Conditions: Hospital-Acquired Bacterial Pneumonia Ventilator-Associated Bacterial Pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 274
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of a FDC of imipenem/cilastatin (IMI) and relebactam (REL) \[IMI/REL, MK-7655A\] compared to piperacillin/tazobactam (PIP/TAZ) in the treatment of adults diagnosed with Hospital-Acquired Bacterial Pneumonia (HABP) or Ventilator-Associated Bacterial Pneumonia (VABP). The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ as measured by the incidence rate of all-cause mortality through Day 28 post-randomization.

Detailed description:

Arms:
arm 1: Imipenem/cilastatin/relebactam (IMI/REL) administered intravenously (IV) as a fixed-dose combination (FDC) at a dosage of 500 mg IMI/250 mg REL, once every 6 hours for a minimum 7 days, up to 14 days. At the start of IMI/REL treatment, participants will be treated empirically with 600 mg open-label linezolid administered IV every 12 hours until methicillin-resistