclusion 
of participants aged birth to <3 months in the 
study. 
Amendment 4
30-SEP-2022
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.
Amendment 3
15-DEC-2021
Amendment 3 (Global)
Reasons for the amendment: 
•
To communicate the dosing regimen of 
MK-7655A for participants enrolled in Age 
Cohorts 4 and 5, based on the interim review of 
safety, tolerability, and PK data from PN20 and 
Age Cohorts 1 through 3 of PN021, and 
•
To add piperacillin/tazobactam IV to the 
list of comparator medications allowed for 
participants with cIAI.
Amendment 2
27-AUG-2019
Amendment 2 (Global)
Reason for the amendment: 
To decrease the planned enrollment numbers 
(including overall, by age group, and by infection 
site).
Amendment 1
28-JAN-2019
Amendment 1 (Global)
Reason for the amendment: 
To correct the EudraCT Number.
Original Protocol
19-NOV-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 021-05
Overall Rationale for the Amendment:
The primary reason for this amendment is to clarify the infection types necessary for inclusion of participants aged birth to <3 months
in the study.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 5.1, Inclusion Criteria
Revised text to clarify the type of infection 
required for enrollment of participants aged 
birth to <3 months in the study. 
This change was made to address investigator/site 
feedback. The rationale is further supported by 
the need to clarify the infection types necessary 
for inclusion of participants aged birth to <3 
months in the study.
Other Changes in Amendment
Throughout
The structure of the protocol has been 
updated. 
To comply with current industry regulations and 
guidelines. This restructuring does not affect the 
clinical or regulatory integrity of the protocol. All 
other relevant changes and their primary reasons 
are included for completeness. 
Title Page
Added NCT identifying number.
To add regulatory agency identifying number.
Section 1.1, Synopsis -
Hypotheses, Objectives, and 
Endpoints
Revised text explaining there are no 
hypotheses evaluated in this study.
To clarify that there is no hypothesis testing in 
this study.
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Section Number and Name
Description of Change
Brief Rationale
Section 1.1, Synopsis –
Intervention Groups and 
Duration Table
Revised column headers and abbreviations 
in Interventions table.
To align with the EU CTR.
Section 1.1, Synopsis -
Intervention Groups and 
Duration Table
Added that IMI/REL is administered as a 
60-minute infusion.
To provide additional clarity about route of 
administration and align with Table 1.
Section 1.1, Synopsis -
Intervention Groups and 
Duration Table
Added note after table referring to Table 2
where the interventions are presented by 
infection type. 
To reference supplementary material. 
Section 1.2, Schema
Revised Figure 2 to change the number of 
participants for Cohort 1 to ≤12 and for 
Cohorts 2 and 3 to ≥20.
To align with PIP commitment.
Section 1.2, Schema
Revised Figure 2 to change the number of 
participants for Cohorts 4 and 5 to ≥28.
To align with the minimum enrollment targets for 
Cohorts 4 and 5.
Section 1.3, Schedule of 
Activities
Revised text to state (1) that vital signs 
should be collected daily during IV 
intervention, (2) that follow-up safety 
laboratory tests can be taken at either EFU 
or LFU through 14 days after EOT, and (3) 
that screening procedures should be 
completed before randomization.
To further clarify the timing of these procedures.
Section 1.3, Schedule of 
Activities
Revised text to refer to Table 4 for 
minimizing blood volumes in neonates.
To clarify the reduced number of blood collection 
timepoints required in neonates.
Section 1.3, Schedule of 
Activities
Added text stating that repeat 
catheterization is not required from 
participants unable to provide a clean urine 
specimen for post-baseline culture. 
To clarify the requirements for urine specimen 
collection.
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Section Number and Name
Description of Change
Brief Rationale
Section 2.2.2, Preclinical and 
Clinical Studies
Added PN016 to list of completed clinical 
studies.
To reflect the current status of the clinical 
development program.
Section 2.2.3, Ongoing Clinical 
Studies
Removed PN016.
To reflect the current status of the clinical 
development program.
Section 3, Hypotheses, 
Objectives, and Endpoints
Revised text explaining there are no 
hypotheses evaluated in this study.
To clarify that there is no hypothesis testing in 
this study.
Section 4.1, Overall Design
Revised the text describing enrollment 
targets for HABP/VABP and cIAI 
combined.
To align with enrollment targets for the evaluated 
infection types.
Section 4.1, Overall Design
Added text to explain that an interim 
analysis may be performed to assess safety, 
tolerability, efficacy, and PK when final 
data from Age Cohorts 1 to 3 are available.
To provide an option for interim analysis of all 
data from Age Cohorts 1 to 3.
Section 4.2.1.2, Rationale for 
Exclusion of Patients With 
Meningitis
Added the various options for meningitis 
evaluation, including LP or other 
procedures or assessments. 
To clarify the options allowed for ruling out 
meningitis.
Section 4.4, Beginning and End-
of-Study Definition
Added the definition of end of study for the 
purposes of analysis and reporting and the 
definition of local start of the study when an 
EEA Member State is included.
To align with the EU CTR.
Section 4.4, Beginning and End-
of-Study Definition
Added a cross-reference to Section 7.3.
To clarify definition of lost to follow-up by 
referring to Section 7.3.
Section 4.4.1, Clinical Criteria 
for Early Study Termination
Removed text and instead added a cross-
reference to Appendix 1.10.
To ensure clarity regarding when the Sponsor 
may stop the study or study-site participation.
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Section Number and Name
Description of Change
Brief Rationale
Section 5, Study Population
Revised text for specific populations as 
applicable to the study.
To clarify the collection, use, and confidentiality 
of demographic data provided by the participants.
Section 5.1, Inclusion Criteria
Change in term from “participant” to 
“individual” regarding eligibility.
To ensure clarity and intent of this section.
Section 5.2, Exclusion Criteria
Added text to exclusion criterion #4 to 
further define ileal loop reflux. 
Revised text in exclusion criterion #8 to add 
clarity regarding empiric antibiotic usage 
for suspected meningitis.
Revised text in exclusion criterion #9 to 
include patients <3 months of age without 
suspected meningitis and to specify that the 
note pertains to all participants.
To add clarity to exclusion criteria.
Section 6.1, Study 
Intervention(s) Administered
Revised column headers, dose formulations, 
abbreviations, and notes in Table 1 -
Interventions Table.
To align with the EU CTR.
Section 6.1, Study 
Intervention(s) Administered
Added footnote to Table 1 explaining where 
to find generic names for protocol-allowed 
comparator medications by infection type 
and referred to Table 2 for additional 
information listed by infection type.
To clarify the study interventions by infection 
type. 
Section 6.1, Study 
Intervention(s) Administered
Added Table 2 – Intervention, Dose, and 
Regimen by Infection Type.
To facilitate understanding of the study 
interventions.
Section 6.5, Concomitant 
Therapy
Added text regarding COVID-19 vaccine 
allowance.
To clarify COVID-19 vaccine information.
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Section Number and Name
Description of Change
Brief Rationale
Section 7.1, Discontinuation of 
Study Intervention
Revised text regarding monitoring of 
participants who discontinue study 
intervention and deleted redundant text.
To ensure clarity and intent of the section.
Section 8, Study Assessments 
and Procedures
Table 4: Merged cells and added footnotes 
to explain requirements regarding
approximate blood volumes drawn at early 
and late follow-up visits combined. 
To clarify blood volumes to be collected from 
neonates.
Section 8.1.6, Assignment of 
Screening Number
Added text regarding pretrial screening logs 
and removal of participant-identifying 
information.
To allow collection of participant screening logs.
Section 8.1.7, Assignment of 
Treatment/Randomization 
Number
Removed the terms “treatment” and 
“treatment allocation.”
To simplify wording for random treatment 
assignment. 
Section 8.1.8, Study Intervention 
Administration
Added text to describe who is qualified to 
administer study intervention(s).
To clarify who may administer study 
intervention.
Section 8.1.8.1.2, Optional Oral 
Switch (cIAI, cUTI)
Deleted “q6h” in study intervention 
description.
To make preceding text relevant to any dosing 
schedule. 
Section 8.1.8.1.2, Optional Oral 
Switch (cIAI, cUTI)
Added text stating that repeat 
catheterization not required for post-
baseline cultures.
To align with note in SoA pertaining to urine 
culture collection.
Section 8.3.4, Meningitis 
Evaluation
Restructured paragraph to list together the 
various options for meningitis evaluation, 
including LP or other procedures or 
assessments. 
To clarify the options allowed for ruling out 
meningitis.
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Section Number and Name
Description of Change
Brief Rationale
Section 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. 
Section 8.4.1, Time Period and 
Frequency for Collecting AE, 
SAE, and Other Reportable 
Safety Event Information
In Table 10, added text to reporting 
requirements for pregnancy/lactation 
exposure and for cancer.
To clarify reporting requirements for 
pregnancy/lactation and cancer.
Section 8.4.5, Pregnancy and 
Exposure During Breastfeeding
Added text advising the investigators to 
report pregnancy complications and 
medical reasons for elective terminations as 
AEs or SAEs. 
To ensure investigators are reporting medical 
reasons for elective termination of pregnancy.
Section 8.4.7, Events of Clinical 
Interest
Clarified definition of a potential DILI. 
To improve consistency.
Section 9.1, Statistical Analysis 
Plan Summary
Revised the text describing enrollment 
targets for HABP/VABP and cIAI 
combined.
To align with enrollment targets for the evaluated 
infection types.
Section 9.6.2, Statistical 
Methods for Safety Analyses
Clarified definition of a potential DILI.
To improve clarity and consistency.
Section 9.7, Interim Analyses
Added text to explain that an interim 
analysis may be performed to assess safety, 
tolerability, efficacy, and PK when final 
data from Age Cohorts 1 to 3 are available.
To provide an option for interim analysis of all 
data from Age Cohorts 1 to 3.
Section 9.9, Sample Size and 
Power Calculations
Revised the text describing enrollment 
targets for HABP/VABP and cIAI 
combined.
To align with enrollment targets for the evaluated 
infection types.
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Section Number and Name
Description of Change
Brief Rationale
Appendix 1, Section 10.1.3 -
Data Protection
Added statement specifying that Sponsor 
will conduct this study in compliance with 
data protection regulations.
To align with updated Code of Conduct 306.1.
Appendix 1, Section 10.1.7 -
Compliance with Law, Audit, 
and Debarment
Added paragraph to provide guidance to 
investigators in countries with serious 
breach reporting requirements and to define 
“serious breach.”
To align with the EU CTR.
Appendix 1, Section 10.1.10 -
Study and Site Closure
Added text to sentence regarding premature 
closure of a study site.
To add clarity regarding who can notify the site’s 
IRB/IEC and how.
Appendix 3, Section 10.3.1 
Definitions of Medication Error, 
Misuse, and Abuse
Added definitions of medication error, 
misuse, and abuse.
To align with the EU CTR.
Appendix 3, Section 10.3.2 -
Definition of AE
Added “medical device” and “combination 
product” to the definition of study 
intervention. 
To add clarity to AE definitions.
Appendix 3, Section 10.3.2 -
Definition of AE
Replaced “Sponsor’s product” with “study 
intervention” to be consistent with rest of 
protocol. 
To improve consistency throughout the 
document. 
Appendix 3, Section 10.3.5 -
Recording AE and SAE
Replaced “Sponsor’s product” with “study 
intervention” to be consistent with rest of 
protocol. 
To improve consistency throughout the 
document. 
Appendix 5, Section 10.5.1 -
Definitions
Expanded the definition of WOCBP.
To provide consistency and clarity related to 
contraceptive language within this section.
Appendix 5, Section 10.5.2 -
Contraceptive Requirements
Revised text for contraceptives allowed 
during the study.  
To align with CTFG 1.1 Recommendations 
related to contraception.
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Section Number and Name
Description of Change
Brief Rationale
Appendix 8, Section 10.8.3 -
cUTI
Added sentence specifying the collection of 
a urine specimen from which pyuria is 
identified should be obtained within 48 
hours prior to randomization.  
To align with investigator feedback that pyuria is 
intermittent in neonates.
Appendix 9, Section 10.9.3 -
cUTI
Added meropenem IV to the list of drugs 
allowed for the treatment of cUTI.
To align with local standard of care.
Appendix 10, Abbreviations
Moved List of Abbreviations to end of 
appendices and updated numbering of 
Appendices.
To align with other protocols and make 
abbreviations easier to find.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................20
1.1
Synopsis.................................................................................................................20
1.2
Schema ..................................................................................................................25
1.3
Schedule of Activities...........................................................................................27
2
INTRODUCTION..........................................................................................................42
2.1
Study Rationale....................................................................................................42
2.2
Background ..........................................................................................................42
2.2.1
Pharmaceutical and Therapeutic Background .............................................42
2.2.2
Preclinical and Clinical Studies ...................................................................43
2.2.3
Ongoing Clinical Studies.............................................................................44
2.2.4
Information on Other Study-related Therapy ..............................................44
2.2.4.1
Optional Oral Switch (cIAI, cUTI)....................................................44
2.3
Benefit/Risk Assessment......................................................................................45
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................46
4
STUDY DESIGN............................................................................................................47
4.1
Overall Design......................................................................................................47
4.2
Scientific Rationale for Study Design.................................................................49
4.2.1
Rationale for Study Population....................................................................49
4.2.1.1
Rationale for Exclusion of Patients With Renal Impairment.............50
4.2.1.2
Rationale for Exclusion of Patients With Meningitis ........................50
4.2.2
Rationale for Endpoints ...............................................................................51
4.2.2.1
Efficacy Endpoints.............................................................................51
4.2.2.1.1
All-cause Mortality/Survival Status.........................................51
4.2.2.1.2
Clinical Response.....................................................................52
4.2.2.1.3
Microbiological Response .......................................................52
4.2.2.1.4
Exploratory Endpoint: By-pathogen Microbiological 
Response ..................................................................................53
4.2.2.2
Safety Endpoints................................................................................54
4.2.2.3
Pharmacokinetic Endpoints ...............................................................54
4.2.3
Rationale for the Use of Active Controls.....................................................55
4.3
Justification for Dose...........................................................................................56
4.3.1
Starting Dose for This Study........................................................................56
4.3.2
Maximum Dose Exposure for This Study ...................................................56
4.3.3
Rationale for Dose Interval and Study Design ............................................56
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4.3.3.1
Hospital-Acquired and Ventilator-Associated Bacterial 
Pneumonia (HABP/VABP) ...............................................................57
4.3.3.2
Complicated Intra-Abdominal Infection (cIAI).................................58
4.3.3.3
Complicated Urinary Tract Infection (cUTI).....................................58
4.4
Beginning and End-of-Study Definition ............................................................59
4.4.1
Clinical Criteria for Early Study Termination .............................................59
5
STUDY POPULATION ................................................................................................60
5.1
Inclusion Criteria.................................................................................................60
5.2
Exclusion Criteria................................................................................................61
5.3
Lifestyle Considerations......................................................................................64
5.4
Screen Failures.....................................................................................................64
5.5
Participant Replacement Strategy......................................................................64
6
STUDY INTERVENTION............................................................................................65
6.1
Study Intervention(s) Administered...................................................................65
6.1.1
Dose by Age Cohort.....................................................................................73
6.2
Preparation/Handling/Storage/Accountability .................................................73
6.2.1
Dose Preparation..........................................................................................73
6.2.2
Handling, Storage, and Accountability........................................................73
6.3
Measures to Minimize Bias: Randomization and Blinding..............................74
6.3.1
Intervention Assignment..............................................................................74
6.3.2
Stratification.................................................................................................74
6.3.3
Blinding........................................................................................................74
6.4
Study Intervention Compliance..........................................................................75
6.5
Concomitant Therapy..........................................................................................75
6.5.1
Rescue Medications and Supportive Care ...................................................76
6.6
Dose Modification (Escalation/Titration/Other)...............................................76
6.7
Intervention After the End of the Study............................................................76
6.8
Clinical Supplies Disclosure................................................................................76
6.9
Standard Policies..................................................................................................76
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................77
7.1
Discontinuation of Study Intervention...............................................................77
7.2
Participant Withdrawal From the Study...........................................................78
7.3
Lost to Follow-up .................................................................................................78
8
STUDY ASSESSMENTS AND PROCEDURES........................................................79
8.1
Administrative and General Procedures ...........................................................80
8.1.1
Informed Consent/Assent.............................................................................80
8.1.1.1
General Informed Consent/Assent.....................................................81
8.1.2
Inclusion/Exclusion Criteria ........................................................................81
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8.1.3
Participant Identification Card.....................................................................81
8.1.4
Medical History ...........................................................................................82
8.1.5
Prior and Concomitant Medications Review...............................................82
8.1.5.1
Prior Medications...............................................................................82
8.1.5.2
Concomitant Medications..................................................................82
8.1.6
Assignment of Screening Number...............................................................82
8.1.7
Assignment of Treatment/Randomization Number.....................................83
8.1.8
Study Intervention Administration ..............................................................83
8.1.8.1
Timing of Dose Administration.........................................................83
8.1.8.1.1
IV Study Intervention ..............................................................83
8.1.8.1.2
Optional Oral Switch (cIAI, cUTI)..........................................84
8.1.9
Discontinuation and Withdrawal .................................................................85
8.1.10
Participant Blinding/Unblinding..................................................................85
8.1.11
Calibration of Equipment.............................................................................85
8.2
Efficacy Assessments ...........................................................................................85
8.2.1
All-cause Mortality (28-day Survival Assessment).....................................85
8.2.2
Clinical Response.........................................................................................85
8.2.2.1
Clinical Signs and Symptoms Review...............................................85
8.2.2.2
Investigator Rating and Sponsor Categorization of Clinical 
Response ............................................................................................86
8.2.3
Microbiological Response ...........................................................................88
8.2.3.1
Infection Site and Blood Specimens for Gram Stain, Culture, and 
Susceptibility Testing.........................................................................88
8.2.3.1.1
HABP/VABP: Lower Respiratory Tract Specimen(s) for 
Gram Stain, Culture, and Susceptibility Testing .....................89
8.2.3.1.2
cIAI: Intra-abdominal Specimen(s) for Culture and 
Susceptibility Testing...............................................................90
8.2.3.1.3
cUTI: Urine Specimens for Culture and Susceptibility 
Testing......................................................................................90
8.2.3.1.4
Blood Specimen(s) for Culture and Susceptibility Testing .....91
8.2.3.2
Investigator Rating and Sponsor Categorization of 
Microbiological Response .................................................................91
8.2.4
By-pathogen Microbiological Response......................................................94
8.3
Safety Assessments...............................................................................................94
8.3.1
Full and Directed Physical Examinations....................................................94
8.3.2
Height and Weight .......................................................................................95
8.3.3
Vital Signs....................................................................................................95
8.3.4
Meningitis Evaluation..................................................................................96
8.3.5
Adverse Event Monitoring...........................................................................96
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8.3.5.1
Clinical Adverse Events.....................................................................96
8.3.5.2
Local Infusion Site Tolerability.........................................................96
8.3.5.3
Laboratory Adverse Experiences.......................................................96
8.3.5.4
Adverse Events Leading to Death......................................................96
8.3.6
Clinical Signs and Symptoms of Infection ..................................................97
8.3.6.1
Infection Source Control Review.......................................................97
8.3.6.2
O2 Saturation (HABP/VABP Only)..................................................97
8.3.6.3
Chest X-ray ........................................................................................98
8.3.7
Clinical Safety Laboratory Assessments .....................................................98
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................98
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................99
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....101
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.101
8.4.4
Regulatory Reporting Requirements for SAE ...........................................101
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................102
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................102
8.4.7
Events of Clinical Interest..........................................................................102
8.5
Treatment of Overdose......................................................................................103
8.6
Pharmacokinetics...............................................................................................103
8.6.1
Blood Collection for Plasma Relebactam, Imipenem, and Cilastatin........103
8.7
Pharmacodynamics............................................................................................103
8.8
Future Biomedical Research Sample Collection.............................................103
8.9
Planned Genetic Analysis Sample Collection..................................................103
8.10
Visit Requirements.............................................................................................104
8.10.1
Screening....................................................................................................104
8.10.2
Intervention Period.....................................................................................104
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................104
8.10.4
Poststudy....................................................................................................105
9
STATISTICAL ANALYSIS PLAN ...........................................................................106
9.1
Statistical Analysis Plan Summary...................................................................106
9.2
Responsibility for Analyses/In-house Blinding ...............................................108
9.3
Hypotheses/Estimation ......................................................................................108
9.4
Analysis Endpoints.............................................................................................108
9.4.1
Efficacy Endpoints.....................................................................................108
9.4.2
Safety Endpoints........................................................................................109
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9.4.3
Pharmacokinetics Endpoints......................................................................110
9.5
Analysis Populations..........................................................................................110
9.5.1
Efficacy Analysis Populations...................................................................110
9.5.2
Safety Analysis Populations ......................................................................111
9.5.3
Pharmacokinetics Populations ...................................................................111
9.6
Statistical Methods.............................................................................................112
9.6.1
Statistical Methods for Efficacy Analyses.................................................112
9.6.2
Statistical Methods for Safety Analyses ....................................................113
9.6.3
Statistical Methods for Pharmacokinetics Analysis...................................115
9.6.4
Demographic and Baseline Characteristics ...............................................116
9.7
Interim Analyses ................................................................................................116
9.8
Multiplicity .........................................................................................................117
9.9
Sample Size and Power Calculations ...............................................................117
9.10
Subgroup Analyses.............................................................................................118
9.11
Compliance (Medication Adherence)...............................................................119
9.12
Extent of Exposure.............................................................................................119
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................120
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......120
10.1.1
Code of Conduct for Clinical Trials...........................................................120
10.1.2
Financial Disclosure...................................................................................123
10.1.3
Data Protection...........................................................................................123
10.1.3.1
Confidentiality of Data ....................................................................123
10.1.3.2
Confidentiality of Participant Records.............................................124
10.1.3.3
Confidentiality of IRB/IEC Information..........................................124
10.1.4
Committees Structure.................................................................................124
10.1.4.1
Executive Oversight Committee......................................................124
10.1.4.2
External Data Monitoring Committee (eDMC)...............................124
10.1.5
Publication Policy......................................................................................125
10.1.6
Compliance with Study Registration and Results Posting Requirements .125
10.1.7
Compliance with Law, Audit, and Debarment ..........................................125
10.1.8
Data Quality Assurance .............................................................................126
10.1.9
Source Documents .....................................................................................127
10.1.10
Study and Site Closure...............................................................................127
10.2
Appendix 2: Clinical Laboratory Tests............................................................128
10.2.1
Renal Function Ranges ..............................................................................129
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................131
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................131
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10.3.2
Definition of AE ........................................................................................131
10.3.3
Definition of SAE ......................................................................................132
10.3.4
Additional Events Reported.......................................................................133
10.3.5
Recording AE and SAE .............................................................................133
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................136
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................138
10.5
Appendix 5: Contraceptive Guidance..............................................................139
10.5.1
Definitions..................................................................................................139
10.5.2
Contraceptive Requirements......................................................................139
10.5.3
Pregnancy Testing......................................................................................141
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................142
10.7
Appendix 7: Country-specific Requirements..................................................143
10.8
Appendix 8: Disease Definitions and Diagnostic Criteria..............................144
10.8.1
HABP/VABP.............................................................................................144
10.8.2
cIAI ............................................................................................................145
10.8.3
cUTI...........................................................................................................147
10.9
Appendix 9: Protocol-allowed Comparator Medications by Drug Name ....150
10.9.1
HABP/VABP.............................................................................................150
10.9.2
cIAI ............................................................................................................150
10.9.3
cUTI...........................................................................................................151
10.10 Appendix 10: Abbreviations .............................................................................153
11
REFERENCES.............................................................................................................156
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LIST OF TABLES
Table 1
Study Interventions......................................................................................66
Table 2
Intervention, Dose, and Regimen by Infection Type...................................70
Table 3
IMI/REL Dose by Age Cohort.....................................................................73
Table 4
Approximate Blood Volumes Drawn in Neonates by Study Visit, 
Sample Type ................................................................................................80
Table 5
Clinical Signs and Symptoms for Each Infection Type...............................86
Table 6
Clinical Response Ratings at the EOIV and EOT Visits.............................87
Table 7
Clinical Response Ratings at the EFU and LFU Visits ...............................87
Table 8
By-Pathogen Microbiological Response Ratings at the EOIV and EOT 
Visits ............................................................................................................92
Table 9
By-pathogen Microbiological Response Ratings at the EFU and LFU 
Visits ............................................................................................................93
Table 10
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...........................................................................100
Table 11
Summary of Efficacy Endpoints and Components of a Favorable 
Response ....................................................................................................109
Table 12
Analysis Strategy for Efficacy Variables...................................................113
Table 13
Analysis Strategy for Safety Parameters....................................................115
Table 14
Two-Sided 95% Confidence Intervals.......................................................118
Table 15
Protocol-required Safety Laboratory Assessments....................................128
Table 16
Acceptable Renal Function Ranges for Study Inclusion Based on 
Estimated Creatinine Clearance or Estimated Glomerular Filtration Rate 
by Age Range.............................................................................................129
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LIST OF FIGURES
Figure 1
Study Design Diagram.................................................................................25
Figure 2
Enrollment Plan ...........................................................................................26
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2/3 Open-label, Randomized, Active-controlled Clinical Study to 
Evaluate the Safety, Tolerability, Efficacy and Pharmacokinetics of MK-7655A in Pediatric 
Participants From Birth to Less Than 18 Years of Age With Confirmed or Suspected Gram-
negative Bacterial Infection
Short Title: Open-label Active-control Pediatric Safety, Efficacy, PK Study of MK-7655A
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There are no formal statistical hypotheses to be evaluated in this study.
The following objectives and endpoints will be evaluated in pediatric participants from birth 
to less than 18 years of age with confirmed or suspected gram-negative bacterial infection 
involving 1 of 3 primary infection types: HABP/VABP, cIAI, or cUTI:
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of 
IMI/REL (imipenem/cilastatin/relebactam) 
from the first dose of intravenous (IV) study 
intervention through 14 days after the end 
of therapy (EOT)
Adverse events (AEs)
IV study intervention discontinuations due 
to AEs
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of IMI/REL by 
assessing all-cause mortality at Day 28 
postrandomization and clinical and 
microbiological response at the EOT, Early 
Follow-up (EFU, 7 to 14 days after EOT), 
and Late Follow-up (LFU, 7 to 14 days after 
EFU) visits
All-cause mortality
Favorable clinical response
Favorable microbiological response
To characterize the PK profile of imipenem 
and relebactam following administration of 
IMI/REL
Plasma concentrations of imipenem and 
relebactam
AUC0-24hr and Ceoi for imipenem and 
relebactam
%T>MIC for imipenem
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Overall Design:
Study Phase
Phase 2/3
Primary Purpose
Treatment
Indication
Bacterial infection in pediatric populations
Population
Participants from birth to less than 18 years 
of age with confirmed or suspected gram-
negative bacterial infection
Study Type
Interventional
Intervention Model
Parallel
This is a multisite study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 4 years 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.
Number of Participants:
Approximately 140 participants will be randomized in a 3:1 ratio to receive IMI/REL or 
active control as described in Section 9.9.
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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/
Vaccination 
Regimen
Use
IMI/
REL
IMI/REL
relebactam, 
imipenem, 
cilastatin 
250/500/500 
mg
Age Cohort 1: 
500/250 mg 
q6h 
Age Cohort 2: 
15/7.5 mg/kg 
q6h 
Age Cohort 3: 
15/7.5 mg/kg 
q6h 
Age Cohort 4: 
15/7.5 mg/kg 
q6h 
Age Cohort 5:
15/7.5 mg/kg 
q8h
All 
administered
as 60-minute 
infusions
IV Infusion
cIAI and cUTI: 
Total duration of 
all study 
intervention: 
Minimum 5 days 
(IV alone or IV 
then oral, of which 
at least 3 days must 
be IV alone before 
optional oral 
switch) up to a 
maximum of 14 
days;
HABP/VABP: 
Minimum 7 days 
up to a maximum 
of 14 days.
Test Product
Active 
Control
Acceptable 
control 
options for 
each 
infection 
type
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
Per authorized 
PI, SPC, or 
international 
treatment 
guidelines
IV Infusion
cIAI and cUTI:
Total duration of 
all study 
intervention: 
Minimum 5 days 
(IV alone or IV 
then oral, of which 
at least 3 days must 
be IV alone before 
optional oral 
switch) up to a 
maximum of 14 
days; HABP/ 
VABP: Minimum 
7 days up to a 
maximum of 14 
days. All 
administered per 
authorized PI, SPC, 
or international 
treatment 
guidelines.
Comparator
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Arm Name Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMI/
REL
Acceptable 
oral switch 
options for 
cIAI and 
cUTI
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
Per authorized 
PI, SPC, or 
international 
treatment 
guidelines
Oral
Per authorized PI, 
SPC, or 
international 
treatment 
guidelines
Systemically 
Prescribed
Active 
Control
Acceptable 
oral switch 
options for 
cIAI and 
cUTI
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
Per authorized 
PI, SPC, or 
international 
treatment 
guidelines
Oral
Per authorized PI, 
SPC, or 
international 
treatment 
guidelines
Systemically 
Prescribed
cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; EDC=electronic data collection; 
HABP/VABP=hospital-acquired or ventilator-associated bacterial pneumonia; IMI/REL=imipenem/cilastatin/relebactam 
(MK-7655A); IV=intravenous; PI=Package Insert; PO=per os (by mouth); q6h=every 6 hours; q8h=every 8 hours;
SPC=Summary of Product Characteristics.
Note: In both intervention arms (IMI/REL and Active Control), participants with cIAI or cUTI may have an optional switch 
to a specified oral antibacterial therapy after the indicated minimum number of days of IV study intervention at the 
investigator’s discretion based on the participant’s clinical condition and local standard of care. The choice of oral switch
therapy should be guided by culture results and based on local antibiotic susceptibility patterns.
Note: Protocol-allowed comparator medications for each infection type are detailed by generic drug name in the EDC 
system, EDC guidelines, and Appendix 9.
Note: Study intervention, dose, and regimen are listed by infection type in Table 2.
IMI/REL Dose by Age Cohort
Age Cohort
Age Range
IMI/REL Dosea
1
12 to <18 years
500/250 mg q6h
2
6 to <12 years
15/7.5 mg/kg q6h
3
2 to <6 years
15/7.5 mg/kg q6h
4
3 months to <2 years
15/7.5 mg/kg q6hb
5
Birth to <3 months
15/7.5 mg/kg q8hb
FDC=fixed-dose combination; IMI/REL=imipenem/cilastatin/relebactam (MK-7655A); q6h=every 6 hours; q8h=every 8 
hours.
a
Doses for all age cohorts will be administered as 60-minute infusions and will not exceed the adult maximum single 
dose of IMI/REL 500 mg/250 mg. IMI/REL is provided as a single-vial FDC; therefore, the dose for each 
component will be adjusted proportionally during preparation. 
b
Initial doses of IMI/REL for participants in Age Cohorts 4 and 5 were selected based on results from the single-dose 
safety and pharmacokinetics (PK) study in pediatric participants from birth to less than 18 years of age with proven 
or suspected gram-negative infections (MK-7655A-020) and confirmed based on review of safety, tolerability, 
efficacy, and PK data from Age Cohorts 1 through 3 in the current study (PN021). Initial doses for Age Cohorts 4 
and 5 have been communicated to investigators and sites via Protocol Amendment (03) prior to initiation of 
enrollment of Age Cohorts 4 and 5.
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Total Number of Intervention Groups/Arms
2 treatment arms (IMI/REL or Active 
Control)
Duration of Participation
Each participant will participate in the study 
for approximately 44 days from the time 
that the participant (or their legally 
acceptable representative) provides 
documented informed consent/assent 
through the final contact. After a screening 
phase of up to 2 days, each participant will 
receive all assigned study intervention for a 
total of a minimum of 5 days (cIAI, cUTI, 
IV alone or IV then oral, of which at least 3 
days must be IV alone before optional oral 
switch) or 7 days (HABP/VABP, IV alone) 
up to a maximum of 14 days of all study 
intervention (IV alone or IV then oral). 
After the end of all study intervention, each 
participant will be followed for up to 28 
days.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations used in this document can be found in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1 and the enrollment plan is depicted in Figure 2.
Figure 1
Study Design Diagram
AE=adverse event; cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; EFU=early 
follow-up; EOIV=end of IV therapy; EOT=end of therapy; HABP/VABP=hospital-acquired or ventilator-associated 
bacterial pneumonia; IMI/REL=fixed-dose combination imipenem/cilastatin and relebactam (MK-7655A); IV=intravenous; 
LFU=late follow-up; OTX=on therapy; PK=pharmacokinetic.
a
Participants receiving IMI/REL will have blood samples for PK analysis collected on Day 1 at 3 time points: (1) 30 
minutes prior to the start of the first dose of IV study intervention; (2) within 10 minutes after the end of the first 
infusion; and (3) at 2 to 6 hours after the start of the first infusion; and once at the OTX visit (on Day 2 OR Day 3) at 2 
to 6 hours after the start of any infusion that day. 
b
The EOIV visit will occur only in participants with cIAI or cUTI whom the investigator deems eligible to switch to oral 
antibacterial therapy (after completion of at least 3 days of IV alone) based on the participant’s clinical condition and 
local standard of care. If performed, the EOIV visit must occur ≤24 hours after the last IV dose.
c
The total duration of all study intervention (IMI/REL or active control) must be a minimum of 5 days (cIAI and cUTI, 
IV alone or IV then oral, of which at least 3 days must be IV alone before optional oral switch) or 7 days 
(HABP/VABP, IV alone) up to 14 days (IV alone or IV then oral). Participants with bacteremia or Pseudomonas 
aeruginosa infection should receive 14 days of antibiotic therapy. Extension beyond 14 days requires Sponsor approval. 
Participants with cIAI or cUTI who are switched to oral therapy will have the EOT visit ≤24 hours after the last oral 
dose. For all participants, EOT is the end of all study intervention, and the EOT visit must occur ≤24 hours after 
completion of the last IV or oral dose. 
d
Safety and efficacy assessments must occur at the EOIV (for participants who switch to oral therapy), EOT, EFU, and 
LFU visits.
e
The 28-day survival assessment is to be performed on Day 28 post-randomization at either the EFU or LFU visit or by 
telephone call on Day 28 (+3 days) post-randomization. 
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Figure 2
Enrollment Plan
eDMC=external data monitoring committee; IMI/REL=imipenem/cilastatin/relebactam (MK-7655A); IV=intravenous; 
mos=months; PK=pharmacokinetic; q6h=every 6 hours; q8h=every 8 hours; yrs=years.
a
Dose for any age cohort will not exceed the maximum adult single IV dose of IMI/REL 500 mg/250 mg. IMI/REL will 
be administered as a 60-minute IV infusion for all cohorts.
b
Target enrollment is approximately 140 participants to target having 132 participants in the safety population (ie, who 
received at least 1 dose of study intervention).
c
No more than 84 participants will be enrolled across Age Cohorts 1, 2, and 3.
d
PK and/or efficacy data will be provided to the eDMC upon request to support benefit-to-risk evaluation.
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1.3
Schedule of Activities
Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Administrative Procedures
Informed 
Consent/Assent
X
Documented 
informed consent 
from the 
participant’s 
legally acceptable 
representative and 
age-appropriate 
assent.
Inclusion/
Exclusion Criteria
X
Participant 
Identification 
Card
X
X
Treatment/
randomization 
number added at 
time of 
randomization.
Medical History, 
including full 
assessment of 
details of 
infection-site 
diagnoses
X
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Prior/Concomitant 
Medication 
Review
X
X
X
X
X
X
X
X
For breastfed 
participants, 
include mother’s 
medications. 
Intervention 
Randomization 
and Stratification
X
IRT Contact
X
-------- If applicable -------
X
Required for any 
local or central 
laboratory
abnormalities in 
serum creatinine
or weight changes
that may result in a 
CrCl value 
meeting 
discontinuation
criteria and for
additional 
IMI/REL supply.
IMI/REL or 
Active Control
Administrationc
----------------- Daily ------------- 
Table 1and Table 
3
Safety Procedures
Full Physical 
Examination
X
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Directed Physical 
Examination
X
X
X
X
X
X
X
Height
X
Weight
X
-------------- If applicable ---------
See IRT Contact 
Note and Section 
8.3.2.
Vital Signs (heart 
rate, blood 
pressure, 
respiratory rate, 
temperature)
X
Daily during IV study intervention 
X
X
X
On Day 1, assess 
prior to the 
initiation of IV 
study intervention.
Perform 
assessments daily 
during IV study 
intervention, and 
at the EOIV (as
applicable) and
EOT visits.
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Serum β-hCG
(female 
participants of 
childbearing 
potential only)
X
X
X
Rapid urine 
β-HCG may be 
used for screening, 
but, if positive, the 
result must be 
confirmed by 
central laboratory
serum β-HCG and 
the participant 
must be 
discontinued. 
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Hematology
X
X
X
X
X
X
X
For screening, the 
most recent local 
laboratory results 
available ≤48 hr 
prior to 
randomization 
may be used
(repeat testing not 
needed on Day 1).
See Table 4 for 
blood collection in 
neonates. Follow-
up safety 
laboratory tests
can be taken at 
either EFU or LFU 
through 14 days 
after EOT.
Chemistry
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Meningitis 
Evaluation 
(Participants 
<3 months of age)
X
Investigator 
assessment of 
absence of 
meningitis must be 
documented on the 
appropriate source 
documents. 
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
AE/SAE 
Monitoring
Daily during IV study intervention 
X
X
X
Monitor for AEs 
daily during IV
study intervention, 
at EOIV (if 
applicable), at 
EOT, and through
14 days after 
completion of all 
study intervention 
(IV or IV then 
oral). Any SAE 
brought to the
attention of the 
investigator 
outside 14 days 
post-EOT must be 
reported 
immediately to the
Sponsor if 
considered drug 
related. 
Local Infusion 
Tolerability
Monitoring
Daily during IV study intervention 
X
Monitor for local 
infusion 
tolerability AEs
daily during IV 
study intervention.
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Review of 
Clinical Signs and 
Symptoms of 
Infection 
(associated with
both primary and 
any secondary
bacterial infection
sites)
Daily during IV study intervention 
X
X
X
Presence/absence 
of infection-
specific clinical 
signs and 
symptoms will be 
reviewed daily 
during IV study 
intervention, and 
at the EOIV (as 
applicable) and 
EOT visits. Table 
5.
Infection Source 
Control Review
X
X
X
X
X
Document source 
control 
information per 
the infection type
on the appropriate 
eCRF.
O2 Saturation 
(HABP/VABP 
only)
Daily during IV study intervention 
X
X
X
PaO2/FiO2 ratio 
should also be 
recorded if 
available.
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Chest X-ray 
(HABP/VABP)
X
If clinically indicated during IV 
study intervention
X
Perform on Day 1 
if a prior chest x-
ray or CT was not 
performed for 
current infection 
≤48 hr prior to
randomization. 
Perform at DC 
only if clinically 
indicated. Record 
relevant 
radiographic 
findings on the
appropriate eCRF. 
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Gram stain, Culture, and Susceptibility Testing
HABP/VABP: 
Lower 
Respiratory Tract
(LRT) Specimen 
for Gram stain, 
Culture and 
Susceptibility
Testing
X
Collect post-baseline LRT infection-site specimen only from 
participants who otherwise require a procedure that allows for 
specimen collection.
Per Appendix 8 –
Section 10.8.1, 
obtain baseline 
culture prior to
initiation of IV
study intervention 
for local 
laboratory testing 
and central 
laboratory analysis 
of pathogens. 
Record findings on 
the appropriate 
eCRF on the 
respective study 
day(s). 
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
cIAI: Intra-
abdominal 
Specimen for 
Culture and 
Susceptibility
Testing
X
Collect post-baseline intra-abdominal infection-site specimen only 
from participants who otherwise require a procedure that allows for 
specimen collection.
Per Appendix 8 –
Section 10.8.2, 
obtain baseline 
culture prior to or 
within 24 hr after 
initiation of IV
study intervention 
for local 
laboratory testing 
and central 
laboratory analysis 
of pathogens. 
Record findings on 
the appropriate 
eCRF on the 
respective study 
day(s). 
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
cUTI: Urine
Specimen for 
Culture with 
Colony Count and 
Susceptibility
Testing
X
X
X
X
X
X
X
Per Appendix 8 -
Section 10.8.3, 
collect baseline 
urine culture prior 
to initiation of IV 
study intervention 
on Day 1. Per 
Section 8.2.3.1.3, 
collect post-
baseline only from 
participants able to 
provide a clean 
specimen (repeat 
catheterization not 
required). All 
samples will be 
used for local 
laboratory testing 
and central 
laboratory analysis 
of pathogens. 
Record findings on 
the appropriate 
eCRF on the 
respective study 
day(s). 
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Blood Specimen 
for Culture and 
Susceptibility
Testing
As clinically indicated, 
prior to the initiation of 
IV study intervention
As clinically indicated or, if 
prestudy blood culture was 
positive, repeat until negative on a
subsequent culture
If performed, 
record on the 
appropriate eCRF. 
Efficacy Evaluation
Survival 
Assessment
28-day survival assessed on Day 28 at either the 
EFU or LFU visit or by telephone call on Day 28 
(+3 days) post-randomization
Clinical Response 
Assessment
X
X
X
X
X
Investigator 
assessment for 
presence/absence 
of infection-
specific clinical 
signs and 
symptoms at the 
indicated visits 
compared with 
baseline. Table 6
and Table 7.
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Microbiological 
Response 
Assessment 
X
X
X
X
X
Investigator 
assessment of 
participants with a 
post-baseline 
infection-site 
specimen (as 
clinically 
appropriate) for 
microbiological 
response at the 
indicated visits.
Table 8 and Table 
9.
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Study Period
Screening
Intervention
Follow-up: 
up to 42 days post-randomization
DC
Notes
Visit 
Number/Title
1 
Screeninga
2 
Day 1b
3 
OTXb
4 
EOIVc
(oral switch 
only)
5 
EOTd
(all)
6 
EFUe
7 
LFUe
TCf
Ug
Scheduled Day
Day 
-2 to 1
Day 
1
Day 
2-3
Day 
3-14
Day 
5-14
7-14 days 
after EOT
7-14 days 
after EFU
28 days post-
randomization
DC
Scheduling 
Window
≤48 hr pre-
randomization
NA
NA
≤24 hr 
post-final 
IV dose
≤24 hr
post-final 
dose
NA
NA
+3 days
NA
Pharmacokinetics/Pharmacodynamics/ Biomarkers
Plasma 
Pharmacokinetic 
Sampling for 
relebactam, 
imipenem, and 
cilastatin assay 
(only participants 
receiving 
IMI/REL)
X
X
Blood samples for 
PK analysis will
be collected on 
Day 1 at 3 time 
points: (1) 30 min 
prior to start of 
first dose of IV 
study intervention; 
(2) within 10 
minutes after the 
end of the first 
infusion; and (3) 2 
to 6 hr after start 
of first infusion; 
and once at the 
OTX visit on 
Day 2 OR 3 at 2 to 
6 hr after start of 
any infusion that 
day. 
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AE=adverse event; β-hCG=β-human chorionic gonadotropin; cIAI=complicated intra-abdominal infection; CrCl=creatinine clearance; CT=computed tomography; 
cUTI=complicated urinary tract infection; DC=discontinuation from the study; eCRF=electronic case report form; EFU=Early Follow-up; EOIV=end of IV therapy; EOT=End of 
Therapy; HABP/VABP=hospital-acquired or ventilator-associated bacterial pneumonia; hr=hours; IMI/REL=imipenem/cilastatin/relebactam (MK-7655A); IRT=interactive 
response technology; IV=intravenous; LFU=Late Follow-up; LRT=lower respiratory tract; min=minutes; NA=not applicable; OTX=on therapy; PaO2/FiO2 ratio=ratio of partial 
pressure of oxygen to the fraction of inspired oxygen; PK=pharmacokinetic; SAE=serious adverse event; TC=telephone call; U=unscheduled visit.
a
Screening procedures must be completed within 48 hours prior to randomization.  
b
Participants who receive IMI/REL will have blood sampling for PK analysis on 2 days during the study: on Day 1 (at the 3 time points indicated) and at the OTX visit (at the 
1 time point indicated) on Day 2 OR 3. The OTX and EOIV visits may be combined if both occur on Day 3. 
c
Visit 4 (EOIV) will occur only in participants with cIAI or cUTI whom the investigator deems eligible to switch to oral antibacterial therapy after completion of at least 3 
days of IV study intervention based on the participant’s clinical condition (see Section 8.1.8.1.2 for the oral switch criteria). The list of acceptable oral switch options is 
provided in Table 2. If performed, the EOIV visit must occur ≤24 hr after the last IV dose. The OTX and EOIV visits may be combined if both occur on Day 3. 
d
The total duration of all study intervention (IMI/REL group or active control group) must be a minimum of 5 days (cIAI and cUTI, IV alone or IV then oral, of which the first 
3 days must be IV before optional oral switch) or 7 days (HABP/VABP, IV alone) up to a maximum of 14 days (IV alone or IV then oral). Participants with bacteremia or 
Pseudomonas aeruginosa infection should receive 14 days of antibacterial therapy. Participants with cIAI or cUTI who switch to oral therapy will have the EOT visit ≤24 hr 
after the last oral dose up to a maximum of 14 days of all study intervention (IV then oral). For all participants, EOT is the end of all study intervention and the EOT visit 
must occur ≤24 hours after completion of the last IV or oral dose. Extension beyond 14 days requires Sponsor approval (see Section 4.3.3).
e
The EFU visit will occur 7 to 14 days after EOT and the LFU visit will occur 7 to 14 days after the EFU visit. EOT is the end of all study intervention (IV or IV then oral). 
f
A telephone call will be made on Day 28-31 post-randomization if the EFU and LFU visits take place prior to Day 28.
g
Discontinuation procedures are to be performed for all participants who discontinue from any study intervention; ie, those who discontinue study intervention or withdraw 
from the study at any point after the initiation of IV study intervention.
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2
INTRODUCTION
2.1
Study Rationale
This is the second study in support of the pediatric development of IMI/REL 
(imipenem/cilastatin/relebactam, MK-7655A) for the treatment of bacterial infections caused 
by gram-negative bacteria, including HABP/VABP, cIAI, and cUTI, in patients who may be 
infected with carbapenem-resistant gram-negative bacteria.
The goals of this study are to gain additional safety data for IMI/REL in pediatric patients, to 
confirm dose recommendations derived from the first pediatric study (MK-7655A-020), and 
to describe efficacy in the pediatric population.
2.2
Background
The FDC of imipenem, cilastatin, and REL was approved as RECARBRIO™ by the US 
FDA on 16 JUL 2019 for use in patients 18 years of age and older who have limited or no 
alternative treatment options for the treatment of cUTI, including pyelonephritis, caused by 
the following susceptible gram-negative microorganisms: Enterobacter cloacae, Escherichia 
coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa and for the 
treatment of cIAI caused by the following susceptible gram-negative microorganisms: 
Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, 
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter 
freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella 
aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis, and P.
aeruginosa. Refer to the IB for detailed background information on REL (relebactam, 
MK-7655) and IMI/REL (imipenem/cilastatin/relebactam, MK-7655A) and to the 
PRIMAXIN® USPI [U.S. Prescribing Information 2017] or TIENAM® SPC (ex-US) 
[Summary of Product Characteristics 2011] for background information on IMI 
(imipenem/cilastatin).
2.2.1
Pharmaceutical and Therapeutic Background
β-lactam antibacterials (penicillins, cephalosporins, carbapenems, and monobactams) are 
among the most frequently used antimicrobial agents in clinical practice. The continuing 
development of resistance to these β-lactam antibacterials poses an ongoing threat to the 
clinical utility of all β-lactams. The production of β-lactamases is the most important 
resistance mechanism among gram-negative bacteria. Therefore, there is an urgent need for 
new BLIs that can be combined with existing β-lactam antibacterials to protect against 
hydrolysis by 1 or more of the 4 classes (A, B, C, and D) of β-lactamase enzymes.
Pediatric patients are particularly vulnerable to infections caused by drug resistant gram-
negative pathogens due to the few broad-spectrum antibacterials approved for use in pediatric 
patients. For treatment of carbapenem-resistant Enterobacteriaceae infections in pediatric 
patients, for example, there are few treatment alternatives; these include aminoglycosides, 
fluoroquinolones, trimethoprim-sulfamethoxazole, fosfomycin, and nitrofurantoin (mostly 
for treatment of uncomplicated UTI). Many of these antibacterials have limitations, such as 
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the rapid emergence of resistance when aminoglycosides are used as single agents for 
bacteremia and the caution that needs to be exercised when prescribing fluoroquinolones to 
pediatric patients due to osteoarticular side-effects observed in animal models as well as 
pediatric patients [Hsu, A. J. 2014] [U.S. Food and Drug Administration 2018].
REL is a parenteral (IV), small-molecule BLI that has been developed for administration as 
an FDC in a single vial with imipenem/cilastatin (IMI) for the treatment of infections caused 
by carbapenem-resistant, gram-negative bacteria. The FDC of 
imipenem/cilastatin/relebactam (MK-7655A) is referred to as IMI/REL.
REL represents a new generation of BLIs to combat evolving antibacterial resistance and to 
maintain the usefulness of the β-lactam class of antibacterials. REL is an inhibitor of Ambler 
class A and class C β-lactamases. This BLI is highly potent for AmpC, a common class C β-
lactamase encountered in many bacteria, most predominantly P. aeruginosa. REL is also 
active against the class A β-lactamases, including the KPC present in some 
Enterobacteriaceae, including Klebsiella strains. The IMI/REL β-lactam/BLI combination 
builds on a long history of pediatric safety and efficacy of IMI (Section 2.2.2) and its broad 
spectrum of activity.
2.2.2
Preclinical and Clinical Studies
Details of preclinical and clinical studies are described in the IB. Overall, the preclinical 
toxicity profile observed with REL supported continuation of clinical studies with this 
compound. In addition, there were no REL-related findings in a 1-month juvenile toxicity 
study conducted in rats, up to 450 mg/kg/day (maximum feasible dose) administered 
subcutaneously (postnatal Day 14 to 34) or intravenously (postnatal Day 35 to 56/57) at 65, 
200, or 450 mg/kg/day (~6-fold the clinical exposure).
REL has been evaluated in adults either alone or in combination with IMI (as IMI + REL or 
the FDC IMI/REL) in 10 completed Phase 1 studies, 2 completed Phase 2 studies (MK-7655
003 [PN003] and MK-7655-004 [PN004]), and 4 completed Phase 3 studies (MK-7655A-013 
[PN013], and MK-7655A-014 [PN014], MK-7655A-016 [PN016], MK-7655A-017 
[PN017]). The details and results of these studies are described in the IB [IB Edition 14 
2021]. A brief summary of the results is as follows:
•
In the Phase 2 studies, coadministration of 500 mg IMI and either 125 mg or 250 mg of 
REL was noninferior to treatment with 500 mg IMI alone in the treatment of cUTI 
(PN003) and cIAI (PN004) in a population in which most participants had an imipenem-
susceptible infection.
•
In the Phase 3 studies, the FDC IMI/REL was at least as efficacious as colistin (in the 
form of colistimethate sodium) + IMI for the treatment of imipenem-nonsusceptible and 
imipenem/REL- and colistin-susceptible bacterial infections (specifically HABP/VABP, 
cIAI, and cUTI) (PN013) and IMI/REL (500 mg/250 mg) q6h IV was generally well 
tolerated, with a favorable safety profile, and was an effective treatment for Japanese 
participants with cIAI or cUTI (PN017). In a study of safety and efficacy of IMI/REL 
compared to PIP/TAZ in 274 participants with HABP/VABP, IMI/REL was noninferior 
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to PIP/TAZ for the primary endpoint of all-cause mortality through Day 28 and the safety 
profile of IMI/REL was comparable to PIP/TAZ (PN016).
•
Safety data from the 835 unique participants exposed to REL across the adult clinical 
development program demonstrate that IMI/REL is well tolerated in healthy participants 
and in patients with serious bacterial infections, including critically ill patients and those 
infected with carbapenem resistant gram-negative bacteria. IMI/REL has a favorable 
safety profile that is similar to that of IMI alone and has a more favorable safety profile 
than that of colistin.
There is 1 completed pediatric clinical study with MK-7655A at this time (MK-7655A-020 
[PN020]). PN020 was an open-label, single-dose study to evaluate the PK, safety, and 
tolerability of IMI/REL in pediatric participants from birth to less than 18 years of age with 
proven or suspected gram-negative infections. The main objective of the study was to 
determine safe starting doses for pediatric cohorts that yielded exposures associated with 
efficacy in adults.
PN020 showed that imipenem, REL, and cilastatin exhibited approximately dose-
proportional PK across Cohorts 1 to 5; and both imipenem and REL exceeded protocol-
defined PK targets across Cohorts 1 to 5. A single dose of IV IMI/REL was generally well 
tolerated in pediatric participants from birth to less than 18 years of age and no safety 
concerns were identified.
There has been considerable experience with the use of IMI (imipenem/cilastatin) in both 
adults and pediatric patients since its initial approval over 30 years ago. The 2 pediatric 
clinical studies conducted by the Sponsor were open-label studies to evaluate the efficacy, 
safety, tolerability, and PK of IMI in approximately 233 hospitalized pediatric participants of 
3 months to 12 years of age with serious bacterial infections, including respiratory tract, 
intra-abdominal, and urinary tract infections. IMI was efficacious and generally well 
tolerated in both pediatric studies.
2.2.3
Ongoing Clinical Studies
The current study in pediatric participants, MK-7655A-021, abbreviated as PN021, is the 
only ongoing clinical study.
2.2.4
Information on Other Study-related Therapy
Multiple active control regimens will be permitted in this study, as listed in Appendix 9 (see 
Section 4.2.3 on the rationale for their selection), consistent with real-world practice for the 
treatment of HABP/VABP, cIAI, and cUTI in pediatric patients. The selected regimen will 
ultimately depend on the needs of the patient per local standard of care.
2.2.4.1
Optional Oral Switch (cIAI, cUTI)
In the treatment of cIAI and of cUTI, it is common practice to switch from parenteral to oral 
antibacterials when the patient is afebrile and/or improving [Becknell, B., et al 2015] [Grabe, 
M., et al 2013] [Stein, R., et al 2015], [Zorc, J. J., et al 2005]. For participants with cIAI or 
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cUTI, this study allows the investigator to opt to switch the participant to oral antibacterial 
study intervention after at least 3 days of IV study intervention, based on the participant’s 
clinical condition. See Section 8.1.8.1.2 for investigator criteria for determining whether the 
participant’s clinical condition warrants switch to oral antibacterial therapy for treatment of 
cIAI or cUTI in this study.
The acceptable oral switch options listed in Appendix 9 are common oral antibacterials with 
appropriate activity against the most common gram-negative pathogens encountered in cIAIs 
and cUTIs, respectively.
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.
Efficacy data from the Phase 2 and Phase 3 adult development program have demonstrated 
that IMI/REL is noninferior to IMI alone in the treatment of cUTI and cIAI, and is at least as 
efficacious as colistin for the treatment of gram-negative, imipenem-nonsusceptible, colistin-
susceptible bacterial infections (specifically HABP/VABP, cIAI, and cUTI). The 
pathogenesis and microbiology of these diseases are similar in pediatric patients and in 
adults.
In this study, participants will either receive multiple IV infusions of IMI/REL or standard-
of-care treatment (Section 4.1). The risks of administration of multiple doses of IMI/REL are 
considered to be minimal. IMI has a well-established safety and tolerability profile among 
pediatric patients, both from the pediatric development program and from decades of clinical 
use for serious bacterial infections. Furthermore, there are no significant or excessive adverse 
effects observed among other preclinical or clinical studies involving REL or IMI/REL to 
date (see Section 2.2.2). There is no evidence of additional risk posed by the addition of REL 
to IMI; the safety profile of the combination is similar to that of IMI alone.
Obtaining blood samples for PK analysis does pose a small risk, which is minimized by 
imposing blood sampling volume limits and reducing the frequency of sampling (Table 4). 
Although more frequent, the proposed study procedures described in Section 1.3 – SoA are 
generally standard procedures performed for the target patient population (eg, chemistry and 
hematology measurements).
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no formal statistical hypotheses to be evaluated in this study.
The following objectives and endpoints will be evaluated in pediatric participants from birth 
to less than 18 years of age with confirmed or suspected gram-negative bacterial infection 
involving 1 of 3 primary infection types: HABP/VABP, cIAI, or cUTI:
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of 
IMI/REL (imipenem/cilastatin/relebactam) 
from the first dose of intravenous (IV) study 
intervention through 14 days after the end 
of therapy (EOT)
Adverse events (AEs)
IV study intervention discontinuations due 
to AEs
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of IMI/REL by 
assessing all-cause mortality at Day 28 
postrandomization and clinical and 
microbiological response at the EOT, Early 
Follow-up (EFU, 7 to 14 days after EOT), 
and Late Follow-up (LFU, 7 to 14 days after 
EFU) visits
All-cause mortality
Favorable clinical response
Favorable microbiological response
To characterize the PK profile of imipenem 
and relebactam following administration of 
IMI/REL
Plasma concentrations of imipenem and 
relebactam
AUC0-24hr and Ceoi for imipenem and 
relebactam
%T>MIC for imipenem
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To evaluate the efficacy of IMI/REL by 
assessing clinical and microbiological 
response at the End of IV (EOIV) visit (for 
participants who switch to oral therapy)
To evaluate the efficacy of IMI/REL by 
assessing by-pathogen microbiological 
response at the EOIV (for participants who 
switch to oral therapy), EOT, EFU, and 
LFU visits
Favorable clinical response
Favorable microbiological response
Favorable by-pathogen microbiological 
response
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4
STUDY DESIGN
4.1
Overall Design
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.
This is a randomized, active-controlled, parallel-group, multi-site, open-label study of 
IMI/REL in pediatric participants from birth to less than 18 years of age with confirmed or 
suspected gram-negative bacterial infection. Participants with HABP/VABP, cIAI, or cUTI 
will be randomized in a 3:1 ratio to receive IMI/REL or active control. Participants will be 
stratified by age group and infection type prior to randomization (see Section 6.3.2).
Approximately 140 participants will be enrolled to target having 132 participants 
(approximately 99 in the IMI/REL group and 33 in the active control group) included in the 
safety population (ie, who received at least 1 dose of IV study intervention).
Five pediatric age cohorts will be evaluated in the study as follows, with the following 
minimum or maximum number of participants enrolled in each:
•
Age Cohort 1: Adolescents (12 to <18 years) - No more than 12 participants
•
Age Cohort 2: Older Children (6 to <12 years) - At least 20 participants
•
Age Cohort 3: Younger Children (2 to <6 years) - At least 20 participants
•
Age Cohort 4: Infants and Toddlers (3 months to <2 years) - At least 28 participants
•
Age Cohort 5: Neonates and Young Infants (birth to <3 months) - At least 28 participants
Three infection types will be evaluated in the study as follows. As differences in the 
distribution of infection types within each age cohort are likely, a balance of infection types 
across age cohorts is unlikely to be achievable; therefore, an IRT system will be used to meet 
the following enrollment targets: 
•
At least 28 participants with any of the following infections: HABP/VABP or cIAI.
•
cIAI - At least 10% of participants with cIAI have a diagnosis other than complicated 
appendicitis.
•
cUTI - No more than 48 participants with cUTI in Age Cohorts 3, 4, and 5 combined.
All participants will receive multiple IV doses of either IMI/REL or active control for a total 
duration of all study intervention of a minimum of 5 days (cIAI and cUTI, IV alone or IV 
then oral, of which at least 3 days must be IV alone before optional oral switch) or 7 days 
(HABP/VABP, IV alone) up to a maximum of 14 days (IV alone or IV then oral). Extension 
of study therapy beyond 14 days requires Sponsor approval as described in Section 4.3.3. 
Doses and treatment regimens are specified in Table 3. For IMI/REL, adolescent participants 
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(Age Cohort 1) will receive the approved adult dose and participants <12 years of age (Age 
Cohorts 2-5) will receive weight-based dosing, not to exceed the adult dose. 
Safety, tolerability, efficacy, and PK assessments will be conducted during the intervention 
and follow-up periods as described in Figure 1 and the SoA (Section 1.3). Study visits will be 
performed at randomization (Day 1), OTX, at the end of IV therapy (EOIV, only for 
participants who switch to oral therapy), and at the EOT. The EOT is the end of all study 
intervention (IV alone or IV then oral). Following the completion of all study intervention, 
participants will be evaluated 7 to 14 days after EOT (at the EFU visit) and 7 to 14 days after 
the EFU visit (at the LFU visit). The investigator may decide to switch participants with cIAI 
or cUTI to oral antibacterial therapy based on the participant’s clinical condition (see the oral 
switch criteria in Section 8.1.8.1.2) after a minimum of 3 days of IV study intervention; these 
participants will have an EOIV visit (see the SoA) and complete a total duration of all study 
intervention (IV then oral) of a minimum of 5 days up to a maximum of 14 days. All 
participants will have a Day 28 post-randomization survival assessment, which may be 
performed on the same day as the EFU or LFU visit or as a separate telephone contact. In 
addition, all deaths that occur during the study period will be reported as part of routine 
safety assessment.
Safety and tolerability will be monitored periodically throughout the study and at the planned 
interim analysis (described below) by an eDMC in conjunction with the Sponsor EOC as 
described in Section 9.7 and Appendix 1 - Section 10.1.4. The enrollment strategy is 
described in Figure 2. For Age Cohorts 1, 2, and 3, enrollment will be initiated in parallel. To 
assess whether the safety and tolerability profile is acceptable overall and for each age cohort 
and to confirm the proposed initial doses for Age Cohorts 4 and 5, an interim analysis will be 
performed when at least 20 participants in each of Age Cohorts 2 and 3 have complete data 
available (all complete data available from Age Cohorts 1, 2, and 3 will be reviewed at this 
time). No formal efficacy analyses will be conducted for eDMC review; however, PK and/or 
efficacy data will be provided to the eDMC on request to support benefit-to-risk evaluation. 
Once the proposed initial doses for Age Cohorts 4 and 5 are confirmed based on the findings 
from internal interim review, as described in Section 9.7, enrollment in Age Cohorts 4 and 5 
will begin in parallel. Enrollment in Age Cohorts 1, 2, and 3 will continue beyond the interim 
review up to a maximum of approximately 84 participants across Age Cohorts 1, 2, and 3, 
until at least 28 participants each in Age Cohorts 4 and 5 have final data available and the 
target of 132 participants across all age cohorts in the safety analysis population has been 
achieved.
An interim analysis to assess safety, tolerability, efficacy, and PK may be performed when 
final data from Age Cohorts 1 to 3 are available. The final analysis of aggregated safety, 
tolerability, efficacy, and PK data from Cohorts 1 through 5 will be performed when 
enrollment in Age Cohorts 4 and 5 has completed and the total enrollment has been achieved.
If needed, dose modifications will be determined and communicated as described in Section 
6.6 – Dose Modification.
Each participant will remain in the study for up to 44 days from the time the participant’s 
legally acceptable representative provides documented informed consent through the final 
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contact. This includes a screening phase of up to 2 days before receiving the first dose of IV 
study intervention, up to 14 days of study intervention (IV alone or IV then oral), and up to 
28 days of follow-up after the last IV or oral dose of study intervention.
4.2
Scientific Rationale for Study Design
This study is randomized to minimize bias. A 3:1 randomization ratio has been selected to 
gain greater experience with IMI/REL and to maximize the opportunity to assess safety and 
efficacy. Randomization is stratified by age and by infection type for balanced distribution 
across age cohorts and infection types. The oldest 3 age cohorts (Age Cohorts 1, 2, and 3) 
will be studied in parallel. Enrollment in the 2 youngest age cohorts (Age Cohorts 4 and 5) 
will be initiated after completion of the internal interim review of aggregated safety, 
tolerability, efficacy, and PK data from Age Cohorts 1, 2, and 3, and confirmation of doses.
A comparative design is used for descriptive analysis of safety and efficacy data and to 
confirm dose selection for all age cohorts based on PN020 results. As described in Section 
4.2.3, multiple active control regimens are permitted; as such, this is an open-label study, as 
blinding of multiple active control regimens is not feasible and the need to administer 
placebo infusions is avoided.
There is no formal statistical testing of hypotheses in this study. Instead, the goal is to 
provide estimates of important safety, efficacy, and PK endpoints in the overall study 
population as well as within the different age cohorts.
4.2.1
Rationale for Study Population
Participants with 1 of 3 primary infection types (HABP/VABP, cUTI, or cIAI) will be 
enrolled in this study. These 3 infection types are consistent with the infections studied in the 
adult development program for IMI/REL. It is well documented that the lungs, abdomen, and 
urinary tract are some of the most common sites of infection in patients with MDR 
infections, including CR, gram-negative infections (P. aeruginosa and KPC), as well as 
healthcare-associated infections [Markou, Nikolaos, et al 2003], [Reina, R., et al 2005], 
[Falagas, M. E., et al 2005], [Pintado, V., et al 2008], [Garnacho-Montero, J., et al 2003], 
[Cheng, C.-Y., et al 2010], [Kallel, H., et al 2007], [Hachem, Ray Y., et al 2007], [Bader, M. 
S., et al 2010]. In addition, HABP/VABP, cUTI, and cIAI are important healthcare-
associated infections in pediatric patients, as evidenced by the following:
•
Among ventilated PICU patients, VABP occurs in 3% to 9% of patients [Elward, A. M., 
et al 2002] [Patria, M. F. 2013] [Roeleveld, P. P., et al 2011]. Among neonatal ICU 
patients, pneumonia is the second most common healthcare-associated infection, 
occurring at a rate of 0.2 to 1.7 per 1000 ventilator days, with higher rates in the smallest 
weight subsets [Hooven, T. A. 2014] [Dudeck, M. A., et al 2013].
•
Among patients with cIAI, appendicitis as a single entity occurs at an overall rate of 10.9 
cases per 10,000 population for all ages, and at a rate of 12.9 cases per 10,000 population 
for the age group <15 years of age [DeFrances, C. J., et al 2007]. Appendicitis is more 
common in pediatric and young adult populations compared with older adults
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[Addiss, D. G., et al 1990] [Andersen, S. B., et al 2009]; it occurs in 7% of the population 
over their lifetime [Addiss, D. G., et al 1990].
•
Catheter-associated urinary tract infection (CAUTI) is a subset of cUTI and is the most 
common type of nosocomial infection, accounting for 40% of hospital-acquired 
infections. The Pediatric Prevention Network reported the US point prevalence of 
pediatric CAUTI in PICUs to be 13.3 per 1000 urinary catheter days [Davis, K. F., et al 
2014] [Grohskopf, L. A., et al 2002].
This study does not limit enrollment to participants with CR infections. In the pivotal Phase 3 
study PN013, adult participants were required to have screening susceptibility testing and 
confirmed CR infection for study entry. However, in this study, the primary objective is to 
evaluate safety and tolerability in pediatric participants, and no formal statistical testing will 
be performed for the efficacy endpoints. Since efficacy against infections due to resistant 
pathogens is not being evaluated, confirmed CR infection is not required for study entry.
4.2.1.1
Rationale for Exclusion of Patients With Renal Impairment
Patients with renal impairment are excluded from participating in this study (Section 5.2).
Imipenem, cilastatin, and REL are all known to be substantially excreted by the kidney, and 
the risk of toxic reactions to them may be greater in patients with impaired renal function. 
Please refer to the PRIMAXIN® (imipenem/cilastatin) USPI [U.S. Prescribing Information 
2017] or TIENAM® Summary of Product Characteristics (ex-US) [Summary of Product 
Characteristics 2011] and to the IB on dose adjustment and detailed considerations regarding 
IMI/REL use in participants with renal impairment. IMI is not recommended in pediatric 
patients weighing <30 kg with renal impairment, as no data are available on use in this 
population, and there are no dosing recommendations for pediatric patients with renal 
impairment in the USPI.
Patients requiring hemodialysis are likewise excluded from this study, as are patients 
requiring peritoneal dialysis, for whom there is inadequate information to recommend usage. 
In adults, patients with CrCl <90 mL/min (calculated using the Cockcroft-Gault equation) 
require dosage reduction of IMI. In patients with CrCl <30 to ≥15 mL/min, there may be an 
increased risk of seizures. Patients with CrCl <15 mL/min should not receive IMI unless 
hemodialysis is instituted within 48 hours. For patients on hemodialysis, IMI is 
recommended only when the benefit outweighs the potential risk of seizures. Administration 
of IMI to such patients would require individual patient-level evaluation of the risk/benefit of 
treatment (ie, the same rule cannot be applied to all study participants) [U.S. Prescribing 
Information 2017].
4.2.1.2
Rationale for Exclusion of Patients With Meningitis
Participants less than 3 months of age will be enrolled in this study only after the investigator 
rules out meningitis by performing an LP with CSF culture (if clinically indicated per local 
standard-of-care) or by other standard-of-care procedures or clinical assessments (see Section 
5.2 and Section 8.3.4). Neonates and young infants less than 3 months of age with fever are 
generally treated empirically for meningitis until it can be ruled out 
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[Kadish, H. A., et al 2000] [Ferrera, P. C., et al 1997] [Bonadio, W. A., et al 1993] [Bachur, 
R. G. 2001] [Bedetti, L., et al 2018]. IMI is not indicated in pediatric patients with CNS 
infections, including meningitis, because of the risk of seizures [U.S. Prescribing Information 
2017]. The investigator’s assessment of the absence of meningitis must be documented on 
the source documents at the time of screening. This study excludes participants less than 3 
months of age who have had more than 72 hours of prior empiric antibacterial treatment for 
suspected meningitis prior to initiation of IV study intervention. This 72-hour window for 
this age cohort allows time for LP with CSF culture results to rule out meningitis (see Section 
8.3.4). Exclusion of meningitis is consistent with the well-established clinical management of 
young infants with serious bacterial infections and guidance on the treatment of bacterial 
infections [European Medicines Agency 2013], nosocomial pneumonia [West, M., et al 
2003], HABP/VABP, [Food and Drug Administration 2014], cIAI [Food and Drug 
Administration 2018], and cUTI [Food and Drug Administration 2018].
4.2.2
Rationale for Endpoints
4.2.2.1
Efficacy Endpoints
A secondary objective of this study is to evaluate the following efficacy endpoints in 
randomized pediatric participants with HABP/VABP, cUTI, or cIAI:
•
All-cause mortality through Day 28 post-randomization
•
Clinical response assessed at the EOT, EFU (7 to 14 days after EOT), and LFU (7 to 14 
days after EFU) visits 
•
Microbiological response assessed at the EOT, EFU, and LFU visits
Exploratory objectives of this study are to evaluate the following efficacy endpoints:
•
Clinical response assessed at the EOIV visit (for participants who switch to oral therapy)
•
Microbiological response assessed at the EOIV visit (for participants who switch to oral 
therapy)
•
By-pathogen microbiological response assessed at the EOIV visit (for participants who 
switch to oral therapy) and at the EOT, EFU, and LFU visits (for all participants)
4.2.2.1.1
All-cause Mortality/Survival Status
Survival status (ie, whether the participant is alive or dead) through Day 28 post-
randomization will be evaluated for all participants in support of the key secondary objective.
Evaluation of mortality is appropriate in this study population given the severity of illness in 
hospitalized patients who may have acquired MDR gram-negative bacterial infections and 
routinely require in-hospital treatment with IV antibacterials. For example, in recently 
conducted studies in adults with HABP/VABP, approximately 15% of adult participants died 
despite receiving antibacterial drug therapy [Freire, A. T., et al 2010] [Joshi, M., et al 2006] 
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[Torres, A., et al 2000] [Chastre, J., et al 2008]. As in adults, HABP/VABP in pediatric 
patients has been associated with increased mortality and increased hospital and/or ICU 
length of stay [Foglia, E., et al 2007] [Gupta, S., et al 2015] [Gautam, A., et al 2012] [Patria, 
M. F. 2013] [Roeleveld, P. P., et al 2011]. Although published data in pediatric populations 
have been criticized for being unmatched for severity of illness and univariate, they have 
suggested that pediatric patients with VAP may have excess mortality and length of ICU stay 
[Foglia, E., et al 2007]; a European epidemiology study of hospital-acquired infections found 
a mortality rate of 10% in PICU patients with nosocomial infections [Foglia, E., et al 2007]
and a US multicenter, prospective study found pediatric patients with VAP to have an 
unadjusted mortality rate of 10% to 20% [Gupta, S., et al 2015].
A 1-month mortality endpoint has commonly been used for evaluation of efficacy of 
antibacterial therapy against HABP/VABP [Kollef, M. H., et al 2012] [Chastre, J., et al 2008] 
[West, M., et al 2003] and against MDR gram-negative infections [Markou, Nikolaos, et al 
2003] [Pintado, V., et al 2008] [Cheng, C.-Y., et al 2010]. In addition to assessing all-cause
mortality at Day 28, all deaths that occur during the entire study period will be reported as 
part of routine safety assessment.
4.2.2.1.2
Clinical Response
As in the adult studies, clinical response will be assessed for all participants based on 
evaluation by the investigator at the time points specified in the SoA. Based on comparison 
to baseline clinical signs and symptoms of the participant’s infection, the investigator will 
determine the clinical response rating, and the Sponsor will classify the response as 
“favorable” or “unfavorable” at each visit as described in Section 8.2.2.2 (Table 6 and Table 
7).
The evaluation of clinical response at these time points will provide data to characterize the 
response profile of the test product, relative to the active control. Most cIAI studies evaluate 
efficacy based on clinical response because secondary microbiological cultures are generally 
not available. These analyses are routinely performed at the end-of-study therapy and at post-
therapy follow-up visits, which is consistent with the time points selected in this study.
4.2.2.1.3
Microbiological Response
As in the adult studies in the IMI/REL development program, microbiological response will 
be assessed based on each infection-site pathogen isolated in the baseline infection-site 
culture (ie, by pathogen) for:
•
Participants with HABP/VABP or cIAI who require a procedure that allows for specimen 
collection postbaseline and in whom at least 1 gram-negative baseline pathogen is 
isolated; and
•
Participants with cUTI who are able to provide a clean urine specimen postbaseline and 
in whom at least 1 gram-negative baseline pathogen is isolated at the minimum colony 
count specified in the cUTI Microbiology criteria (Appendix 8 - Section 10.8.3).
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Assessment of microbiological response (Section 8.2.3.2) will also consider blood pathogens 
isolated in the baseline blood culture for participants with blood cultures available (Section 
8.2.3.1.4).
The investigator will determine the by-pathogen response rating at visits specified in the SoA 
based on the local laboratory results of infection-site cultures collected for participants at 
each of these visits, when available, relative to the pathogen(s) isolated at baseline as 
described in Section 8.2.3.2 (Table 8 and Table 9).
The Sponsor will assess the overall microbiological response (ie, overall microbiological 
response for the participant based on the response of all pathogens present in the baseline 
culture) as “favorable” or “unfavorable” for determining participants’ microbiological 
response for the respective infection type in this study.
See Section 8.2.3.1 for details of the infection-site specimen and blood culture procedures.
In participants with cUTI, it is usually feasible to collect appropriate follow-up specimens 
(ie, urine) at each of the endpoint visits throughout the study. However, collection of 
respiratory and/or intra-abdominal specimens after initiation of study antibacterials may not 
be feasible or medically appropriate for participants with HABP/VABP or cIAI, making it 
difficult to document microbiological eradication in participants with these infections. 
Therefore, presumed eradication may be inferred when no respiratory or intra-abdominal 
specimen is available because a participant is deemed clinically improved or cured of the 
pathogen that was found at the time of study entry.
In participants with HABP/VABP, LRT cultures would preferentially include samples 
collected from a tracheostomy or endotracheal aspirates, or bronchoscopy specimens. 
Expectorated or induced sputum samples are also accepted provided the sample does not 
represent oropharyngeal contamination (ie, sample contains fewer than 10 squamous 
epithelial cells and greater than 25 neutrophils on low-power microscopy review of the Gram 
stain).
Most cUTI studies evaluate efficacy based on microbiological eradication of the bacterial 
pathogens from subsequent urine cultures. Such analyses are routinely performed at the end-
of-study therapy and following completion of all antibacterial therapy (usually 1 week and 4 
to 6 weeks following completion of all antibacterial therapy). This is consistent with the time 
points for microbiological response specified in the SoA. Although not typically measured as 
a primary efficacy outcome in HABP/VABP or cIAI studies, microbiological response will 
also be measured in participants with these infection types who have post-baseline cultures 
available (as described above) to allow for further characterization of IMI/REL efficacy. 
4.2.2.1.4
Exploratory Endpoint: By-pathogen Microbiological Response
In addition to evaluating microbiological response for each participant who has an acceptable 
post-baseline infection-site specimen available, microbiological response will also be 
evaluated separately for each infection-site pathogen isolated in the baseline culture. See 
Sections 8.2.3 and 8.2.4 for details of the procedures, assessments, ratings (Table 8 and 
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Table 9), and categories (“favorable” or “unfavorable”) for determining participants’ by-
pathogen microbiological response for the respective infection type in this study.
4.2.2.2
Safety Endpoints
The primary objective of the study is to evaluate the safety and tolerability of IMI/REL from 
the first dose of IV study intervention through 14 days after completion of all study 
intervention. The safety and tolerability of IMI/REL (as well as of the active control) will be 
assessed through descriptive statistics within the safety analysis population for each age 
cohort by clinical evaluation of AEs and inspection of other safety parameters including local 
tolerability assessments and standard clinical laboratory evaluations at the time points 
specified in the SoA. Adverse events are graded and recorded as set out in Section 8.4. 
Participants may be asked to return for unscheduled visits to perform additional safety 
monitoring.
4.2.2.3
Pharmacokinetic Endpoints
Another secondary objective of this study is to characterize the PK profile of imipenem and 
REL following administration of IMI/REL.
At the time points specified in the SoA, only participants randomized to receive IMI/REL 
will have whole blood samples collected for determination of plasma concentrations of REL, 
imipenem, and cilastatin. These samples will support further evaluation of the PK profiles of 
these drugs by confirming that participants achieve expected exposures, and will also aid in 
further assessment of the clinical relationship between imipenem and REL plasma 
concentrations and efficacy.
Sparse PK sampling will be performed at 4 time points per participant to minimize the 
number of samples and blood volume drawn from pediatric participants. The sample at the 
end of the first infusion on Day 1 will help further characterize the maximum concentration 
(Cmax), and each sample during the elimination phase window (Day 1 sample taken 2 to 6 
hours after first dose, and the Day 2 to 3 sample) will help characterize the elimination phase. 
Together, these data will help characterize the entire PK profile using the population PK 
modeling and confirm the ratio of the free area under the plasma concentration-time curve to 
the imipenem/REL MIC (fAUC0-24h/MIC) and the percentage of time free imipenem 
concentration is above the imipenem/REL MIC (% fT>MIC) estimation for REL and 
imipenem, respectively. REL and imipenem PK data will be added to existing pediatric PK 
data from PN020 to further update the pediatric population PK model. Collecting PK data on 
multiple days on therapy will also enable capturing any impact of disease status on the 
PK/dosing of the drugs. See Section 9.4.3 for further details on the PK analysis endpoints.
Based on established literature in the field and data from the adult IMI/REL development 
program, efficacy of IMI/REL is driven by the % fT>MIC within the dosing interval for 
imipenem and by fAUC0-24h/MIC for REL. Because the pathogenesis and microbiology of the 
infections for which IMI/REL is being developed are similar in adult and pediatric 
populations, the PK targets selected in this study are the same as those for adults. 
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The goal of the model-based simulations is to confirm that these targets are jointly achieved 
in a proportion of pediatric participants similarly covered in adults (~90% probability of 
target attainment) for each age cohort; hence, achieving these targets implies similar efficacy 
as that obtained in adults. An absolute (mg) or weight-based (mg/kg) dose, whichever is 
found most suitable for each age cohort, will be selected based on the simulation results.
Plasma concentrations of REL, imipenem, and cilastatin will be determined. As this is an 
estimation study, no formal statistical testing will be performed for the PK data. The 
additional REL and imipenem PK data collected in this study will be used to update the 
pediatric population PK model, based on the adult model, and confirm the adequacy of 
selected doses. The population PK analysis will be summarized in a separate pediatric 
population PK modeling and simulation report; the model will then be used in simulations to 
determine suitable dosing regimens for subsequent and separate pediatric clinical efficacy 
studies. The PK properties of cilastatin based on data from this study will also be described 
on an as-needed basis.
4.2.3
Rationale for the Use of Active Controls
Acceptable active control options per local standard of care for each respective infection type 
are listed by drug class in Table 2 and by generic drug name in Appendix 9 - Protocol-
allowed Comparator Medications by Drug Name. The Sponsor considers these options to be 
clinically appropriate and acceptable active controls with which to evaluate the safety and 
efficacy of IMI/REL in pediatric participants with HABP/VABP, cIAI, and cUTI.
In contrast to adults, there are no specific guidelines for the treatment of gram-negative 
bacterial infections, with the exception of cIAI, in the pediatric population, and there is 
considerable variation in clinical practice across healthcare facilities. Given the variation in 
practice, as well as geographic differences in epidemiology and the wide variety of pediatric 
health conditions that may result in the need for mechanical ventilation (ranging from healthy 
children with traumatic injuries to pediatric patients with multiple complex medical 
conditions), mandating a single active control regimen would limit study feasibility and 
would be inconsistent with real-world clinical practice. The selected regimen will ultimately 
depend on the needs of the patient.
Empiric gram-positive coverage will similarly be left to the investigator’s judgment, as 
IMI/REL has inherent gram-positive coverage due to its IMI component, as do other 
β-lactam/BLI agents that may be used for HABP/VABP. Coverage for methicillin-resistant 
Staphylococcus aureus (MRSA) should be considered where necessary based on local 
epidemiology, but will not be required for all participants. Specific considerations for 
treatment of each infection type are discussed in Section 4.3.3.
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4.3
Justification for Dose
4.3.1
Starting Dose for This Study
The initial doses of IMI/REL for Age Cohorts 1 through 3 are as follows:
•
Age Cohort 1: 500/250 mg q6h administered as a 60-minute infusion
•
Age Cohort 2: 15/7.5 mg/kg q6h administered as a 60-minute infusion
•
Age Cohort 3: 15/7.5 mg/kg q6h administered as a 60-minute infusion 
These doses were selected based on results from the first 3 age cohorts in PN020 (Section 
2.2.3 – Ongoing Clinical Studies). For weight-based dosing for participants <12 years of age 
(Age Cohorts 2 through 5), the maximum allowed dose is 500/250 mg (or the approved adult 
dose), as noted in Table 3. The doses of IMI/REL for pediatric participants in Age Cohorts 4 
and 5 were selected based on safety, tolerability, and updated PK modeling and simulation 
analyses, after incorporating observed PK data from Age Cohorts 1 through 3 during the 
interim review. The doses for Cohorts 4 and 5 were based on pediatric-model-based 
simulations with the intent of 1) obtaining similar exposures as achieved in adult cUTI/cIAI 
participants with normal renal function receiving IMI/REL 500/250 mg IV q6h, and 2) 
ensuring high PTA comparable to adults, and meeting safety margin criteria. The proposed 
initial doses in the current study were modified as described in Section 6.6 – Dose 
Modification.
4.3.2
Maximum Dose Exposure for This Study
As described in Section 6.6 – Dose Modification, the doses for each age cohort in this study 
may be modified based on results of observed safety, tolerability, efficacy, and PK data from 
the interim review of Age Cohorts 1 through 3. The final pediatric doses will not exceed the 
dosage studied for adult participants in the Phase 3 studies (ie, maximum single IV dose of 
IMI/REL 500/250 mg).
4.3.3
Rationale for Dose Interval and Study Design
For participants in the IMI/REL intervention arm, multiple doses of IMI/REL will be 
administered as a 60-minute IV infusion q6h or q8h, as set out in Table 3. A multiple-dose 
study design was selected based on the expected clinical use of IMI/REL in both adult and 
pediatric participants. A short half-life (approximately 30 to 60 minutes) of both imipenem 
and REL and lack of accumulation of any drug components was observed in adult studies. 
These properties are expected to be the same in pediatric participants, as supported by 
interim results from the PN020 single-dose PK study in pediatric participants with confirmed 
or suspected gram-negative infections.
Appropriate duration of therapy for treatment of pediatric suspected or confirmed gram-
negative bacterial infections (HABP/VABP, cIAI, and cUTI) remains controversial, but most 
guidelines suggest 5 to 14 days of antibacterial therapy. In this study, the total duration of all 
antibacterial study intervention must be a minimum of 5 days (cIAI and cUTI, IV alone or IV 
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then oral, of which at least 3 days must be IV alone before optional oral switch) or 7 days 
(HABP/VABP, IV alone) up to a maximum of 14 days (IV alone or IV then oral). Of note, 
participants with evidence of concurrent bacteremia or with P. aeruginosa infection should 
receive 14 days of antibacterial treatment. For participants who may require extended 
durations of treatment (eg, those with suppressed immunity), extension of study intervention 
beyond 14 days may be allowed with Sponsor approval, as discussed between the Principal 
Investigator and Sponsor and documented on the Sponsor consultation form.
The intervention duration is consistent with practice guidelines and data from clinical studies. 
Current clinical practice guidelines suggest limiting treatment of infection types included in 
this study to 2 weeks. Infectious Diseases Society of America (IDSA) guidelines recommend 
limiting treatment of HABP/VABP to as little as 1 week, cIAI to less than 1 week for most 
infections, and CAUTI to less than 2 weeks [Hooton, T. M., et al 2010] [Solomkin, J. S., et al 
2010] [Niederman, M. S. 2005] [Dellinger, R. P., et al 2013]. The requirement of at least 3 
days (cIAI and cUTI) or 7 days (HABP/VABP) of IV study intervention in this study allows 
for evaluation of the safety, efficacy, and PK of IMI/REL while minimizing the need for 
prolonged hospitalization and IV access. Preclinical data for IMI/REL support and the 
clinical complexity of participants in this study warrants up to 14 days of study intervention. 
Refer to the IB for more detailed information on preclinical toxicity studies and Sections 
4.3.3.1 through 4.3.3.3 below for specific considerations for each of the 3 infection types.
AE data from the pivotal Phase 3 study (PN013) have demonstrated that treatment with the 
FDC IMI/REL (500 mg/250 mg) q6h for 5 (cUTI and cIAI) or 7 (HABP/VABP) days up to 
21 days has been generally well tolerated in adult participants with imipenem-nonsusceptible 
gram-negative infections (cUTI, cIAI, or HABP/VABP). AE data from the 2 Phase 2 studies 
(PN003 and PN004) have demonstrated that coinfusion of IMI 500 mg and REL 250 mg q6h 
from 4 to 14 days has been generally well tolerated in adult participants with cUTI and cIAI, 
respectively, with a safety profile similar to that of IMI alone. Phase 1 studies evaluated REL 
as single doses up to 1150 mg, multiple doses up to 625 mg q6h for 7 days, or multiple doses 
up to 500 mg q6h for 14 days; no dose-limiting toxicity was observed over this range of 
doses up to a maximum of 14 days of dosing in a total of 59 adult participants who received 
REL at or above the proposed marketed dose of 250 mg (up to 625 mg REL) coinfused with 
500 mg IMI for >4 days.
Dose interval and study design considerations for participants with HABP/VABP, cIAI, and 
cUTI are discussed in Section 4.3.3.1, Section 4.3.3.2, and Section 4.3.3.3, respectively.
4.3.3.1
Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia 
(HABP/VABP)
For participants with HABP/VABP, IV study intervention will be administered for a 
minimum of 7 days up to a maximum of 14 days. Participants with evidence of concurrent 
bacteremia or with P. aeruginosa infection should receive 14 days of antibacterial treatment. 
Extension of study intervention beyond 14 days must be approved by the Sponsor as 
described in Section 4.3.3.
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American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines 
recommend treatment of HABP/VABP for as few as 7 days, provided that the patient has a 
good clinical response and the infection is not caused by P. aeruginosa [Niederman, M. S. 
2005]. If deemed clinically appropriate, participants may receive up to 14 days of study 
intervention for non-Pseudomonas infections. In the setting of Pseudomonas infection, a 
treatment duration of 14 days is predicated on data from several studies and meta-analyses, 
which show a lesser incidence of persistence or recurrence with ~2 weeks versus ~1 week of 
therapy [Pugh, R., et al 2011] [Chastre, J., et al 2003]. Lower responses and higher mortality 
were also recently seen following treatment with a shorter course of therapy (1 week of 
doripenem) versus a longer course of therapy (10 days of IMI) in P. aeruginosa VABP cases 
[Kollef, M. H., et al 2012]. An antibacterial treatment duration of 14 days for concurrent 
bacteremia is supported by current IDSA guidelines on the treatment of bloodstream 
infections and by standard clinical practice.
Further details of definitive treatment of nosocomial pneumonia in pediatric patients can be 
found in [Bradley, J. S. 2002]. These recommendations are similar to those for treatment of 
adults with HABP/VABP as suggested by the ATS/IDSA [Niederman, M. S. 2005].
4.3.3.2
Complicated Intra-Abdominal Infection (cIAI)
In general, cIAIs require a surgical procedure and parenteral antibacterial therapy. Current 
recommendations are to limit the antibacterial course to 4 to 7 days in cases where adequate 
source control has been achieved [Solomkin, J. S., et al 2010] [Skrupky, L. P., et al 2013]. In 
an effort to evaluate the efficacy in this study, the total duration of all study intervention for 
cIAI has been set at a minimum of 5 days (IV alone or IV then oral, of which at least 3 days 
must be IV alone before optional oral switch) up to a maximum of 14 days (IV alone or IV 
then oral). The investigator, based on the participant’s clinical condition, may decide to 
switch the participant to oral antibacterial therapy after at least 3 days of IV study 
intervention; participants with cIAI who switch to oral therapy will have a total duration of 
all study antibacterial therapy (IV then oral) of a minimum of 5 days up to a maximum of 14 
days. Extension of study intervention beyond 14 days must be approved by the Sponsor as 
described in Section 4.3.3.
Discussion of empiric treatment options for cIAI in adult and pediatric patients can be found 
in [Solomkin, J. S., et al 2010].
4.3.3.3
Complicated Urinary Tract Infection (cUTI)
Based on American Academy of Pediatrics treatment guidelines, the total duration of 
treatment for cUTIs may vary from 7 days for a lower urinary tract infection to 10 to 14 days 
for acute pyelonephritis [Finnell, S. M., et al 2011]. In this study, participants with cUTI will 
have a total duration of all study antibacterial therapy of a minimum of 5 days (IV alone or 
IV then oral, of which at least 3 days must be IV alone before optional oral switch) up to a 
maximum of 14 days (IV alone or IV then oral). The investigator, based on the participant’s 
clinical condition, may decide to switch the participant to oral antibacterial therapy after at 
least 3 days of IV study intervention; participants with cUTI who switch to oral therapy will 
have a total duration of all study antibacterial therapy (IV then oral) of a minimum of 5 days 
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up to a maximum of 14 days. Extension of study intervention beyond 14 days must be 
approved by the Sponsor as described in Section 4.3.3.
In general, cUTIs requiring parenteral therapy are routinely treated with a short course of IV 
antibacterial therapy followed by oral antibacterial therapy. This switch facilitates step-down 
antibacterial therapy in anticipation of eventual hospital discharge. See Section 2.2.4.1 on the 
rationale for the optional oral switch for participants with cIAI or cUTI in this study.
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 (Section 7.3). For purposes of analysis and reporting, the overall study ends when 
the Sponsor receives the last laboratory test result or at the time of final contact with the last 
participant, whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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 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 as described in Appendix 1.10.
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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.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Require hospitalization and treatment with IV antibacterial therapy for confirmed or 
suspected gram-negative bacterial infection (in the absence of meningitis), and is 
expected to require hospitalization through completion of IV study intervention, with at
least 1 of the following primary infection types, based on the specific criteria required to 
be met for the respective infection type in Appendix 8: Disease Definitions and 
Diagnostic Criteria:
-
Hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial 
pneumonia (VABP) (see Appendix 8 - Section 10.8.1)
-
Complicated intra-abdominal infection (cIAI) (see Appendix 8 - Section 10.8.2)
-
Complicated urinary tract infection (cUTI) (see Appendix 8 - Section 10.8.3)
NOTE: Participants less than 3 months of age can be enrolled after ruling out meningitis per 
Exclusion #2. 
Demographics
2. Participant is male or female and is from birth to less than 18 years of age inclusive, at 
the time of providing documented informed consent/assent. For Age Cohorts 4 and 5, 
participant is at least 37 weeks postmenstrual age at the time of providing documented 
informed consent/assent. Postmenstrual age is calculated by adding the gestational age at 
the time of birth to the chronological age at the time of providing documented informed 
consent/assent.
Female Participants
3. Not be pregnant (Appendix 5) or breastfeeding, and at least 1 of the following conditions 
applies:
a.
Not be a woman of childbearing potential (WOCBP) as defined in Appendix 5.
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OR
b. A WOCBP must agree to follow the contraceptive guidance in Appendix 5 during the 
intervention period and for at least 24 hours after the last dose of study intervention.
Informed Consent/Assent
4. The participant (or legally acceptable representative if applicable) has provided 
documented informed consent/assent for the study.
Additional Categories
5. Have sufficient intravascular access to receive study intervention through an existing 
peripheral or central line.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Is expected to survive less than 72 hours
2. Has a concurrent infection that would interfere with evaluation of response to the study 
antibacterials (IMI/REL or Active Control), including any of the following:

Endocarditis

Osteomyelitis

Meningitis (Participants less than 3 months of age must have documentation that 
meningitis has been ruled out prior to initiation of IV study intervention, in 
accordance with the labeled use of imipenem and cilastatin [PRIMAXIN® (US) [U.S. 
Prescribing Information 2017] or TIENAM® (ex-US) [Summary of Product 
Characteristics 2011]], which is not indicated in pediatric patients with CNS 
infections.)

Prosthetic joint infection

Active pulmonary tuberculosis 

A disseminated fungal infection 

A concomitant infection at the time of randomization that requires nonstudy systemic 
antibacterial therapy in addition to IV study intervention or oral step-down therapy 
(medications with only gram-positive activity [eg, vancomycin, linezolid] are 
allowed).
3. Has HABP/VABP caused by an obstructive process, including lung cancer (or other 
malignancy metastatic to the lungs resulting in pulmonary obstruction) or other known 
obstruction.
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4. Has a cUTI that meets any of the following:

Complete obstruction of any portion of the urinary tract (ie, requiring a permanent 
indwelling urinary catheter or instrumentation)

Documented reflux of ileal loop urinary diversion 

Suspected or confirmed perinephric or intrarenal abscess

Suspected or confirmed prostatitis, urethritis, or epididymitis

Trauma to pelvis/urinary tract

Presence of indwelling urinary catheter which cannot be removed at study entry
NOTE: All indwelling urinary catheters must be removed prior to the start of IV study 
intervention. Unless medically necessary, it is recommended that an indwelling urinary 
catheter not be reinserted while on IV study intervention.
5. Has any of the following medical conditions at screening:

A history of a seizure disorder (requiring ongoing treatment with anticonvulsive 
therapy or prior treatment with anticonvulsive therapy within the last 3 years)

Cystic fibrosis
6. Has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious 
reaction to IMI or to any of the following:

Any carbapenem, cephalosporin, penicillin, or other β-lactam agent 

Other BLIs (eg, tazobactam, sulbactam, clavulanic acid, avibactam) 
7. Has a history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might expose the participant to risk by participating in the study, 
confound the results of the study, or interfere with the participant’s participation for the 
full duration of the study.
Prior/Concomitant Therapy
8. If less than 3 months of age, has received more than 72 hours of empiric antibacterial 
treatment for suspected meningitis prior to initiation of IV study intervention.
9. If 3 months of age or older, or <3 months without suspected meningitis, has received 
potentially therapeutic antibacterial therapy (eg, with gram-negative activity), including 
bladder infusions with topical urinary antiseptics or antibacterial agents, for a duration of 
more than 24 hours during the 48 hours preceding the first dose of study intervention.
NOTE: For all Age Cohorts, provided all other eligibility criteria are met, the following 
participants may be enrolled:

A participant failing prior antibiotic therapy for a current episode of cUTI or 
HABP/VABP who:
a.
Has received the prior antibacterial treatment for at least 48 hours
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b. Has persistent clinical or radiographic findings clearly indicating ongoing 
infection
c.
Fulfills other laboratory or microbiology criteria for enrollment
However, participants with cUTI whose final culture result does not meet the 
CFU/mL criteria defined in Appendix 8 - Section 10.8.3 must discontinue study 
intervention following the negative culture result.

A participant failing prior antibiotic therapy for a current episode of cIAI who:
a.
Has received the prior antibacterial treatment for at least 48 hours
b.   Has persistent clinical or radiographic findings clearly indicating ongoing
infection
c.   Fulfills other laboratory or microbiology criteria for enrollment
d. Has planned operative intervention no more than 24 hours after first dose of study 
treatment
e.
Has not received any further nonstudy antibiotics postoperatively
10. Is anticipated to be treated with any of the following medications:

Valproic acid or divalproex sodium (or has used valproic acid or divalproex sodium 
in the 2 weeks prior to screening) through 24 hours after completion of the final dose 
of IV study intervention for participants who receive IMI/REL or carbapenem.

Concomitant IV, oral, or inhaled antimicrobial agents with gram-negative activity, in 
addition to those designated in the study intervention groups, during the course of all 
(IV/oral) study intervention.
NOTE: Use of IV vancomycin, IV daptomycin, or IV linezolid to treat confirmed or 
suspected MRSA infection, use of IV linezolid or IV daptomycin to treat confirmed 
or suspected vancomycin-resistant Enterococcus spp. (VRE) infection, or use of 
trimethoprim-sulfamethoxazole (TMP/SMX) or other standard-of-care agent for 
prophylaxis of opportunistic infection (eg, Pneumocystis jiroveci infection) in 
immunocompromised participants is allowed. Daptomycin is not indicated for the 
treatment of HABP/VABP.

Planned receipt of suppressive/prophylactic antibiotics with gram-negative activity 
after completion of study intervention.
NOTE: Based on site-level standard of care, participants at increased risk of 
recurrent pyelonephritis or cUTI (eg, vesico-ureteral reflux Grade 3 through 5) where 
there is a clear benefit to low-dose antibiotic prophylaxis may be enrolled.
Prior/Concurrent Clinical Study Experience
11. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 30 days prior to screening.
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12. Has enrolled previously in the current study and been discontinued, or has received REL 
for any other reason.
Diagnostic Assessments
13. Has an estimated CrCl (based on the Cockcroft-Gault equation, for participants ≥12 years 
of age) or estimated glomerular filtration rate (eGFR, based on the modified Schwartz 
equation, for participants <12 years of age) below that specified for the appropriate age 
range in Table 16; or requires peritoneal dialysis, hemodialysis, or hemofiltration.
14. Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥5 x upper 
limit of normal (ULN) at the time of screening.
NOTE: Patients with acute hepatic failure or acute decompensation of chronic hepatic 
failure should also be excluded.
Other Exclusions
15. Is, based on medical history at the time of providing documented informed 
consent/assent, a user of recreational or illicit drugs or has had a recent history (within the 
last year) of drug or alcohol abuse or dependence.
16. 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; participants will be hospitalized.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies [study interventions provided by the Sponsor] will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1 and organized by 
infection type in Table 2.
Acceptable control options for treatment of each respective infection type in the Active 
Control arm and acceptable oral switch options for step-down treatment of cIAI or cUTI in 
both intervention arms (IMI/REL and Active Control) are:
•
HABP/VABP: IV carbapenem, or IV PIP/TAZ, or IV cefepime 
•
cIAI: IV carbapenem or IV third-generation cephalosporin + metronidazole, IV PIP/TAZ 
with optional oral switch to PO β-lactam/β-lactamase inhibitor combination, or PO 
second- or third-generation cephalosporin in combination with metronidazole, or PO 
quinolone (if ciprofloxacin or levofloxacin, use in combination with metronidazole) 
•
cUTI: IV third- or fourth-generation cephalosporin, IV ciprofloxacin, or IV meropenem 
with optional switch to PO β-lactam/β-lactamase inhibitor combination, or PO 
cephalosporin, or PO quinolone, or PO nitrofurantoin, or PO trimethoprim or 
trimethoprim/sulfamethoxazole 
Protocol-allowed comparator medications for each infection type are detailed by generic drug 
name in the EDC system, EDC guidelines, and Appendix 9. The option to switch a 
participant with cIAI or cUTI to oral therapy after the indicated minimum number of days of 
IV study intervention is at the investigator’s discretion based on the participant’s clinical 
condition and local standard of care. The choice of oral switch therapy should be guided by 
culture results and based on local antibiotic susceptibility patterns.
IMI/REL administered by age-based dose and infusion duration is summarized in Table 3; 
Active Control and oral switch administered per authorized PI, SPC, or international 
treatment guidelines. The total duration of all study intervention must be a minimum of 5 
days (cIAI and cUTI, IV alone or IV then oral, of which at least 3 days must be IV alone 
before optional oral switch) or 7 days (HABP/VABP, IV alone). The total duration of all 
study intervention for any infection type must not exceed 14 days (IV alone or IV then oral). 
Extension of study therapy beyond 14 days requires Sponsor approval (Section 4.3.3).
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Table 1
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/
Vaccination 
Regimen
Use
IMP 
or 
NIMP/
AxMP
Sourcing
IMI/
REL
Experimental IMI/REL
Drug
Powder, For 
Suspension
relebactam, 
imipenem, 
cilastatin 
250/500/500 
mg
Age Cohort 
1: 500/250 
mg q6h 
Age Cohort 
2: 15/7.5 
mg/kg q6h 
Age Cohort 
3: 15/7.5 
mg/kg q6h 
Age Cohort 
4: 15/7.5 
mg/kg q6h 
Age Cohort 
5:
15/7.5 
mg/kg q8h
All 
administered
as 60-
minute 
infusions
IV Infusion
cIAI and 
cUTI: Total 
duration of all 
study 
intervention: 
Minimum 5 
days (IV alone 
or IV then 
oral, of which 
at least 3 days 
must be IV 
alone before 
optional oral 
switch) up to 
a maximum of 
14 days;
HABP/VABP: 
Minimum 7 
days up to a 
maximum of 
14 days.
Test Product IMP
Sponsor
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Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP 
or 
NIMP/
AxMP
Sourcing
Active 
Control
Active 
Comparator
Acceptable 
control 
options for 
each 
infection 
type
Drug
Powder, For 
Suspension
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
IV Infusion
cIAI and 
cUTI: Total 
duration of all 
study 
intervention: 
Minimum 5 
days (IV alone 
or IV then 
oral, of which 
at least 3 days 
must be IV 
alone before 
optional oral 
switch) up to 
a maximum of 
14 days;
HABP/ 
VABP: 
Minimum 7 
days up to a 
maximum of 
14 days. All 
administered 
per authorized 
PI, SPC, or 
international 
treatment 
guidelines.
Comparator
IMP
Locally
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Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP 
or 
NIMP/
AxMP
Sourcing
IMI/
REL
Experimental Acceptable 
oral switch 
options for 
cIAI and 
cUTI
Drug
Liquid
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
Oral
Per authorized 
PI, SPC, or 
international 
treatment 
guidelines
Systemically 
Prescribed
IMP
Locally
Active 
Control
Active 
Comparator
Acceptable 
oral switch 
options for 
cIAI and 
cUTI
Drug
Liquid
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
Per 
authorized 
PI, SPC, or 
international 
treatment 
guidelines
Oral
Per authorized 
PI, SPC, or 
international 
treatment 
guidelines
Systemically 
Prescribed
IMP
Locally
cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; EDC=electronic data collection; EEA=European Economic Area; HABP/VABP=hospital-
acquired or ventilator-associated bacterial pneumonia; IMI/REL= imipenem/cilastatin/relebactam (MK-7655A); IMP=investigational medicinal product; IV=intravenous; 
NIMP/AxMP=noninvestigational/auxiliary medicinal product; PI=Package Insert; PO=per os (by mouth); q6h=every 6 hours; q8h=every 8 hours; SPC=Summary of Product 
Characteristics.
Note: 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.
Note: Protocol-allowed comparator medications for each infection type are detailed by generic drug name in the EDC system, EDC guidelines, and Appendix 9.
Note: Study intervention, dose, and regimen are listed by infection type in Table 2.
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All supplies indicated in Table 1 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.
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Table 2
Intervention, Dose, and Regimen by Infection Type
Intervention 
Group Name
Druga,b
Dose Strength
Dose Frequency
Route of 
Administrationa
Regimen/Treatment 
Perioda
Use
HABP/VABP
IMI/REL
IMI/REL
Age-based (Table 
3, Section 6.1.1)
C1, C2, C3: 60-
minute infusion 
q6h
C4: 60-minute 
infusion q6h
C5: 60-minute 
infusion q8h
IV 
Minimum 7 days up to a 
maximum of 14 days
Test product
Active control
Acceptable control 
options for treatment of 
HABP/VABP are: 
IV carbapenem or IV 
PIP/TAZ or IV cefepime
Per authorized PI, 
SPC, or 
international 
treatment 
guidelines
Per authorized PI, 
SPC, or 
international 
treatment 
guidelines
IV 
Minimum 7 days up to a 
maximum of 14 days
Standard of 
care
cIAI
IMI/REL
IMI/REL with optional 
oral switch to:a
PO β-lactam/β-lactamase 
inhibitor combination or 
PO second- or third-
generation cephalosporin 
in combination with 
metronidazole or PO 
quinolone (if 
ciprofloxacin or 
levofloxacin, use in 
combination with 
metronidazole)
Age-based (Table 
3, Section 6.1.1)
C1, C2, C3: 60-
minute infusion 
q6h
C4: 60-minute 
infusion q6h
C5: 60-minute 
infusion q8h
IV or IV then oral
Total duration of all study 
interventions must be a 
minimum of 5 days (IV 
alone or IV then oral, of 
which at least 3 days must 
be IV before optional oral 
switch) up to a maximum 
of 14 days (IV alone or IV 
then oral)
Test product
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Intervention 
Group Name
Druga,b
Dose Strength
Dose Frequency
Route of 
Administrationa
Regimen/Treatment 
Perioda
Use
Active control
Acceptable control 
options for treatment of 
cIAI are: 
IV carbapenem or IV 
PIP/TAZ or IV third-
generation cephalosporin 
+ metronidazole with 
optional oral switch to:a
PO β-lactam/β-lactamase 
inhibitor combination or 
PO second- or third-
generation cephalosporin 
in combination with 
metronidazole or PO 
quinolone (if 
ciprofloxacin or 
levofloxacin, use in 
combination with 
metronidazole)
Per authorized PI, 
SPC, or 
international 
treatment 
guidelines
Per authorized PI, 
SPC, or 
international 
treatment 
guidelines
IV or IV then oral
Total duration of all study 
interventions must be a 
minimum of 5 days (IV 
alone or IV then oral, of 
which at least 3 days must 
be IV before optional oral 
switch) up to a maximum 
of 14 days (IV alone or IV 
then oral)
Standard of 
care
cUTI
IMI/REL
IMI/REL with optional 
oral switch to:a
PO β-lactam/β-lactamase 
inhibitor combination or 
PO cephalosporin or PO 
quinolone or PO 
nitrofurantoin or PO 
trimethoprim or 
trimethoprim/sulfametho
xazole
Age-based 
(Table 3, Section 
6.1.1)
C1, C2, C3: 60-
minute infusion 
q6h
C4: 60-minute 
infusion q6h
C5: 60-minute 
infusion q8h
IV or IV then oral
Total duration of all study 
interventions must be a 
minimum of 5 days (IV 
alone or IV then oral, of 
which at least 3 days must 
be IV before optional oral 
switch) up to a maximum 
of 14 days (IV alone or IV 
then oral)
Test product
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Intervention 
Group Name
Druga,b
Dose Strength
Dose Frequency
Route of 
Administrationa
Regimen/Treatment 
Perioda
Use
Active control
Acceptable control 
options for treatment of 
cUTI are: 
IV third- or fourth-
generation 
cephalosporin, IV 
ciprofloxacin, or IV 
meropenem with 
optional oral switch to:a
PO β-lactam/β-lactamase 
inhibitor combination or 
PO cephalosporin or PO 
quinolone or PO 
nitrofurantoin or PO 
trimethoprim or 
trimethoprim/sulfametho
xazole
Per authorized PI, 
SPC, or 
international 
treatment 
guidelines
Per authorized PI, 
SPC, or 
international 
treatment 
guidelines
IV or IV then oral
Total duration of all study 
interventions must be a 
minimum of 5 days (IV 
alone or IV then oral, of 
which at least 3 days must 
be IV before optional oral 
switch) up to a maximum 
of 14 days (IV alone or IV 
then oral)
Standard of 
care
C=cohort; cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; EDC= electronic data collection; HABP/VABP=hospital-acquired or 
ventilator-associated bacterial pneumonia; IMI/REL=imipenem/cilastatin/relebactam (MK-7655A); IV=intravenous; PIP/TAZ=piperacillin/tazobactam; PI=Package Insert; 
PO=per os (by mouth); q6h=every 6 hours; q8h=every 8 hours; SPC=Summary of Product Characteristics.
a
In both intervention arms (IMI/REL and Active Control), participants with cIAI or cUTI may have an optional switch to a specified oral antibacterial therapy after the 
indicated minimum number of days of IV study intervention at the investigator’s discretion based on the participant’s clinical condition and local standard of care. The 
choice of oral switch therapy should be guided by culture results and based on local antibiotic susceptibility patterns.
b
Protocol-allowed comparator medications for each infection type are detailed by generic drug name in the EDC system, EDC guidelines, and Appendix 9.  
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6.1.1
Dose by Age Cohort
Table 3
IMI/REL Dose by Age Cohort
Age Cohort
Age Range
IMI/REL Dosea
1
12 to <18 years
500/250 mg q6h
2
6 to <12 years
15/7.5 mg/kg q6h
3
2 to <6 years
15/7.5 mg/kg q6h
4
3 months to <2 years
15/7.5 mg/kg q6hb
5
Birth to <3 months
15/7.5 mg/kg q8hb
FDC=fixed-dose combination; IMI/REL=imipenem/cilastatin/relebactam (MK-7655A); PK=pharmacokinetics; 
q6h=every 6 hours; q8h=every 8 hours. 
a
Doses for all age cohorts will be administered as 60-minute infusions and will not exceed the adult maximum single 
dose of IMI/REL 500 mg/250 mg. IMI/REL is provided as a single-vial FDC; therefore, the dose for each 
component will be adjusted proportionally during preparation. 
b
Initial doses of IMI/REL and infusion duration for participants in Age Cohorts 4 and 5 were selected based on 
results from the single-dose safety and PK study in pediatric participants from birth to less than 18 years of age with 
proven or suspected gram-negative infections (MK-7655A-020) and confirmed based on review of safety, 
tolerability, efficacy, and PK data from Age Cohorts 1 through 3 in the current study (PN021). Initial doses and 
infusion duration for Age Cohorts 4 and 5 were communicated to investigators and sites via a protocol amendment 
prior to initiation of enrollment of Age Cohorts 4 and 5.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Specific calculations or evaluations required to be performed to administer the proper dose to 
each participant are outlined in a separate document provided by the Sponsor. 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 
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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.
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
Intervention allocation/randomization will occur centrally using an IRT system. There are 2 
study intervention arms. Participants will be assigned randomly in a 3:1 ratio to IMI/REL or 
active control, respectively.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1. Age: 5 pediatric age cohorts will be evaluated in the study as follows:

Age Cohort 1: Adolescents (12 to <18 years)

Age Cohort 2: Older Children (6 to <12 years)

Age Cohort 3: Younger Children (2 to <6 years)

Age Cohort 4: Infants and Toddlers (3 months to <2 years)

Age Cohort 5: Neonates and Young Infants (birth to <3 months)
2. Infection Type: 3 infection types will be evaluated in the study as follows:

HABP/VABP

cIAI

cUTI
The IRT system will be used to limit enrollment in the study and in specific age cohorts by 
infection type as described in Section 4.1.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
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6.4
Study Intervention Compliance
Extensions of any study intervention (IV or oral) of >14 days of therapy and interruptions 
from the protocol-specified study therapy plan of (1) ≥2 doses of IV study intervention 
during the first 3 days of therapy, OR (2) ≥4 doses of IV study intervention from Day 4 to the 
end of IV study intervention, OR (3) ≥4 doses of oral study intervention from the end of IV 
study intervention to the EOT visit all 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 study 
intervention (IV or oral; see Section 5.2). If there is a clinical indication for any medication 
specifically prohibited during the study, discontinuation from study intervention (IV or oral) 
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 (IV or oral) requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
Listed below are specific restrictions for concomitant therapy during the course of the study:
1. Within 2 weeks prior to screening through 24 hours after completion of the final dose of 
IV study intervention: valproic acid or divalproex sodium.
2. During the course of all study intervention (IV alone or IV then oral): concomitant IV, 
oral, or inhaled antimicrobial agents with gram-negative activity, in addition to those 
designated in the study intervention groups.
NOTE: Use of IV vancomycin, IV daptomycin, or IV linezolid to treat confirmed or 
suspected MRSA infection, use of IV linezolid or IV daptomycin to treat confirmed or 
suspected VRE infection, or use of TMP/SMX or other standard of care agent for 
prophylaxis of opportunistic infection (eg, Pneumocystis jiroveci infection) in 
immunocompromised participants is allowed. Daptomycin is not indicated for the 
treatment of HABP/VABP.
3. Planned receipt of suppressive/prophylactic antibiotics with gram-negative activity after 
completion of study intervention.
NOTE: Based on site-level standard of care, participants at increased risk of recurrent 
pyelonephritis or cUTI (eg, vesico-ureteral reflux Grade 3 through 5) where there is a 
clear benefit to low-dose antibiotic prophylaxis may be enrolled.
NOTE: Any licensed COVID-19 vaccine (including for emergency use) in a particular 
country is allowed in the study if it is an mRNA vaccine, replication-incompetent 
adenoviral vaccine, or inactivated vaccine. These vaccines will be treated just as any 
other concomitant therapy.
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Investigational vaccines (ie, those not licensed or approved for emergency use) are not 
allowed.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
6.6
Dose Modification (Escalation/Titration/Other)
The goal of this study is to determine the safety, tolerability, efficacy, and PK profile of 
IMI/REL for each pediatric age cohort at doses that achieve an acceptable safety, tolerability, 
and efficacy profile and similar exposure as that seen in clinical studies in adults and 
pediatric participants. Based on available data from PN020, dose modification for Cohorts 1, 
2, and 3 from those specified in Table 3 is not anticipated in this study.
As noted in Table 3, the initial doses of IMI/REL and infusion duration for participants in 
Age Cohorts 4 and 5 were selected based on results from PN020 and confirmed based on 
review of safety, tolerability, efficacy, and PK data from Age Cohorts 1, 2, and 3 in this 
study (PN021). Initial doses for Age Cohorts 4 and 5 are in Section 6.1.1.
If unexpected PK results require dose modification for any age cohort(s) during the study, a 
protocol amendment will be developed.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
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.
6.9
Standard Policies
Not applicable, as this study uses active controls.
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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 8.10.3 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.
•
The participant has HABP/VABP and the infection-site specimen Gram stain shows the 
presence of gram-positive cocci only.
•
The participant has cUTI, but does not have a positive urine culture result that meets the 
cUTI Microbiological criteria in Appendix 8 - Section 10.8.3.
•
The participant has estimated CrCl (based on the Cockcroft-Gault equation) or eGFR 
(based on the modified Schwartz equation) below the normal level specified for the 
appropriate age range in Table 16; or requires peritoneal dialysis, hemodialysis, or 
hemofiltration.
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.
Discontinuation from study intervention is permanent. Once a participant is discontinued, the 
participant shall not be allowed to restart study intervention.
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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 prescreening log 
to record details of all participants prescreened 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.
It is recognized that pediatric centers reduce required blood volumes for standard clinical 
testing based on the size of the child, with many centers suggesting a 0.5 mL blood draw for 
most standard clinical tests in neonates (eg, blood culture, hematology with differential, and 
clinical chemistry panels). With this in mind, expected blood volumes for the youngest 
participants (neonates) are calculated in Table 4.
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Table 4
Approximate Blood Volumes Drawn in Neonates by Study Visit, Sample 
Type
Study Visit:
Screening 
Visita
Intervention Visits
Follow-up Visits
Overall 
Total
Day 1a
OTX
EOIVb,c
EOTc
EFUd
LFUd
Blood Parameter
Approximate Blood Volume (mL)
Hematology
0.5
0.5
0.5
Blood Chemistry
0.5
0.5
0.5
Blood Culture
As clinically indicated
Plasma 
Pharmacokinetics
0.75 
(3×250 µL)
0.25 
(1×250 µL)
Expected Total
1.75
0.25
1
1
4
cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; EFU=early follow-up; EOIV=end 
of IV therapy; EOT=end of therapy; LFU=late follow-up; OTX=on therapy; SoA=schedule of activities.
Note: Clinically significant abnormal results must be repeated until the values return to normal or baseline or if a new 
baseline is established as determined by the investigator.
a
For screening, the most recent local laboratory results available ≤48 hr prior to randomization may be used (repeat 
testing not needed on Day 1).
b
Only for participants with cIAI or cUTI who switch to oral therapy (see the SoA).
c
Blood collection for Hematology and Blood Chemistry must be performed at: (1) the EOIV visit for participants with 
cIAI or cUTI who switch to oral therapy, OR (2) the EOT visit for participants with cIAI or cUTI who do not switch 
to oral therapy and for all participants with HABP/VABP. 
d
Blood collection for Hematology and Blood Chemistry must be performed within 14 days after EOT at either the 
EFU visit or LFU visit.
The approximate total blood volume to be drawn is within 3% of total blood volume (2.4 mL 
blood per kg of body weight) even for the lowest approximate weight for eligible participants 
in this study (ie, female neonates in the fifth percentile of growth according to World Health 
Organization growth charts). The maximum amount of blood collected from each participant 
over the duration of the study will not exceed 3% of total blood volume (2.4 mL blood per kg 
of body weight).
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 and assent, if applicable, 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 
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majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent/assent is in place.
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/assent 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 informed consent/assent form, 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.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements. The assent, as applicable, will adhere to IRB/IEC requirements, 
applicable laws and regulations, and Sponsor 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/assent. At the time of intervention
allocation/randomization, 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
A medical history will be obtained by the investigator or qualified designee. In addition to 
the evaluation of a participant’s medical history in terms of study eligibility, all medical 
conditions present during the 12 months prior to study entry will be documented at the 
screening visit on the appropriate electronic case report form (eCRF).
Any history of prior HABP or VABP, cIAI, or cUTI episodes or conditions that may 
predispose a participant to the development of a pulmonary, abdominal, or urinary tract 
infection, respectively, will also be documented on the appropriate eCRF, even if the prior 
episode or predisposing condition was diagnosed more than 12 months prior to study entry.
The details of any primary (HABP/VABP, cIAI, cUTI) or secondary bacterial infection-site 
diagnoses will be documented separately on the appropriate eCRF(s). Details should include 
the diagnosis and any additional diagnostic details associated with the infection site (eg, 
characterization of the complicated nature of the cIAI and/or cUTI).
For participants less than 3 months of age (Cohort 5), details specific to neonates and young 
infants, including details of the meningitis evaluation and assessment of absence of 
meningitis, will also be documented on the appropriate eCRF.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 14 days and any antimicrobial medication taken within 30 days prior to the first dose 
of IV study intervention. For breastfed participants, medications taken by the mother during 
the same timeframe will also be recorded. See Section 5.2 on prior antibacterial therapy.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. For breastfed participants, medications taken by the mother during the 
study will also be recorded.
See Section 5.2 for excluded medications and Section 6.5 on concomitant therapy during 
study intervention (IV or oral).
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 randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
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Any individual 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 randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or appropriately qualified 
designee according to the specifications within the pharmacy manual and will be recorded in 
the appropriate eCRF.
Study intervention should begin on the day of randomization or as close as possible to the 
date on which the participant is assigned.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
IV Study Intervention
The frequency of IMI/REL (Intervention Group 1) IV administration will be q6h or q8h as 
shown in Table 3. Each infusion should be administered within 60 minutes of the scheduled 
dose. IMI/REL should be administered over the duration appropriate for the age cohort as 
shown in Table 3.
The frequency and duration of Active Control (Intervention Group 2) IV administration will 
be per the authorized PI, SPC, or international treatment guidelines.
The study intervention must NOT be administered simultaneously through the same infusion 
line/lumen with any other drugs (including other IV study or IV nonstudy interventions). If 
another IV drug is required either prior to or after study intervention and only 1 line/lumen is 
available, an appropriate volume of saline flush must be used between IV infusions. In 
instances when IMI/REL or Active Control require administration at the same hour of the 
day as any other drugs (including other IV study or IV nonstudy interventions), the 2 
infusions should be administered either 1) sequentially with the IMI/REL infusion first 
followed by an appropriate volume of saline flush prior to administration of the other IV 
drug; OR 2) via a separate infusion line at the same time as the other IV drug.
Additional details for preparation and administration of study intervention are provided in the 
pharmacy manual. For participants randomized to receive IMI/REL, sites will contact the 
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IRT to request additional doses beyond the initial supply provided for the minimum 
treatment duration, as needed during the study IV intervention period, as indicated in the 
SoA.
8.1.8.1.2
Optional Oral Switch (cIAI, cUTI)
For participants with cIAI or cUTI, the investigator may decide to switch the participant to 
oral antibacterial therapy, to facilitate step-down in anticipation of discharge, based on the 
participant’s clinical condition and local standard of care. The list of acceptable oral switch 
options is provided in Table 1 and Appendix 9. IV study intervention is intended to be 
administered to participants with cIAI or cUTI for a minimum of 3 full days as in Table 1, 
after which participants with cIAI or cUTI in either intervention arm (IMI/REL or Active 
Control) who have demonstrated adequate response to IV study intervention may be switched 
to oral antibacterial therapy. The frequency of oral administration will be per the authorized 
PI, SPC, or international treatment guidelines (Table 1). Some participants with cIAI or cUTI 
may have limited reliable oral options for treatment of their infections and may still require 
IV study intervention to complete the entire duration of antibacterial treatment.
The decision to switch to oral therapy must be based on investigator assessment of the 
participant’s clinical signs and symptoms related to local and systemic improvement, as 
follows:
1. The participant has received at least 3 full days of IV study intervention, as in Table 1;
2. The participant has been afebrile for at least 24 hours, defined as having a maximal daily 
body temperature <38.0°C (100.4°F) and without the influence of aspirin, acetaminophen 
(paracetamol), or nonsteroidal anti-inflammatory drugs; if the participant is taking 
analgesic medication with antipyretic activity, temperature readings (to determine clinical 
response) should be determined at the end of the analgesic dosing interval.
3. Nausea or vomiting, if present prestudy, has resolved, and improvement is noted in the 
following (if present prestudy) without evidence of worsening:
a.
Flank pain/CVA tenderness, as assessed by severity scoring (none, mild, moderate, or 
severe); AND
b. Leukocytosis
In determining the switch to oral antibacterial therapy, the additional clinical signs and 
symptoms of cIAI or cUTI listed in Table 5 may also be considered.
4. For participants with cUTI, at least 1 follow-up urine culture has shown eradication of the 
uropathogen (Table 8 and Table 9). All participants with cUTI must have a repeat urine 
culture obtained after completion of at least 3 days of IV study intervention (ie, prior to 
the oral switch) to assess whether suppression/eradication of admission uropathogens has 
occurred (repeat catheterization not required).
These findings will be documented on the appropriate eCRFs for each of these participants.
See also Section 8.2.2.1 on cIAI and cUTI clinical signs and symptoms and Section 9.11 on 
oral therapy compliance.
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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 8.10.3.
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.
8.2
Efficacy Assessments
Definition of the efficacy endpoints and a summary of favorable response by efficacy 
endpoint and analysis population are provided in Table 11.
8.2.1
All-cause Mortality (28-day Survival Assessment)
For each participant, 28-day survival status (ie, whether the participant is alive or dead at 
Day 28 post-randomization) will be collected. Results of the assessment, including date and 
cause of death if relevant, will be recorded on the appropriate eCRF at the EFU or LFU visit 
or telephone call, as specified in the SoA. In addition to the Day 28 post-randomization 
survival assessment, all deaths that occur during the study period will be reported as part of 
routine safety assessment. 
8.2.2
Clinical Response
8.2.2.1
Clinical Signs and Symptoms Review
A detailed diagnosis as well as relevant clinical information associated with diagnosis, 
including clinical signs and symptoms, relevant radiographic, and laboratory characteristics 
related to the primary and any secondary bacterial infections sites, will be reviewed and 
documented on the appropriate eCRFs at the time points specified in the SoA.
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Presence or absence of specific clinical signs and symptoms for each infection type (Table 5) 
will be recorded daily during IV study intervention and at the visits specified in the SoA. 
Intensity of signs and symptoms will also be graded by the investigator as mild, moderate, or 
severe as described in Appendix 3.
Clinical signs and symptoms for each infection type, including those listed in Table 5 and in 
Appendix 8, will be monitored by the Primary Investigator (or designee) at baseline and 
throughout the study to determine resolution, persistence, or progression at each time point 
specified in the SoA, Table 6, and Table 7.
Table 5
Clinical Signs and Symptoms for Each Infection Type
Infection Type
Clinical Signs and Symptomsa
HABP/VABP
New onset or worsening of cough, dyspnea, tachypnea (eg, respiratory rate greater than 
25 breaths per minute), expectorated sputum production, requirement for mechanical 
ventilation, hypoxemia, need for acute changes in the ventilator support system to 
enhance oxygenation, as determined by worsening oxygenation (via ABG or PaO2/FiO2
assessment), needed changes in the amount of positive end-expiratory pressure, new 
onset of suctioned respiratory secretions, fever or hypothermia, chills/rigors, chest pain
cIAI
Fever or hypothermia, hypotension, abdominal pain, flank pain, pain caused by cIAI 
that is referred to another anatomic area such as back or hip, tenderness to palpation, 
rebound tenderness, guarding, mass, nausea and vomiting, anorexia, altered mental 
status
cUTI
If 0 to <2 years of age:
-
Fever
-
Failure to thrive
-
Recent weight loss
-
Irritability
-
Poor feeding
-
Lack of normal level of activity
-
Abdominal pain/tenderness on 
physical examination
-
Vomiting
-
Jaundice
If 2 to <18 years of age:
-
Fever 
-
Chills or rigors
-
Dysuria
-
Urinary urgency
Urinary frequency
New-onset urinary 
incontinence
-
Suprapubic pain, flank pain, 
abdominal pain, or pelvic pain
-
Suprapubic tenderness or 
CVA tenderness on physical 
examination
-
Nausea or vomiting
ABG=arterial blood gas; cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; 
CVA=costovertebral angle; HABP/VABP=hospital-acquired or ventilator-associated bacterial pneumonia; 
PaO2/FiO2=partial pressure of oxygen to the fraction of inspired oxygen.
a
Evaluation of clinical response for infection type may also include resolution of laboratory abnormalities present at 
baseline (see Appendix 8 for relevant laboratory abnormalities for each infection type).
8.2.2.2
Investigator Rating and Sponsor Categorization of Clinical Response
The investigator will determine and record the clinical response rating at each visit (per the 
SoA) as described in Table 6 and Table 7 based on comparison to baseline clinical signs and 
symptoms of the participant’s infection.
The Sponsor will use this rating to categorize the clinical response as “favorable” or 
“unfavorable”.
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Table 6
Clinical Response Ratings at the EOIV and EOT Visits
Clinical 
Responsea
Response Definition
Cure
All preintervention signs and symptomsb of the index infection have resolved (or returned 
to “preinfection status", with no new symptoms) AND no additional antibacterial 
intervention is required for the index infection.
Improved
The majority of preintervention signs and symptomsb of the index infection have improved 
or resolved (or returned to “preinfection status", with no new symptoms) AND no 
additional antibacterial intervention is required.
Failure
No apparent response to study intervention in prestudy signs and symptomsb of the index 
infection: persistence or progression of the majority of or all preintervention signs and 
symptoms.
Indeterminate
Study data are not available for evaluation of clinical response for any reason at the visit, 
including:
Complication related to underlying medical condition; OR
Participant was withdrawn for any reason before sufficient data had been obtained to 
permit evaluation for any reason; OR
Extenuating circumstances (eg, an important protocol deviation) preclude classification as 
"cure," "improved," or "failure;" OR
Death occurred during the study period and the index infection was clearly 
noncontributory.
EOIV=end of IV therapy; EOT=end of therapy.
a
A favorable clinical response at EOT requires an assessment of “cure” or “improved”.
b
Refer to Section 8.2.2.1 and Table 5 for a description of relevant clinical signs and symptoms.
Table 7
Clinical Response Ratings at the EFU and LFU Visits
Clinical 
Responsea
Response Definition
Sustained Cure
All preintervention signs and symptomsb of the index infection have resolved (or 
returned to "preinfection status", with no new symptoms) with no evidence of 
resurgence AND no additional antibacterial intervention is required for the index 
infection.
Cure
All preintervention signs and symptomsb of the index infection have resolved (or 
returned to “preinfection status", with no new symptoms) AND no additional 
antibacterial intervention is required for the index infection.
Failure
No apparent response or insufficient response to study intervention in prestudy signs 
and symptoms of the index infection: persistence, progression, or improvement (without 
full resolution) of all preintervention signs and symptoms.b
Relapse
Participants with a favorable clinical response (cure or improvement) at the EOT visit 
have new or worsening signs and symptomsb of the index infection by the EFU or LFU 
visit.
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Clinical 
Responsea
Response Definition
Indeterminate
Study data are not available for evaluation of efficacy for any reason, including:
a)
Complication related to underlying medical condition; OR
b)
Participant was withdrawn for any reason before sufficient data had been obtained 
to permit evaluation of clinical response; OR
c)
Extenuating circumstances (eg, an important protocol deviation) preclude 
classification as "sustained cure," "failure," or "relapse;" OR
d)
Death occurred during the study period and the index infection was clearly 
noncontributory.
EFU=early follow-up; EOT=end of therapy; LFU=late follow-up.
a
A favorable clinical response at EFU or LFU requires an assessment of “cure” or “sustained cure”. To be considered 
“sustained cure”, the clinical response for the prior visit (EOT or EFU) must have been considered “cure”.
b
Refer to Section 8.2.2.1 and Table 5 for a description of clinical signs and symptoms.
8.2.3
Microbiological Response
As described in Section 4.2.2.1.3, microbiological response will be evaluated separately for 
each baseline pathogen meeting the culture criteria in Section 8.2.3.1 (ie, by-pathogen).
The investigator will determine the by-pathogen microbiological response rating at the visits 
specified in the SoA based on local laboratory results of available infection-site and blood 
cultures collected relative to the pathogen(s) isolated at baseline, as detailed in Section 
8.2.3.2.
8.2.3.1
Infection Site and Blood Specimens for Gram Stain, Culture, and 
Susceptibility Testing
The requirements for collection of infection-site specimens for culture and susceptibility 
testing for participants with HABP/VABP, cIAI, and cUTI are outlined in Section 8.2.3.1.1, 
Section 8.2.3.1.2, and Section 8.2.3.1.3, respectively. Gram stain is only required for 
participants with HABP/VABP (see Section 8.2.3.1.1). The requirements for collection of 
blood samples for culture and susceptibility testing are outlined in Section 8.2.3.1.4.
Infection site and blood specimens should be processed by the local laboratory for Gram 
stain (HABP/VABP only), culture, and susceptibility testing according to recognized 
methods for each specimen/infection type. All organisms isolated from culture that are 
considered to be etiologic pathogens by the investigator will be retained by the local clinical 
microbiology laboratory and sent to the central microbiology laboratory as instructed in the 
microbiology laboratory manual. Suspected causative bacterial pathogens should also be 
stored at the local laboratory for possible future testing, if needed. 
In addition to testing by the central microbiology laboratory, culture (aerobic and anaerobic) 
and in vitro susceptibility testing may be performed for medical management by the site’s
local laboratory per each laboratory’s standard procedures. Relevant culture data, including 
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date of collection, specimen type (including method of collection), and pathogen 
identification (to the species level, if identified) must be collected on the appropriate eCRFs.
8.2.3.1.1
HABP/VABP: Lower Respiratory Tract Specimen(s) for Gram Stain, 
Culture, and Susceptibility Testing
Baseline Lower Respiratory Tract Specimen
Participants with HABP/VABP will have a baseline (at or within 48 hours of the screening 
visit) LRT sample obtained, as medically acceptable, from the infection site for Gram stain, 
culture, and susceptibility testing prior to initiation of IV study intervention as specified in 
the SoA and Appendix 8 – Section 10.8.1.
Microscopic examination of Gram-stained smears must be performed for LRT specimens 
collected prior to randomization to ensure the adequacy/quality of the specimen and to 
discontinue participants with only gram-positive cocci detected (Section 7.1). For specimens 
obtained by direct sampling of the LRT (ie, via BAL, mini-BAL, or protected brush 
specimen [PBS]), no predefined requirements are required to ascertain the quality of the 
respiratory specimen. However, for baseline specimens not obtained by direct sampling of 
the LRT, such as those obtained by expectorated sputum, the low-power microscopic view of 
the Gram stain can be used to ascertain the quality of the respiratory specimen. This helps to 
ensure that the respiratory specimen sent for culture does not represent oropharyngeal 
contamination (eg, fewer than 10 squamous epithelial cells and greater than 25 neutrophils is 
an example of an adequate expectorated/suctioned sputum specimen). In addition, a high-
power microscopic view of the Gram stain can be used to characterize the general type of 
bacteria causing the pneumonia. Specimens should be processed for culture according to 
recognized methods.
Post-baseline Lower Respiratory Tract Specimen (If Clinically Indicated)
Participants with HABP/VABP who have an LRT sample collected from the infection site 
post-baseline (post-randomization), if clinically indicated, will also have culture and 
susceptibility testing of any identified pathogens.
Post-baseline LRT cultures would preferentially include samples collected from a 
tracheostomy or endotracheal aspirates, or bronchoscopy specimens. Expectorated or induced 
sputum samples are also accepted provided the sample does not represent oropharyngeal 
contamination (ie, sample contains fewer than 10 squamous epithelial cells on low-power 
microscopy review of the Gram stain).
LRT samples may also be collected if there is clinical or laboratory evidence of persistence 
or progression of the infectious process (including persistent fever, elevated WBC count, or 
significant changes in the participant’s clinical condition). Of note, specimens should also be 
collected at any time of surgical or drainage procedure (if required).
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8.2.3.1.2
cIAI: Intra-abdominal Specimen(s) for Culture and Susceptibility Testing
Baseline Intra-abdominal Specimen
Participants with cIAI will have a baseline intra-abdominal specimen collected at or within 
48 hours of the screening visit (intra- or post-operatively) or within 24 hours of 
randomization (preoperative), as medically acceptable, from purulent material from an intra-
abdominal surgical procedure or percutaneous drainage from the infection site for culture (of 
aerobic and anaerobic organisms) and susceptibility testing prior to initiation of IV study 
intervention as specified in the SoA and Appendix 8 - Section 10.8.2.
Specimens should be collected at the beginning of the surgical procedure prior to 
debridement, removal, or disinfection of the primary site of infection. Aspirates (collected 
with a needle or syringe) or needle biopsy samples are recommended, and swabs of purulent 
material are discouraged. Specimens should not be obtained from in situ abdominal drains. 
Specimens should not be taken from the gallbladder bile, gallbladder wall, or from bile in the 
common bile duct.
Post-baseline Intra-abdominal Specimen(s) (If Clinically Indicated)
Post-baseline (post-randomization) intra-abdominal specimens for culture and susceptibility 
testing are to be obtained from the site of infection if clinically indicated (eg, if reintervention 
is required, collection during the additional surgical procedure in participants with cIAI who 
have clinical failure) to evaluate the microbiological assessment. Specimens should not be 
obtained from in situ abdominal drains. All culture and susceptibility testing of any post-
baseline specimens should be performed as for the baseline sample. 
8.2.3.1.3
cUTI: Urine Specimens for Culture and Susceptibility Testing
Baseline Urine Specimen
Participants with cUTI will have a baseline (at or within 48 hours of screening) urine 
specimen collected prior to the start of IV study intervention, preferably obtained prior to 
administration of any potentially therapeutic antibacterials. Testing will be performed on all 
organisms considered to be pathogens (quantification of uropathogens is required) in urine 
specimens obtained by MSCC, straight catheter, indwelling urethral catheter, or SPA (urine 
samples obtained from collection bags are not allowed for the study-qualifying baseline urine 
culture specimen), as specified in the SoA and Appendix 8 - Section 10.8.3.
Post-baseline Urine Specimens
Post-baseline (post-randomization) urine specimens will be collected for culture and 
susceptibility testing at the time points indicated in the SoA from participants able to provide 
a clean urine specimen as for the baseline urine specimen. 
The use of sterile urine collection bags is allowed for young children who are unable to 
provide MSCC or other urine specimens at post-baseline visits. However, urine microscopy 
must be performed to detect pyuria in the urine sample; if pyuria is not present (as defined in 
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Appendix 8 - Section 10.8.3), then bacterial growth other than the uropathogen at study entry 
may be considered a contaminant rather than a true superinfection or new infection.
8.2.3.1.4
Blood Specimen(s) for Culture and Susceptibility Testing
Baseline Blood Sample
As clinically indicated, participants will have a blood sample collected at baseline 
(screening) for blood culture and susceptibility testing.
Postbaseline Blood Sample(s) (If Positive Baseline Culture And As Clinically Indicated)
Participants with positive baseline blood cultures should have follow-up blood cultures 
collected until a subsequent follow-up culture demonstrates no growth. Follow-up blood 
cultures in participants with no evidence of bacteremia (ie, positive blood cultures) at study 
entry should also be performed as clinically indicated, at the investigator’s discretion.
8.2.3.2
Investigator Rating and Sponsor Categorization of Microbiological Response
Microbiological response will be determined for each pathogen for participants with 
infection-site cultures available (see Section 8.2.3.1). For a bacterial organism to be 
considered a pathogen at admission, it must be a typical lung, abdominal, or urinary pathogen 
(ie, not a normal colonizer or contaminant).
The investigator will determine a by-pathogen microbiological response rating for the 
respective infection type at the EOIV (for participants with cIAI or cUTI who switch to oral 
therapy) and EOT visits (Table 8) and at the EFU and LFU visits (Table 9). This rating will 
be based on the local laboratory results of infection-site cultures (Section 8.2.3.1) collected 
for participants at each of these visits (when available) relative to the pathogen(s) isolated at 
baseline.
The Sponsor will use the by-pathogen microbiological response rating determined by the 
investigator at each of the EOIV (for participants with cIAI or cUTI who switch to oral 
therapy), EOT, EFU, and LFU visits to categorize the overall microbiological response (ie, 
overall microbiological response for the participant based on the response of all pathogens 
present in the baseline culture) as “favorable” or “unfavorable”.
For participants from whom only 1 pathogen is isolated in the baseline infection-site culture, 
the microbiological response assessment will be based on the microbiological response rating 
for that pathogen. For participants from whom more than 1 baseline pathogen is isolated in 
the baseline infection-site culture, the microbiological response outcome will be based on 
microbiological culture results for all pathogens (ie, a “favorable” overall microbiological 
response requires eradication or presumed eradication of all baseline pathogens).
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Table 8
By-Pathogen Microbiological Response Ratings at the EOIV and EOT Visits
Microbiological 
Responsea,b,c
Response Definition
Eradication
HABP/VABP: A lower respiratory tract culture taken at the EOT visitc shows 
eradication of the pathogen found at study entry.
cIAI: An intra-abdominal culture taken at the EOIV or EOT visitc shows 
eradication of the pathogen found at study entry.
cUTI: A urine culture taken at the EOIV or EOT visitc shows eradication of the
uropathogen (reduced to <103 CFU/mL) found at study entry.
Presumed Eradication
No specimen taken because participant is deemed clinically improved or cured of 
the pathogen found at study entry.
Persistenced
HABP/VABP: A lower respiratory tract culture taken at the EOT visitc grows the 
pathogen found at study entry.
cIAI: An intra-abdominal culture taken at the EOIV or EOT visitc grows the 
pathogen found at study entry.
cUTI: A urine culture taken at the EOIV or EOT visitc grows the uropathogen (at 
≥103 CFU/mL) found at study entry.
Superinfectione
HABP/VABP: A lower respiratory tract culture taken at the EOT visitc grows a 
pathogen other than a baseline pathogen during the course of IV study intervention
OR emergence during IV study intervention of a new pathogen at a distant sterile 
site along with new or worsening signs and symptoms of infection.
cIAI: An intra-abdominal culture taken at the EOIV or EOT visitc grows a pathogen 
other than a baseline pathogen during the course of IV study intervention OR
emergence during IV study intervention of a new pathogen at a distant sterile site 
along with new or worsening signs and symptoms of infection.
cUTI: A urine culture taken at the EOIV or EOT visitc grows a uropathogen (at 
≥105 CFU/mL) other than a baseline pathogen during the course of IV study
intervention OR emergence during IV study intervention of a new pathogen at a 
distant sterile site along with new or worsening signs and symptoms of infection.
Indeterminate
Follow-up culture is not available at the EOIV or EOT visitc due to participant
death or withdrawal from study; OR
Available microbiological data are incomplete (eg, sample collected, but no results 
available); OR
Extenuating circumstances (eg, an important protocol deviation) preclude 
microbiological assessment; OR
Any other circumstance which makes it impossible to define the microbiological 
response.
CFU=colony-forming unit; cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; 
EOIV=end of IV therapy; EOT=end of therapy; HABP/VABP=hospital-acquired or ventilator-associated bacterial 
pneumonia; IV=intravenous.
a
A microbiological response rating must be completed separately for each pathogen isolated at study entry. If a 
new/emergent pathogen is identified at this visit, which was not identified at baseline, the microbiological response 
rating should be recorded as “superinfection” for any new/emergent pathogen isolated after initiation of IV study 
therapy.
b
A favorable by-pathogen microbiological response at EOT requires “eradication” or “presumed eradication” of the 
pathogen found at study entry.
c
If a culture is not available at EOT, an assessment at this visit can be made from the last available culture collected 
after at least 72 hours of IV study intervention. If a culture is not available at EOT for cIAI or cUTI participants who 
receive oral switch, an assessment at this visit can be made from the last available culture collected after at least 48
hours of oral study intervention.
d
If a participant is discontinued from IV or oral study intervention due to clinical failure (ie, unfavorable clinical 
response), but persistence of the admission pathogen is not confirmed by culture results or no culture is obtained at 
the time of clinical failure, the admission pathogen will be presumed to have persisted.
e
For cUTI, if sterile urine collection bag method is used for post-baseline sampling, see Section 8.2.3.1.3.
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Table 9
By-pathogen Microbiological Response Ratings at the EFU and LFU Visits
Microbiological 
Responsea,b,c
Response Definition
Eradication
HABP/VABP: A lower respiratory tract culture taken at the EFU or LFUc visit 
shows eradication of the pathogen found at study entry.
cIAI: An intra-abdominal culture taken at the EFU or LFU visitc shows 
eradication of the pathogen found at study entry.
cUTI: A urine culture taken at the EFU or LFU visitc shows eradication of the 
uropathogen (reduced to <103 CFU/mL) found at study entry.
Presumed Eradication
No specimen taken because participant is deemed clinically improved or cured 
of the pathogen found at study entry.
Persistence
HABP/VABP: A lower respiratory tract culture taken at the EFU or LFU visit 
grows the pathogen found at study entry.
cIAI: An intra-abdominal culture taken at the EFU or LFU visitc grows the 
pathogen found at study entry.
cUTI: A urine culture taken at the EFU or LFU visitc grows the uropathogen 
(at ≥103 CFU/mL) found at study entry.
New Infectiond
HABP/VABP: A pathogen other than an original microorganism found at 
study entry is present in the lower respiratory tract culture any time after 
completion of IV or oral study intervention; OR A pathogen is isolated from a 
distant sterile site after completion of IV or oral study intervention.
cIAI: A pathogen other than an original microorganism found at study entry is 
present in the intra-abdominal culture any time after completion of IV or oral 
study intervention; OR A pathogen is isolated from a distant sterile site after 
completion of IV or oral study intervention.
cUTI: A urine culture grows a uropathogen (at ≥105 CFU/mL) other than a 
baseline pathogen during the course of IV study intervention, OR emergence
during IV study intervention of a new pathogen at a distant sterile site along 
with new and/or worsening signs and symptoms of infection.
Recurrenced
HABP/VABP: A lower respiratory tract culture grows the baseline pathogen 
taken any time after documented eradication. 
cIAI: An intra-abdominal culture grows the baseline pathogen taken any time 
after documented eradication.
cUTI: A urine culture grows the baseline uropathogen (at ≥105 CFU/mL) 
taken any time after documented eradication.
Indeterminate
a)
Follow-up culture is not available at the EFU or LFU visit due to 
participant death or withdrawal from study; OR
b)
Available microbiological data are incomplete (eg, sample collected, but 
no results available); OR
c)
Extenuating circumstances (eg, an important protocol deviation) preclude 
microbiological assessment; OR
d)
Any other circumstance which makes it impossible to define the 
microbiological response.
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Microbiological 
Responsea,b,c
Response Definition
CFU=colony-forming unit; cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; 
EFU=early follow-up; EOT=end of therapy; HABP/VABP=hospital-acquired or ventilator-associated bacterial 
pneumonia; IV=intravenous; LFU=late follow-up.
a
A microbiological response rating must be completed separately for each pathogen isolated at study entry. If a 
new/emergent pathogen is identified at this visit, which was not identified at study entry, the microbiological 
response rating should be recorded as “new infection” for any new/emergent pathogen isolated after initiation of IV 
study intervention.
b
A favorable by-pathogen microbiological response at the EFU or LFU visit requires “eradication” or “presumed 
eradication” of the pathogen found at study entry.
c
If a culture is not available at EFU or LFU, an assessment at this visit can be made based on the culture collected at 
EOT as long as it was collected at least 24 hours after the completion of IV or oral study intervention and before the 
EFU or LFU visit and provided the participant had fully resolved clinical symptoms/signs of the index infection at 
the EFU or LFU visit.
d
For cUTI, if sterile urine collection bag method is used for post-baseline sampling, see Section 8.2.3.1.3.
8.2.4
By-pathogen Microbiological Response
Microbiological response will also be evaluated separately for each baseline pathogen and 
the Sponsor will categorize individual by-pathogen microbiological response for participants 
with post-baseline infection-site culture(s) as favorable or unfavorable based on the 
individual pathogen rating determined by the investigator, as described in Section 8.2.3.2.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn by visit and by 
sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Full and Directed Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard.
A complete physical examination, performed at randomization includes the following 
assessments: general appearance, head, eyes, ears/nose/ throat, neck, lymph nodes, skin, 
lungs, heart, abdomen, musculoskeletal, and neurologic evaluations. Breast, rectal, and 
genitourinary/pelvic exams should be performed when clinically indicated. After the initial 
full physical examination, brief directed physical examinations targeted to the participant’s 
illness, condition, and complaints will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard at the visits indicated 
in the SoA. 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.
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Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Any abnormal or clinically significant findings from the physical examinations must be 
recorded on the appropriate eCRF. If observed prior to initiation of IV study therapy, changes 
in physical examination findings (abnormalities) that the investigator considers clinically 
significant will be recorded on the medical history eCRF. If observed after initiation of IV 
study intervention (including during oral therapy), changes in physical examination findings 
(abnormalities) that the investigator considers clinically significant must be recorded as AEs 
(see Section 8.4.1).
8.3.2
Height and Weight
An investigator or medically qualified designee (consistent with local requirements) as per 
institutional standard will measure and record the participant’s height (cm) and weight (kg) at 
the visits indicated in the SoA. Weight will be measured without shoes, jacket, or diaper (for 
participants using diapers). A bed scale may be used if needed for participants who cannot sit 
up for any reason (eg, infants, intubated participants).
If applicable, any weight change that occurs during IV study intervention that may result in 
discontinuation (based on the estimated CrCl or eGFR value per Section 7.1 and Table 16) 
must be reported to the IRT as indicated in the SoA (IRT Contact) as well as recorded on the 
appropriate eCRF.
8.3.3
Vital Signs
•
The following will be assessed by an investigator or medically qualified designee 
(consistent with local requirements) as per institutional standard as indicated in the SoA:
-
Temperature: Oral or rectal temperatures should be taken as appropriate for the 
participant’s clinical condition and age; if not possible, then tympanic or axillary 
methods are acceptable. Temperature readings should be taken at approximately the 
same time each day.
-
Systolic and diastolic blood pressure
-
Heart rate
-
Respiratory rate
•
Blood pressure and heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
•
Vital signs will be measured before blood collection for laboratory tests with the 
participants in a seated or semisupine position or, for participants who cannot sit up for 
any reason (eg, infants, intubated participants), in a supine or semisupine position, after 
10 minutes rest.
Any abnormal or clinically significant findings from the vital sign measurements must be 
recorded on the appropriate eCRF.
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8.3.4
Meningitis Evaluation
As required in Section 5.2 exclusion criterion #2 for participants <3 months of age, the 
investigator must rule out meningitis and document its absence prior to initiation of IV study 
intervention. The investigator may rule out meningitis by performing an LP with CSF culture
(if clinically indicated per local standard-of-care) or by other standard-of-care procedures or 
clinical assessments. Negative results from a previous procedure or assessment may be used 
to document that meningitis has been ruled out for such participants provided these results 
are available at the time of screening. Investigator assessment of the absence of meningitis 
must be recorded on the appropriate source documents.
8.3.5
Adverse Event Monitoring
8.3.5.1
Clinical Adverse Events
Clinical AEs will be collected from the time of initiation of the first dose of IV study therapy 
through 14 days following completion of all study therapy. All AEs should be documented 
on the appropriate eCRF.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs. Examples of this 
may include, but are not limited to, teething, typical crying in infants and children, and onset 
of menses or menopause occurring at a physiologically appropriate time.
See Section 8.4 for details regarding assessment and documentation of AEs.
8.3.5.2
Local Infusion Site Tolerability
Local infusion site tolerability will be evaluated daily during IV study therapy. The 
tolerability of all study therapy at the local IV infusion site will be based on investigator 
inspection and participant comments regarding signs and symptoms of intolerance. The IV 
infusion site should be observed daily during IV therapy to determine the presence/absence 
of erythema, induration, pain, tenderness, warmth, swelling, ulceration, local phlebitis, rash, 
or other reactions.
8.3.5.3
Laboratory Adverse Experiences
Laboratory adverse experiences will be based on safety laboratory tests (both central and 
local results), including hematology and chemistry tests from blood and urinalysis from 
urine. See the SoA on the timing of sample collection and Section 8.3.7 and Appendix 2 for 
the types of laboratory tests to be performed.
8.3.5.4
Adverse Events Leading to Death
All deaths that occur during the study period will be reported as part of routine safety 
assessment, as described.
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8.3.6
Clinical Signs and Symptoms of Infection
A detailed diagnosis and relevant clinical information associated with diagnosis including 
clinical signs and symptoms, radiographic, and laboratory characteristics (see Appendix 2) 
related to the primary (HABP/VABP, cIAI, cUTI) and any secondary bacterial infections 
sites will be reviewed by the investigator and documented on the appropriate eCRFs at the 
time points specified in the SoA.
Presence or absence of specific clinical signs and symptoms relevant for the infection site of 
interest will be reviewed by the investigator and recorded daily during IV study intervention
and at the visits specified in the SoA. Intensity of signs and symptoms will also be graded by 
the investigator as mild, moderate, or severe as described in Appendix 3.
8.3.6.1
Infection Source Control Review
Information related to infection source control must be collected for all participants at the 
visits specified in the SoA. The following information specific to the site(s) of bacterial 
infection must be collected for participants with:
•
HABP/VABP: (a) details regarding intubation, extubation, reintubation, or replacement 
of the endotracheal tube, (b) details regarding lung procedures/surgeries performed to 
drain/remove a loculated pulmonary infection; and (c) details regarding a thoracentesis 
procedure to drain any accompanying pleural fluid;
•
cIAI: details associated with the qualifying abdominal surgical intervention or any 
subsequent interventions, including an anonymized narrative of the operative note and/or 
interventional radiology report; or
•
cUTI: baseline information associated with catheterization (eg, recent surgical procedure
or instrumentation, presence of catheter/stent) as well as any details related to removal 
and/or replacement of urinary catheters at any time during the study.
Relevant information regarding infection source control should be documented on the 
appropriate eCRF.
8.3.6.2
O2 Saturation (HABP/VABP Only)
In participants with HABP/VABP, oxygen (O2) saturation via pulse oximetry will be 
collected on Day 1 prior to the initiation of IV study intervention, then daily until completion 
of IV study intervention, as well as at the EOT, EFU, and LFU visits. All measured values 
should be documented on the appropriate eCRF.
If available, as clinically indicated, in ventilated participants with HABP/VABP who have an 
existing arterial line, PaO2 and FiO2 measured via ABG should also be recorded on the 
appropriate eCRF.
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8.3.6.3
Chest X-ray
In participants with HABP/VABP, a baseline chest x-ray must be performed as required in 
Appendix 8 - Section 10.8.1 and indicated in the SoA. For randomization, a chest x-ray is not 
required if a prior chest x-ray or chest CT has been performed in association with the current 
infection within 48 hours of randomization.
Post-baseline (including at EOT and, if applicable, at the discontinuation visit), chest x-ray is 
only to be performed if clinically indicated.
Chest x-ray results (or prior chest CT results, if relevant) including a description, location, 
and extent of infiltrates or consolidation must be documented on the appropriate eCRF. The 
presence of a pleural effusion and other abnormalities should also be noted.
8.3.7
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.
8.4
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).
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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/assent, but before intervention allocation/randomization, must 
be reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment; if the event causes the participant to be excluded from the study, or is the result of 
a protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
From the time of intervention allocation/randomization through 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.
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 10.
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Table 10
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)
– causes exclusion
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
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
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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
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 randomized 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.
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.
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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 (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study is reportable to the 
Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing that the fetus will be 
born with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus. Pregnancy outcomes of ectopic 
pregnancy, 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 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× 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).
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2. A confirmed (ie, verified by repeat testing) elevated AST or ALT laboratory value that is 
greater than or equal to 5× ULN as a result of within-protocol-specific testing or 
unscheduled testing.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than 10% of the calculated age-appropriate dose 
specified in Section 6.1.1 – Dose by Age Cohort (Table 3) or in subsequent protocol 
clarification letters.
No specific information is available on the treatment of overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be assayed for evaluation of 
PK/pharmacodynamics will be collaboratively determined by the Sponsor. If indicated, these 
samples may also be assayed and/or pooled for assay in an exploratory manner for additional 
pharmacodynamic markers.
8.6.1
Blood Collection for Plasma Relebactam, Imipenem, and Cilastatin
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. All PK samples must be drawn within the specified time 
windows, and the actual sampling times must be documented.
The method of collection for PK samples is at the discretion of the investigator (eg, 
peripherally inserted central catheter line, indwelling catheter access, individual peripheral 
phlebotomies, peri-operatively placed arterial line). A separate IV line for PK sample 
collection is highly recommended; if a separate IV line is not clinically feasible, refer to the 
operations/laboratory manual for further details of allowable alternative collection methods.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
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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
Approximately 2 days prior to intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
Screening procedures may be repeated after consultation with the Sponsor. If the participant 
is rescreened, screening procedures should be repeated, unless they fall within the window 
specified.
8.10.2
Intervention Period
Details regarding procedures, assessments, and scheduling windows for the Day 1 
(Randomization), OTX, EOIV (only for participants who switch to oral therapy), and EOT 
visits (ie, Visits 2, 3, 4, and 5) are presented in the SoA; notably, for participants who receive 
IMI/REL, blood samples for plasma PK assessments and vital sign measurements will be 
collected several times at Visit 2 and, for participants who switch to oral therapy, the OTX 
and EOIV visits (Visits 2 and 3) may be combined if both occur on Day 3.
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue treatment (eg, participants who discontinue from IV study 
intervention partway through the infusion or who discontinue from oral study intervention) or 
who withdraw from the study at any point after the initiation of IV study intervention will 
continue to be monitored in the study. These participants should have all safety assessments, 
including clinical safety laboratory assessments, vital sign measurements, directed physical 
examination, collection of AEs and concomitant medications, and local tolerability 
monitoring (for participants who discontinue from IV study intervention or withdraw from 
the study between the initiation of IV study intervention and the EOT visit) completed as per 
the SoA, but do not need to have PK sampling performed.
Participants who withdraw from the study prior to initiation of the first dose of study 
intervention (eg, due to removal of consent by the legally acceptable representative or due to 
an emergent condition or circumstance, which, in the opinion of the investigator or Sponsor, 
places the participant at unnecessary risk through continued participation, or does not allow 
adherence to the protocol) do not need to have further visits or assessments.
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8.10.4
Poststudy
Participants will be required to return to the clinic 7 to 14 days (depending on the duration of 
study treatment) after completion of the last dose of all study intervention (IV or oral) for the 
EFU visit and again 7 to 14 days after the EFU visit for the LFU visit (ie, Visits 6 and 7). If 
both poststudy (EFU and LFU) visits occur prior to Day 28 post-randomization, a subsequent 
survival assessment telephone call should be made on Day 28 (+3 days [ie, 28 to 31 days]) 
post-randomization to assess the participant’s 28-day survival. See the SoA for further 
details.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a sSAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 to Section 9.12.
Study Design 
Overview
A Phase 2/3 Open-label, Randomized, Active-controlled Clinical Study to Evaluate the 
Safety, Tolerability, Efficacy and Pharmacokinetics of MK-7655A in Pediatric 
Participants From Birth to Less Than 18 Years of Age With Confirmed or Suspected 
Gram-negative Bacterial Infection
Treatment 
Assignment
Participants with HABP/VABP, cIAI, or cUTI will be randomized in a 3:1 ratio to 
receive IMI/REL or active control. Randomized participants will be stratified by age 
cohort and infection type.
Five pediatric age cohorts will be evaluated in the study:

Age Cohort 1: Adolescents (12 to <18 years)

Age Cohort 2: Older Children (6 to <12 years)

Age Cohort 3: Younger Children (2 to <6 years)

Age Cohort 4: Infants and Toddlers (3 months to <2 years)

Age Cohort 5: Neonates and Young Infants (birth to <3 months)
Three infection types will be evaluated in the study:

HABP/VABP

cIAI

cUTI
Analysis 
Populations
Safety: All Participants as Treated (APaT)
Efficacy: Modified intent-to-treat (MITT) and microbiological MITT (mMITT)
Pharmacokinetics: Pharmacokinetic (PK)
Primary 
Endpoint(s)
Safety endpoints:

Adverse events (AEs)

IV study intervention discontinuations due to AEs
Key Secondary 
Endpoints
Efficacy endpoints:

All-cause mortality

Favorable clinical response

Favorable microbiological response
Pharmacokinetic endpoints:

Plasma concentrations of imipenem and relebactam (REL)

AUC0-24hr and Ceoi for imipenem and REL

%T>MIC for imipenem
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Statistical 
Methods for Key 
Efficacy/ 
Pharmacokinetic 
Analyses
Efficacy analysis:
Within-group 95% confidence intervals for the efficacy endpoints will be calculated 
using the Agresti & Coull method. Point estimates and between-group 95% confidence 
intervals for efficacy endpoints will be calculated using unstratified Miettinen and 
Nurminen method.
There will be no efficacy hypothesis testing conducted in this estimation study. 
Pharmacokinetic analysis: 
The pediatric population PK model developed using adult and PN020 pediatric PK 
data will be updated with PN021 PK data and used to calculate the PK endpoints. 
Statistical 
Methods for Key 
Safety Analyses
The tiers differ with respect to the analyses that will be performed. There are no Tier 1 
events. For Tier 2 events, point estimates and 95% CIs will be provided for between-
treatment differences in the percentage of participants with events and these analyses 
will be performed using the Miettinen and Nurminen method. For Tier 3 safety 
parameters, only point estimates by intervention group will be provided. 
The analysis of safety results will be performed for overall participants. In addition, the 
analysis for some Tier 2 endpoints will be performed for each age cohort and for each 
infection type separately. 
Interim Analyses
A review of safety and tolerability data will be conducted by an independent external 
Data Monitoring Committee (eDMC) in this study when Age Cohorts 2 and 3 have 
achieved at least 20 participants each with complete data available (all complete data 
available from Age Cohorts 1, 2, and 3 will be reviewed at this time), along with 
periodic reviews as described in the DMC charter.
No formal efficacy analyses will be conducted for eDMC review; however, protocol-
specific summary statistics for PK data and/or key efficacy endpoints can be provided 
to the eDMC on request to support benefit-to-risk evaluation.
An internal interim review of subgroup analyses of safety, tolerability, efficacy, and 
PK data from each of Age Cohorts 1 through 3 has been performed prior to enrollment 
of Age Cohorts 4 and 5, with the doses communicated via Amendment 03.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and 
Power 
Approximately 140 participants will be randomized in a 3:1 ratio to receive IMI/REL 
or active control to target having 132 participants (approximately 99 in the IMI/REL 
and approximately 33 in the active control group in the safety analysis population). 
In each of the 5 age cohorts, the following number of participants will be randomized:

Age Cohort 1: No more than 12 participants

Age Cohorts 2 and 3: At least 20 participants in each age cohort

Age Cohorts 4 and 5: At least 28 participants in each age cohort
By each of the 3 infection types, the following number of participants will be 
randomized:

HABP/VABP and cIAI - At least 28 participants

cIAI: At least 10% of participants with diagnosis other than complicated 
appendicitis

cUTI: No more than 48 participants in Age Cohorts 3, 4, and 5 combined
There are no hypotheses to be evaluated, but Section 9.9 provides information about 
two-sided 95% confidence intervals for the proportion of participants assessed as a 
success under varying assumptions for the number of successes in both treatment 
groups.
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9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as an open-label study (ie, participants, investigators, and 
Sponsor personnel will be aware of participant intervention assignments after each 
participant is enrolled and intervention is assigned).
The Sponsor will generate the randomized allocation schedule(s) for study intervention 
assignment.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study and no formal 
hypothesis testing will be performed.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
A full description of efficacy assessments is contained in Section 8.2.
The efficacy endpoints of interest include:
•
All-cause mortality through Day 28 post-randomization
•
Favorable clinical response at the EOT, EFU, and LFU visits
•
Favorable microbiological response at the EOT, EFU, and LFU visits
The exploratory efficacy endpoints include:
•
Favorable clinical response at the EOIV visit (for oral switch participants)
•
Favorable microbiological response at the EOIV visit (for oral switch participants)
•
Favorable by-pathogen microbiological response at the EOIV (for oral switch 
participants), EOT, EFU, and LFU visits
The efficacy measures and assessments required to achieve a favorable response are 
summarized in Table 11.
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Table 11
Summary of Efficacy Endpoints and Components of a Favorable Response
Objective
Endpoint
Timing
Assessment for 
Favorable Response
Analysis Population
References
(Section/Table) 
Secondary 
All-Cause 
Mortality
Day 28 Survival
MITT
Section 8.2.1
Favorable 
Clinical 
Response
EOT

Cure

Improved
MITT 
Section 8.2.2
Table 6
Favorable 
Clinical 
Response 
EFU, 
LFU

Sustained cure

Cure
MITT  
Section 8.2.2
Table 7
Favorable 
Microbiological 
Response
EOT, 
EFU, 
LFU

Eradication

Presumed 
eradication
mMITT 
Section 8.2.3
Table 8
Table 9
Exploratory Favorable 
Clinical 
Response
EOIV

Cure

Improved
For oral switch 
participants in MITT 
Section 8.2.2
Table 6
Favorable 
Microbiological 
Response
EOIV

Eradication

Presumed 
eradication
For oral switch 
participants in mMITT
Section 8.2.3
Table 8
Favorable By-
pathogen 
Microbiological 
Response
EOIV

Eradication

Presumed 
eradication
For oral switch 
participants in mMITT 
Section 8.2.3
Table 8
Section 8.2.4
Favorable By-
pathogen 
Microbiological 
Response
EOT, 
EFU, 
LFU

Eradication

Presumed 
eradication
mMITT 
Section 8.2.3
Table 8
Table 9
Section 8.2.4
Day 28=Day 28 post-randomization; EFU=early follow-up; EOIV=end of IV therapy; EOT=end of therapy; LFU=late 
follow-up; MITT=modified intent-to-treat population; mMITT=microbiological modified intent-to-treat population.
9.4.2
Safety Endpoints
A description of safety measures is contained in Sections 8.3 and 8.4. The analysis of safety 
results is described in Section 9.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, local tolerability assessments, clinical laboratory evaluations, vital sign measurements 
and physical examinations.
The safety analysis endpoints are:
•
AEs, including:
o
Any AE, a drug-related AE, a serious AE, an AE which is both drug-related and 
serious, and an AE that resulted in death
o
A local infusion site intolerance AE (erythema, induration, pain, tenderness, 
warmth, swelling, ulceration, local phlebitis, rash, etc.) during IV study 
intervention
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o
Safety laboratory AEs (based on safety laboratory test results, including 
hematology and chemistry tests from blood and urinalysis from urine)
•
IV study intervention discontinuations due to AEs, including:
o
Discontinuation of IV study intervention due to an AE
o
Discontinuation of IV study intervention due to a drug-related AE
9.4.3
Pharmacokinetics Endpoints
The PK endpoints are: 
•
Plasma concentrations of imipenem and REL
•
AUC0-24hr and Ceoi for imipenem and REL. AUC0-24hr for REL will be used to 
calculate fAUC0-24hr/MIC.
•
%T>MIC for imipenem
Plasma concentrations of REL, imipenem, and cilastatin will be measured. Sparse PK 
sampling will be performed during the IV study intervention period on all participants 
enrolled in the study, consisting of 3 samples per participant (30 minutes prior to start of the 
first dose of IV study intervention; within 10 minutes after the end of the first infusion ; and 2 
to 6 hours after the start of the first IV infusion) on Day 1, plus 1 sample on 1 additional day 
from Day 2 to 3 at 2 to 6 hours after the start of any infusion that day. Cilastatin PK data will 
be collected and analyzed, but further analyses on cilastatin PK will not be performed unless 
required.
For REL, plasma exposure (AUC0-24hr), fAUC0-24hr/MIC and Cmax will be the primary 
endpoints. For imipenem, % fT>MIC, plasma exposure (AUC0-24hr), and Cmax will be the 
primary endpoints. Imipenem % fT>MIC represents the percentage of the total dosing 
interval in which the imipenem free (adjusted for protein binding) concentration is higher 
than the MIC. In addition, the following population PK model-based mean PK parameters for 
both REL and imipenem will be determined: clearance (CL) and volume of distribution for 
the central compartment (Vc). All REL and imipenem endpoints and parameters will be 
calculated using a pediatric population PK model. In fAUC0-24hr/MIC and % fT>MIC, f
means adjusted for REL and imipenem protein binding, respectively. The population PK 
analysis will be summarized in a separate pediatric population PK modeling and simulation 
report.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The MITT and the mMITT populations will serve as the efficacy analysis populations. 
For analyzing all-cause mortality through Day 28 post-randomization and clinical responses 
in this study, the MITT population will include randomized participants who received at least 
1 dose of IV study intervention. 
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For analyzing microbiological responses in this study, the mMITT population will include 
randomized participants who meet the following conditions:
•
For participants with HABP/VABP and cIAI:
1. The participant received at least 1 dose of IV study intervention; AND
2. The participant’s baseline infection-site culture grew at least 1 gram-negative 
pathogenic organism.
•
For participants with cUTI:
1. The participant received at least 1 dose of IV study intervention; AND
2. The participant’s baseline urine culture grew at least 1 gram-negative pathogenic 
organism at sufficient quantity (ie, growth at ≥105 CFU/mL of uropathogen) as 
specified in the cUTI Microbiological Criteria in Appendix 8 - Section 10.8.3.
Participants will be included in the treatment group to which they were randomized for the 
analysis of efficacy data using both the MITT and mMITT populations. Details on the 
approach to handling missing data are provided in Section 9.6.2.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of IV study intervention. Participants will be 
included in the treatment group corresponding to the study intervention they actually 
received for the analysis of safety data using the APaT population, which will generally be 
the treatment group to which the participants are randomized; however, participants who take 
incorrect study intervention for the entire treatment period will be included in the treatment 
group corresponding to the study intervention actually received.
At least 1 laboratory or vital sign measurement obtained after at least one dose of IV study 
intervention is required for inclusion in the analysis of the respective safety parameter.
9.5.3
Pharmacokinetics Populations
The PK population will be used for the PK analysis. This population is the subset of 
participants who comply with dosing and PK sampling sufficiently to ensure that these data 
will be likely to exhibit the anticipated PK endpoints, according to the underlying scientific 
model. Compliance covers such considerations as exposure to treatment, availability of 
measurements, and absence of major protocol violations. Participants with major protocol 
violations will be identified to the extent possible by individuals responsible for data 
collection/compliance and its analysis and interpretation. Any participants or data values 
excluded from analysis will be identified, along with their reasons for exclusion, in the 
pediatric population PK modeling and simulation report.
At the end of the study, all participants who are compliant with the study procedure as 
described and have at least 1 postdose PK data point available will be included in the PK 
analysis dataset.
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9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This is an estimation study; no formal statistical testing will be performed for the efficacy 
endpoints. All of the efficacy endpoints in this study are binary. Within-group 95% 
confidence intervals for these endpoints will be calculated using the Agresti & Coull method 
[Agresti, A. and Coull, B. A. 1998]. In addition, 95% confidence intervals for between-
treatment differences in the incidence (or percentage of participants) will be calculated using 
the unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985], an 
unconditional, asymptotic method.
If enrollment in Age Cohorts 4 (3 months to <2 years) and 5 (birth to 3 months) is found to 
considerably delay completion of this study, the primary analysis will be based on Age 
Cohorts 1, 2, and 3 combined.
Missing values
Any participant missing an evaluation for a specific endpoint (clinical or microbiological) at 
any particular visit will be generally considered as being “indeterminate” for that endpoint in 
the MITT and mMITT populations. The following are exceptions to this rule:
•
Participants discontinuing IV or oral study intervention due to lack of efficacy (ie, 
withdrawals with subsequent nonstudy antibacterial therapy) will be considered as 
“failures” with respect to clinical response at the time of discontinuation and all 
subsequent time points.
•
Participants discontinuing IV or oral study intervention due to lack of efficacy will be 
presumed to have “persistence” for the microbiological response at the time of 
discontinuation and all subsequent time points.
The efficacy endpoints, analysis population, and statistical methods that will be used for the 
efficacy analyses are presented in Table 12. Since a favorable clinical response at EOIV, 
EOT requires an assessment of “cure” or “improved”, an assessment of “indeterminate” 
would be considered a failure to achieve a favorable clinical response. In addition, since a 
favorable clinical response at EFU and LFU requires an assessment of “cure” or “sustained 
cure,” an assessment of “indeterminate” would be considered a failure to achieve a favorable 
clinical response. Since a favorable microbiological response at EOIV, EOT, EFU, and LFU 
requires an assessment of “eradication” or “presumed eradication”, an assessment of 
“indeterminate” would be considered a failure to achieve a favorable microbiological 
response.
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Table 12
Analysis Strategy for Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Efficacy Endpoints
Incidence of all-cause mortality through Day 28 
post-randomization
Unstratified 
M&N
MITT
Missing=Failure
Proportion of participants with a favorable clinical 
response at the EOT, EFU, and LFU visits
Unstratified 
M&N
MITT
Missing=Failure
Proportion of participants with a favorable 
microbiological response at the EOT, EFU, and 
LFU visits
Unstratified 
M&N
mMITT
Missing=Failure
Exploratory Efficacy Endpoints
Proportion of participants with a favorable clinical 
response at the EOIV visit
Descriptive 
Statistics
For oral switch 
participants in 
MITT
Missing=Failure
Proportion of participants with a favorable 
microbiological response at the EOIV visit
Descriptive 
Statistics
For oral switch 
participants in 
mMITT
Missing=Failure
Proportion of pathogens with a favorable by-
pathogen microbiological response at the EOIV 
visit
Descriptive 
Statistics
For oral switch 
participants in 
mMITT
Missing=Failure 
Proportion of pathogens with a favorable by-
pathogen microbiological response at the EOT, 
EFU, and LFU visits
Descriptive 
Statistics
mMITT
Missing=Failure 
Day 28=Day 28 post-randomization; EOIV=end of IV therapy; EOT=end of therapy; EFU=early follow-up; LFU=late 
follow-up; MITT=Modified intent-to-treat; mMITT=microbiological modified intent-to-treat; M&N=Miettinen and 
Nurminen method (1985).
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory tests. Safety assessment will also include close monitoring for potential 
hepatic toxicity and include protocol-defined ECIs related to elevated transaminase findings.
The following are considered prespecified ECIs:
1. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3X ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2X ULN and, at the same time, an alkaline phosphatase laboratory value 
that is less than 2X ULN, as a result of within-protocol-specific testing or unscheduled 
testing.
2. A confirmed (ie, verified by repeat testing) elevated AST or ALT laboratory value that is 
greater than or equal to 5X ULN as a result of within-protocol-specific testing or 
unscheduled testing.
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The analysis of safety results will follow a tiered approach (Table 13). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms), protocol predefined ECIs and events that meet predefined limits of change in 
laboratory are either prespecified as “Tier 1” endpoints, or will be classified as belonging to 
“Tier 2” or “Tier 3” based on the number of events observed.
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. There are 
no Tier 1 events for this protocol as this is an estimation study; no formal statistical testing 
will be performed.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the proportion of participants with events, also via the unstratified 
M&N method (1985).
Membership in Tier 2 requires that at least 12 participants in the experimental intervention 
group (Intervention Group 1 [IG1]: IMI/REL) or 2 participants in the control group 
(Intervention Group 2 [IG2]: Active Control) exhibit the event; all other AEs and predefined 
limits of change will belong to Tier 3. 
The thresholds of events were chosen because the 95% confidence interval for the between-
group difference in percent incidence will always include zero when fewer participants per 
group, respectively, experience events and thus would add little to the interpretation of 
potentially meaningful differences. Because many 95% confidence intervals may be provided 
without adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse events and safety parameters that 
meet predefined limits of change. Only targeted measurements of predefined limits of change 
will be summarized/analyzed as described in the sSAP. 
In addition to individual events that occur in 12 or more participants in the experimental 
intervention group and in 2 or more participants in the control group, the broad AE categories 
consisting of the proportion of participants with any AE, a drug-related AE, a serious AE, an 
AE which is both drug-related and serious, discontinuation of IV study intervention due to an 
AE, and discontinuation of IV study intervention due to a drug-related AE will be considered 
Tier 2 endpoints. 
The analysis for some Tier 2 endpoints (any AE, a drug-related AE, a serious AE, a serious 
and drug-related AE, ECIs, discontinuation of IV study intervention due to an AE, and 
discontinuation of IV study intervention due to a drug-related AE) will be provided for each 
age cohort and for each infection type separately.
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Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
No summaries of continuous measures such as changes from baseline in laboratory or vital 
signs are planned.
Table 13
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpointa
95% CI for Treatment 
Comparison
Descriptive 
Statistics
Tier 2
ECI#1
ECI#2
Any AEb
X
X
X
X
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
IV study intervention discontinuation due to AE
X
X
IV study intervention discontinuation due to 
Drug-Related AE
X
X
Specific AEsc by SOC and PT, or PDLCs (incidence 
≥12 participants in the experimental intervention 
group or ≥2 participants in the control group)
X
X
Tier 3
Specific AEsc by SOC and PT, or PDLCsa (incidence 
<12 participants in the experimental intervention
group and <2 participants in the control group)
X
AE(s)=adverse event(s); ECI=event of clinical interest; IV=intravenous; PDLC=predefined limit of change; PT=Preferred 
Term; SOC=System Organ Class; X=results will be provided.
a
AE refers to both clinical and laboratory AEs.
b
Indicates broad AE category of the number of participants reporting any AE.
c
Including local infusion site intolerance AEs during IV study intervention (erythema, induration, pain, tenderness,
warmth, swelling, ulceration, local phlebitis, rash, etc.).
9.6.3
Statistical Methods for Pharmacokinetics Analysis
The sample at end of infusion will help further characterize Cmax and the second sample 
during the elimination phase window will help confirm the AUC and time above MIC 
estimation. Relebactam and imipenem PK data will be added to existing pediatric PK data 
from PN020 to further update the pediatric population PK model. Any missing postdose 
plasma concentrations will be treated as missing. Values below the limit of quantification 
will be assigned a value of zero. A nonlinear mixed effects modeling approach will be used 
for model building.
Adult PK targets for REL and imipenem will be used. The goal of model-based simulations 
will be to confirm that these targets are jointly achieved in a proportion of pediatric 
participants similarly covered in adults (~90% probability of target attainment) for each age 
cohort; hence, achieving these targets implies similar efficacy as that obtained in adults. An 
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absolute (mg) or weight-based (mg/kg) dose, whichever is found most suitable for each age 
cohort, will be selected based on the simulation results.
As this is an estimation study; no formal statistical testing will be performed for the PK data. 
In all, the additional REL and imipenem PK data collected in this study will be used to 
update the population PK model and confirm adequacy of selected doses. The population PK 
analysis will be summarized in a pediatric population PK modeling and simulation report.
9.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of summary tables. No statistical hypothesis tests 
will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, race, and gender), baseline characteristics, 
primary and secondary diagnoses, and prior and concomitant therapies will be summarized 
by treatment either by descriptive statistics or categorical tables.
9.7
Interim Analyses
A review of safety and tolerability data will be conducted by an independent eDMC in this 
study when Age Cohorts 2 and 3 have each achieved at least 20 participants with complete 
data available (all complete data available from Age Cohorts 1, 2, and 3 will be reviewed at 
this time), along with periodic reviews as described in the eDMC charter. A description of 
the structure, function, and guidelines for decision-making by the eDMC, along with the 
timing and content of the safety reviews will be outlined in the eDMC charter. Information 
regarding the composition of the eDMC is provided in Appendix 1. 
No formal efficacy analyses will be conducted for eDMC review; however, protocol-specific 
summary statistics for PK data and/or key efficacy endpoints can be provided to the eDMC 
on request to support benefit-to-risk evaluation.
Study enrollment is likely to be ongoing at the time of any interim analyses. The results of 
interim analyses will not be shared with the investigators prior to the completion of the study.
The eDMC will serve as the primary reviewer of the results of the interim analyses of the 
study and will make recommendations for discontinuation of the study or protocol 
modifications (including any potential dose modifications) to an executive committee of the 
Sponsor. Additional details are provided in the eDMC Charter. 
In addition to the eDMC interim review of safety and tolerability data, an internal interim 
review of complete separate and aggregated safety, tolerability, efficacy, and PK data from 
Age Cohorts 1 through 3 will be performed prior to enrollment of Age Cohorts 4 and 5. This 
internal interim review will be conducted independently from the eDMC interim review, but 
will consider any critical safety findings in the eDMC assessment. Results will be reviewed 
by an internal team to assess whether the safety, tolerability, efficacy, and PK profile is 
acceptable for each age cohort. The findings from the internal interim review were used to 
confirm the proposed doses for Age Cohorts 4 and 5 (Section 6.1.1).
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An interim analysis to assess safety, tolerability, efficacy, and PK may be performed when 
final data from Age Cohorts 1 to 3 are available.
9.8
Multiplicity
No multiplicity adjustment is planned.
9.9
Sample Size and Power Calculations
This study will randomize approximately 140 participants in a 3:1 ratio into 2 treatment 
groups (Intervention Group 1 [IG1]: IMI/REL and Intervention Group 2 [IG2]: active 
control), to obtain 132 participants (approximately 99 participants in IG1 and 33 participants 
in IG2) in the safety analysis population. No more than 12 participants will be randomized to 
Age Cohort 1; at least 20 participants will be randomized to each of Age Cohorts 2 and 3;
and at least 28 participants will be randomized to each of Age Cohorts 4 and 5. At least 28 
participants with HABP/VABP or cIAI will be enrolled. In addition, no more than 48 
participants with cUTI may be enrolled in Age Cohorts 3, 4, and 5 combined, and a target of 
at least 10% of participants with cIAI should have a diagnosis other than complicated 
appendicitis. 
As many of the safety endpoints and all of the efficacy endpoints are binary, justification of 
the sample size is based on the precision of these estimates as assessed by the width of the 
95% within-group confidence intervals (Table 14). Displays of the two-sided 95% 
confidence intervals for the proportion of participants assessed as a success under varying 
assumptions for the number of successes in IG1 (IMI/REL) and IG2 (active control) are 
provided. Estimates are provided for:
•
N=3 (number of IG2 participants in Age Cohort 1)
•
N=9 (number of IG1 participants in Age Cohort 1)
•
N=5 (number of IG2 participants in each of Age Cohorts 2 and 3)
•
N=15 (number of IG1 participants in each of Age Cohorts 2 and 3)
•
N=7 (number of IG2 participants in Age Cohorts 4 and 5)
•
N=21 (number of IG1 participants in Age Cohorts 4 and 5)
•
N=33 (number of IG2 participants combined across age cohorts)
•
N=99 (number of IG1 participants combined across age cohorts)
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Table 14
Two-Sided 95% Confidence Intervals
Number of 
Participants in 
Population
Observed Number 
With Success
(%)
Two-Sided 
95% Confidence Interval 
(Agresti & Coull method) (%)
4
1
25%
(3.4, 71.1)
3
75%
(28.9, 96.6)
5
2
40%
(11.6, 77.1)
4
80%
(36.0, 98.0)
7
2
28.6%
(7.6, 64.8)
4
57.1%
(25.0, 84.3)
6
85.7%
(46.7, 99.5)
8
2
25%
(6.3, 59.9)
4
50%
(21.5, 78.5)
7
87.5%
(50.8, 99.9)
15
5
33.3%
(15.0, 58.5)
10
66.7%
(41.5, 85.0)
13
86.7%
(60.9, 97.5)
21
5
23.8%
(10.2, 45.5)
10
47.6%
(28.3, 67.6)
15
71.4%
(49.8, 86.4)
20
95.2%
(75.6, 100)
33
7
21.2%
(10.4, 38.1)
15
45.5%
(29.8, 62.0)
23
69.7%
(52.5, 82.8)
31
93.9%
(79.4, 99.3)
99
20
20.2%
(13.4, 29.2)
45
45.5%
(36.0, 55.3)
70
70.7%
(61.1, 78.8)
95
96.0%
(89.7, 98.7)
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
incidence of Day 28 all-cause mortality and the proportion of participants with a favorable 
clinical response at EFU within each treatment group (MITT population) will be estimated 
within each category of the following classification variables (assessed prior to or at the point 
of randomization):
•
Stratification variable: Age
o
Age Cohort 1: 12 to <18 years
o
Age Cohort 2: 6 to <12 years
o
Age Cohort 3: 2 to <6 years
o
Age Cohort 4: 3 months to <2 years
o
Age Cohort 5: Birth to <3 months
•
Stratification variable: Baseline Infection type
o
HABP/VABP
o
cIAI
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o
cUTI
•
Gender (female, male)
•
Race (white, non-white)
Additional subgroup analysis summaries with regard to other intrinsic factors may be 
considered as needed.
9.11
Compliance (Medication Adherence)
This is a study in hospitalized participants in whom study medication is initially administered 
IV and in-hospital and is, therefore, expected to follow the protocol strictly without 
compliance issues. Any medication errors will be monitored and recorded.
In this study, at the discretion of the investigator, participants with cIAI or cUTI may be 
switched to oral antibacterial therapy after at least 3 days of IV study intervention. 
Participants with evidence of concurrent bacteremia or with P. aeruginosa infection should 
receive 14 days of antibacterial treatment.
As part of the routine recording of the amount of antibacterial therapy taken by each 
participant, study staff will record any remaining product (eg, pill count or liquid volume) 
following completion of oral therapy. The number of oral doses dispensed and taken will be 
counted, reviewed, and recorded at the EOT visit. This information will be recorded on the 
appropriate eCRF.
9.12
Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics (ie, N, 
mean, median, standard deviation) and/or frequencies for the “Number of Days on Therapy” 
by treatment group.
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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 Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the 
safety and effectiveness of our products. As such, we are committed to designing, 
implementing, conducting, analyzing and reporting these trials in compliance with the 
highest ethical and scientific standards. Protection of participants in clinical trials is 
the overriding concern in the design of clinical trials. In all cases, MSD clinical trials 
will be conducted in compliance with local and/or national regulations (eg, 
International Council for Harmonisation Good Clinical Practice [ICH-GCP]) and in 
accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (eg, contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial. Participants must meet 
protocol entry criteria to be enrolled in the trial.
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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 to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and general principles of Good Clinical Practice (GCP). MSD reviews clinical 
data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-
noncompliance is suspected, the issues are investigated. When necessary, the 
clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results 
of its registered trials of marketed products in which treatment is assigned, according 
to the prespecified plans for data analysis. To the extent scientifically appropriate, 
MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be 
hypothesis-generating rather than hypothesis testing, in such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses 
complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated 
at each site. Significant changes or revisions to the protocol will be approved by the 
ethics committee prior to implementation, except changes required urgently to protect 
participant safety that may be enacted in anticipation of ethics committee approval. 
For each site, the ethics committee and MSD will approve the participant informed 
consent form.
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B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible. Unless required by law, only the investigator, Sponsor (or representative), 
ethics committee, and/or regulatory authorities will have access to confidential 
medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review to identify potentially eligible 
participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
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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 
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 
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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
Committees Structure
10.1.4.1 Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the eDMC regarding the study.
10.1.4.2 External Data Monitoring Committee (eDMC)
To supplement the routine study monitoring outlined in this protocol, an eDMC will 
periodically monitor the interim data from this study. The voting members of the committee 
are external to the Sponsor. The members of the eDMC must not be involved with the study 
in any other way (eg, they cannot be study investigators) and must have no competing 
interests that could affect their roles with respect to the study.
The eDMC will make recommendations to the EOC regarding steps to ensure both 
participant safety and the continued ethical integrity of the study. Also, the eDMC will 
review interim study results, consider the overall risk and benefit to study participants 
(Section 9.7 Interim Analyses) and recommend to the EOC whether the study should 
continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
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of eDMC reports, minutes, and recommendations will be described in the eDMC charter that 
is reviewed and approved by all the eDMC members.
10.1.5
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.
10.1.6
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 
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.
10.1.7
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.
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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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
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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.
10.1.9
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.
10.1.10
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
Safety Laboratory Assessments
•
The tests detailed in Table 15 will be performed by the local laboratory.
•
Local laboratory results used to make either a study intervention decision or response 
evaluation must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 15
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen 
(BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum Glutamic-
Oxaloacetic 
Transaminase (SGOT)
Total bilirubin (and direct 
bilirubin, if total bilirubin is 
elevated above the upper 
limit of normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum Glutamic-
Pyruvic Transaminase 
(SGPT)
Total Protein
Glucose 
nonfasting
Calcium
Alkaline phosphatase
Carbon dioxide
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Serum or urine β-human chorionic gonadotropin (β-hCG) pregnancy test (as 
needed for WOCBP)
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.2.1
Renal Function Ranges
Renal function below that specified in Table 16 for the appropriate age range based on 
estimated CrCl (using the Cockcroft-Gault equation) or eGFR (using the modified Schwartz 
equation) is an exclusion criterion for this study (see Section 5.2).
In addition to values obtained from scheduled chemistry blood draws during the study, the 
serum creatinine values used to calculate CrCl or eGFR for eligibility determination will also 
be recorded on the appropriate eCRF. Only those local laboratory abnormalities in serum 
creatinine that result in an AE or a clinically significant change in estimated CrCl or eGFR, 
which may or may not result in discontinuation, should be collected on the appropriate eCRF.
Participants whose renal function decreases during study medication administration to a CrCl 
or eGFR value below that specified for the appropriate age range (Table 16), confirmed on 
repeat testing, should generally be discontinued from study medication. However, 
investigators may discuss continuing therapy in participants with transient changes in renal 
function due to acute illness with the Sponsor.
Table 16
Acceptable Renal Function Ranges for Study Inclusion Based on Estimated 
Creatinine Clearance or Estimated Glomerular Filtration Rate by Age Range
Age Range
Acceptable Range for Inclusion
CrCla
(mL/min)
eGFRb,c
(mL/min/1.73 m2)
12 to <18 years
≥90
2 to <12 years
≥90
18 months to <2 years
≥76
12 to <18 months
≥73
8 to <12 months
≥65
14 weeks to <8 months
≥57
6 to <14 weeks
≥47
2 to <6 weeks
≥41
1 to <2 weeks
≥25
Birth to <1 week
≥20
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Age Range
Acceptable Range for Inclusion
CrCla
(mL/min)
eGFRb,c
(mL/min/1.73 m2)
CrCl=creatinine clearance; eGFR=estimated glomerular filtration rate.
a
FDA guidance [Food and Drug Administration (CDER) 2014] recommends classifying renal function based on 
estimated creatinine clearance (CrCl, mL/min) using the modified Cockcroft-Gault equation for children ≥12 
years of age, as follows:
Cockcroft-Gault equation (participants ≥12 years of age):
Creatinine clearance (males) = (weight in kg) x (140 minus age)
(72) x (creatinine in mg/dL)
Creatinine clearance (females) = 0.85 × the value obtained using the equation above
b
eGFR ranges taken from published lower-bound standard deviation of age-appropriate means [Brion, L. P., et al 
1986] [Schwartz, G. J. 2009] [Sakellaris, G. 2012].
c
FDA guidance [Food and Drug Administration (CDER) 2014] recommends classifying renal function based on 
estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) using the modified Schwartz equation for children 
<12 years of age, as follows:
eGFR=K × (height in cm) 
(creatinine in mg/dL)
K (proportionality constant):
Male child (≥1 year and <12 years): K=0.70
Female child (≥1 year and <12 years): 
K=0.55
Infant (term <1 year): 
K=0.45
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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.”
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 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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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.
•
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.
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•
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
•
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:
o
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).
o
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
o
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 performed. 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:
o
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention, such as: reliable history, acceptable compliance assessment (infusion 
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completion verification, pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen?
o
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)?
o
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.
o
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.)
o
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?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
o
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.
o
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.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
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 their 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.
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).
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-
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 after 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 with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
10.5.2
Contraceptive Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol-defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM).
•
Male condom with cap, diaphragm, or sponge with spermicide.
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•
Male and female condom cannot be used together.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implanta,b

Intrauterine hormone-releasing system (IUS)b,c

Nonhormonal intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
All sexual partners of the WOCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraceptionb,c
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraceptionb,c
-
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.
Acceptable Contraceptive Methods
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)d
a
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable contraceptive implants 
are limited to those that inhibit ovulation. 
b
Male condoms must be used in addition to female participant’s hormonal contraception. 
c
IUS is a progestin-releasing IUD.
d
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, but 
not highly effective, birth control methods.
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10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Disease Definitions and Diagnostic Criteria
10.8.1
HABP/VABP
•
Definitions:
o
HABP is an acute infection of the pulmonary parenchyma that is associated with 
clinical signs and symptoms accompanied by presence of new or progressive infiltrate 
on chest radiograph occurring in a participant after being hospitalized for more than 
48 hours or within 7 days after discharge from hospital. Of note, such participants 
may or may not require mechanical ventilation (ventilated HABP and nonventilated 
HABP).
o
VABP is an acute infection of the pulmonary parenchyma that is associated with 
clinical signs and symptoms accompanied by presence of new or progressive infiltrate 
on chest radiograph occurring in a participant already receiving mechanical 
ventilation via an endotracheal tube for a minimum of 48 hours.
•
Diagnosis: For a diagnosis of HABP/VABP, participants should have present the 
following supportive radiographic, clinical, and microbiological findings, with onset of 
criteria occurring after more than 48 hours of hospitalization or within 7 days after 
discharge from a hospital (for HABP) or at least 48 hours after mechanical ventilation 
(for VABP):
a) Radiographic: Chest radiograph showing the presence of a new or progressive 
infiltrate(s) characteristic of bacterial pneumonia. 
AND
b) Clinical: At least 1 of the following clinical findings that support a diagnosis of 
HABP/VABP:

New onset or worsening pulmonary signs and symptoms, such as cough, dyspnea, 
tachypnea (eg, respiratory rate greater than 25 breaths per minute), expectorated 
sputum production, or requirement for mechanical ventilation

Hypoxemia (eg, a partial pressure of oxygen less than 60 millimeters of mercury 
while the patient is breathing room air, as determined by arterial blood gas [ABG]
or worsening of the ratio of the partial pressure of oxygen to the fraction of 
inspired oxygen [PaO2/FiO2])

Need for acute changes in the ventilator support system to enhance oxygenation, 
as determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes 
in the amount of positive end-expiratory pressure

New onset of suctioned respiratory secretions
AND
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at least 1 of the following clinical findings:

Fever, defined as body temperature greater than or equal to 38.0°C (100.4°F), or 
hypothermia, defined as core body temperature less than or equal to 35°C 
(95.2°F)

Chills/rigors

Chest pain

Total peripheral WBC count greater than or equal to 10,000 cells/mm3

Leukopenia with total WBC less than or equal to 4,500 cells/mm3

Greater than 15 percent immature neutrophils (bands) noted on peripheral blood 
smear
AND
c) Microbiological: an appropriate baseline (at or within 48 hours of screening) LRT
specimen for Gram stain, culture, and susceptibility testing. See Section 8.2.3.1.1 for 
additional details.
10.8.2
cIAI
•
Definition: Intra-abdominal infection (IAI) is broadly defined as peritoneal inflammation 
in response to microorganisms, resulting in purulence in the peritoneal cavity. IAI are 
classified as uncomplicated or complicated based on the extent of infection. cIAI extends 
beyond the hollow viscus of origin into the peritoneal space and is associated with either 
abscess formation or peritonitis.
•
Diagnosis: For a diagnosis of cIAI, participants must have present the following 
supportive clinical and microbiological findings. Patients may be enrolled pre-operatively
on the basis of compelling preoperative clinical findings as described below OR patients 
may be enrolled intra- or post-operatively on the basis of operative findings. Surgical 
intervention includes open laparotomy, laparoscopy, and percutaneous drainage of intra-
abdominal abscess.
Preoperative Enrollment: Patients may be enrolled preoperatively based on the 
following clinical and microbiological criteria that must be met at screening:
a) Clinical: at least 1 of the following clinical signs and symptoms of infection:

Fever, defined as body temperature greater than or equal to 38.0°C (100.4°F), or 
hypothermia, defined as core body temperature less than or equal to 35°C 
(95.2°F) 

Hypotension 
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
Abdominal pain, flank pain, or pain caused by cIAI that is referred to another 
anatomic area such as back or hip

Tenderness to palpation, rebound tenderness, guarding 

Abdominal mass

Nausea or vomiting

Anorexia 

Altered mental status 

WBC count elevated beyond the upper limit of the normal laboratory range or the 
proportion of band forms of the white blood cell differential count beyond the 
upper limit of the normal laboratory range 
AND
b) Radiographic: Radiographic evidence consistent with intra-abdominal abscess or 
peritonitis
AND
c) Microbiological: Participants enrolled preoperatively must have an infection-site 
specimen obtained within 24 hours after the start of IV study intervention. This 
baseline intra-abdominal specimen is collected from purulent material from an intra-
abdominal surgical procedure or percutaneous drainage for culture and susceptibility 
testing. See Section 8.2.3.1.2 for additional details.
OR
Intra- or Post-operative Enrollment: Patients may be enrolled intra- or post-
operatively based on the following visual confirmation (eg, presence of pus within the 
abdominal cavity) of an intra-abdominal infection and microbiological criteria that 
must be met at screening:
a) Clinical: at least 1 of the following as evidence of intraperitoneal infection:

Intra-abdominal abscess, including splenic or liver abscess 

Appendicitis complication by perforation or abscess formation 

Diverticulitis complicated by perforation or abscess formation 

Cholecystitis with evidence of perforation or empyema

Perforation of the large or small intestine with abscess or fecal contamination 
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
Gastric or duodenal ulcer perforation

Peritonitis due to perforated viscus, surgical intervention, or other focus of 
infection. Spontaneous bacterial peritonitis associated with cirrhosis and 
chronic ascites are not eligible. 
AND
b) Microbiological: Participants enrolled intra- or post-operatively must have had an 
operative procedure during which an infection-site culture specimen was obtained 
within 48 hours of screening and prior to the start of IV study intervention. This 
baseline intra-abdominal specimen is collected from purulent material from an 
intra-abdominal surgical procedure or percutaneous drainage for culture and 
susceptibility testing. See Section 8.2.3.1.2 for additional details.
10.8.3
cUTI
•
Definition: cUTI is an infection of 1 or more structures in the urinary system in the 
presence of a functional or anatomical abnormality of the urinary tract or catheterization
and includes:
o
Complicated lower UTI (cLUTI): a type of cUTI that does not involve the upper 
urinary tract
o
Pyelonephritis: a type of cUTI that affects 1 or both kidneys, regardless of underlying 
abnormalities of the urinary tract
UTIs are a clinical syndrome characterized by pyuria and a documented microbial 
pathogen on culture of urine or blood, accompanied by local and systemic signs and 
symptoms of infection. Establishing a diagnosis of UTI requires both urinalysis results 
that suggest infection (pyuria and/or bacteriuria) and the presence of a uropathogen 
cultured from a urine specimen obtained by midstream clean catch (MSCC), straight 
catheter (clean intermittent urethral catheterization), indwelling urethral catheter, or 
suprapubic aspiration (SPA) [Roberts, K. B. 2011] [Stein, R., et al 2015].
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•
Diagnosis: For a diagnosis of cUTI (including cLUTI and pyelonephritis), participants 
must have present the following supportive clinical, anatomical, and microbiological
findings:
a) Clinical:

Participants with cUTI (including cLUTI and pyelonephritis) must have at least 2
of the following new or worsening clinical signs and symptoms of cUTI at the 
Screening Visit:
If <2 years of age:
If 2 to <18 years of age:
-
Fever, defined as body temperature 
greater than or equal to 38.0°C 
(100.4°F)
-
Failure to thrive
-
Recent weight loss
-
Irritability
-
Poor feeding
-
Lack of normal level of activity
-
Abdominal pain/tenderness on physical 
examination
-
Vomiting
-
Jaundice
-
Fever, defined as body temperature 
greater than or equal to 38.0°C (100.4°F)
-
Chills or rigors
-
Dysuria
-
Urinary urgency
-
Urinary frequency
-
New-onset urinary incontinence
-
Suprapubic pain, flank pain, abdominal 
pain, or pelvic pain
-
Suprapubic tenderness or costovertebral 
angle (CVA) tenderness on physical 
examination
-
Nausea or vomiting
IN ADDITION

Participants with cLUTI must have at least 2 of the above new or worsening 
clinical signs and symptoms AND at least 1 of the following complicating factors:
-
Obstructive uropathy
-
Congenital, functional, or anatomic abnormality of the urogenital tract
-
Temporary indwelling urinary catheter
-
Bladder instrumentation within <24 hours
-
Recurrent UTI (≥2 events within a 12-month period)
AND
Participants with cUTI (including cLUTI and pyelonephritis) must also have 
pyuria, as determined by MSCC or catheterized (indwelling or straight catheter) 
urine specimen with ≥10 WBCs per high-power field (hpf) on standard 
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examination of urine sediment or ≥10 WBCs/mm3 in unspun urine. The 
requirement for pyuria may be fulfilled on any urine specimen obtained within 48 
hours prior to randomization.
NOTE: If pyuria cannot be determined by urinalysis in a clinically relevant 
timeframe, a urine dipstick may be used as a rapid diagnostic aid. If urine dipstick 
is used, a positive test for leukocyte esterase is the preferred indicator for the 
presence of pyuria.

If ≥1 year of age: WBC count >10 cells/µL in unspun urine or ≥10 cells/hpf in 
spun urine; OR

If <1 year of age: WBC count >5 cells/µL in unspun urine or ≥5 cells/hpf in 
spun urine
AND
b) Microbiological: Participants with cUTI must have a pretreatment baseline urine 
culture specimen obtained within 48 hours of screening, prior to the start of IV study 
intervention, and preferably prior to administration of any potentially therapeutic 
antibiotics. Specimen is to be obtained by MSCC, indwelling urethral catheter, SPA, 
or clean intermittent urethral catheterization. Culture results must show ≥105 CFU/mL 
of uropathogen.
NOTE: Participants may be enrolled in this study while urine culture results are still 
pending. IV study intervention can be started before the investigator knows the results 
of the baseline urine culture; however, participants who do not have a positive culture 
result that meets 1 of the above criteria must discontinue study intervention following
the negative culture result.
For participants with an indwelling catheter, samples should be collected following 
the placement of a new catheter. If the placement of a new catheter is contraindicated 
or is not feasible, specimens should be collected using aseptic techniques with the 
urine obtained through a properly disinfected collection port. Urine samples obtained 
from a collection bag are not allowed for the study-qualifying baseline urine culture 
specimen.
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10.9
Appendix 9: Protocol-allowed Comparator Medications by Drug Name
The active comparators listed in the EDC and EDC guidelines for each infection type are as 
follows (by generic drug name).
10.9.1
HABP/VABP
•
Doripenem IV
•
Ertapenem IV
•
Imipenem IV
•
Meropenem IV 
•
Piperacillin/Tazobactam IV
•
Cefepime IV
10.9.2
cIAI
•
Doripenem IV
•
Ertapenem IV
•
Imipenem IV
•
Meropenem IV
•
Cefotaxime IV
•
Ceftazidime IV
•
Ceftazidime plus avibactam IV
•
Ceftriaxone IV
•
Metronidazole IV
•
Piperacillin/Tazobactam IV
•
Amoxicillin plus clavulanate Oral
•
Cefaclor Oral
•
Cefprozil Oral
•
Cefuroxime Oral
•
Cefdinir Oral
•
Cefditoren Oral 
•
Cefixime Oral
•
Cefpodoxime Oral
•
Ceftibuten Oral
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•
Ciprofloxacin Oral 
•
Delafloxacin Oral
•
Gemifloxacin Oral 
•
Levofloxacin Oral
•
Moxifloxacin Oral
•
Norfloxacin Oral 
•
Ofloxacin Oral
•
Metronidazole Oral
10.9.3
cUTI
•
Cefotaxime IV
•
Ceftazidime IV
•
Ceftazidime plus avibactam IV
•
Ceftriaxone IV
•
Cefepime IV
•
Ciprofloxacin IV
•
Meropenem IV
•
Amoxicillin plus clavulanate Oral
•
Cefadroxil Oral
•
Cephalexin Oral
•
Cephradine Oral
•
Cefaclor Oral
•
Cefprozil Oral
•
Cefuroxime Oral
•
Cefdinir Oral
•
Cefditoren Oral 
•
Cefixime Oral
•
Cefpodoxime Oral
•
Ceftibuten Oral
•
Ciprofloxacin Oral 
•
Delafloxacin Oral
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•
Gemifloxacin Oral 
•
Levofloxacin Oral
•
Moxifloxacin Oral
•
Norfloxacin Oral 
•
Ofloxacin Oral
•
Nitrofurantoin Oral
•
Trimethoprim Oral
•
Trimethoprim/Sulfamethoxazole Oral
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
ABG
arterial blood gas
AE
adverse event
ALT
alanine aminotransferase
APaT
All Participants as Treated
AST
aspartate aminotransferase
ATS
American Thoracic Society
AUC
Area under the curve
AUC0-24 hr
area under the plasma concentration-time curve from time zero to 24 hours
BAL
bronchoalveolar lavage
BLI
β-lactamase inhibitor
CAUTI
catheter-associated urinary tract infection
Ceoi
concentration at end of infusion
CFU
colony-forming unit
cIAI
complicated intra-abdominal infection
CL
clearance
cLUTI
complicated lower urinary tract infection
Cmax
maximum concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CR
carbapenem-resistant
CrCl
creatinine clearance
CRF
case report form
CSF
cerebrospinal fluid
CSR
case study report
CT
computed tomography
CTFG
Clinical Trial Facilitation Group
cUTI
complicated urinary tract infection
CVA
costovertebral angle
DILI
drug-induced liver injury
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EEA
European Economic Area
EFU
early follow-up
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EOIV
end of IV therapy
EOT
end of therapy
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDC
fixed-dose combination
fAUC0-24hr/MIC
ratio of the free area under the plasma concentration-time curve to the imipenem/REL 
minimum inhibitory concentration
GCP
Good Clinical Practice
HABP
hospital-acquired bacterial pneumonia
HIV
human immunodeficiency virus
hpf
high-power field
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Abbreviation
Expanded Term
hr
hours
IA(s) 
interim analysis(ses)
IAI
intra-abdominal
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
ICU
intensive care unit
ID
identification
IDSA
Infectious Diseases Society of America
IEC
Independent Ethics Committee
IG
Intervention Group
IMI
imipenem and cilastatin, also referred to as PRIMAXIN® and TIENAM®
IMI/REL
imipenem/cilastatin/relebactam fixed-dose combination, also referred to as 
MK-7655A
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
KPC
Klebsiella pneumoniae carbapenemase
LAM
lactational amenorrhoea method
LFU
late follow-up
LP
lumbar puncture
LRT
lower respiratory tract
M&N
Miettinen and Nurminen
MDR
multi-drug resistance
MIC
minimum inhibitory concentration
MITT
modified intent-to-treat
mMITT
microbiological modified intent-to-treat
mRNA
messenger ribonucleic acid
MRSA
methicillin-resistant S. aureus
MSCC
midstream clean catch
O2
oxygen
OTX
on therapy
PaO2/FiO2 
ratio of partial pressure of oxygen to the fraction of inspired oxygen
% fT>MIC
percentage of time the free imipenem concentration is above the imipenem/REL 
minimum inhibitory concentration
PI
Package Insert
PICU
pediatric intensive care unit
PIP
Pediatric Investigation Plan
PIP/TAZ
piperacillin/tazobactam
PK
pharmacokinetic(s)
PO
per os (orally)
PTA
Pharmacokinetic-pharmacodynamic target attainment
PTD
patient treatment days
q6h
every 6 hours
q8h
every 8 hours
REL
relebactam, also referred to as MK-7655
SAE
serious adverse event
sSAP
supplemental statistical analysis plan
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Abbreviation
Expanded Term
SLAB
supplemental laboratory electronic case report form
SoA
schedule of activities
SOC
System Organ Class
SPA
suprapubic aspiration
SPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
TMP/SMX
trimethoprim-sulfamethoxazole
t1/2
Half-life
ULN
upper limit of normal
US
United States
USPI
United States Package Insert
UTI
urinary tract infection
VABP
ventilator-associated bacterial pneumonia
VAP
ventilator-associated pneumonia
VRE
vancomycin-resistant Enterococcus spp.
WBC
white blood cell
Vc
volume of distribution for the central compartment
WOCBP
woman/women of childbearing potential
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11
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08RP9Y


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PRODUCT: MK-7655A
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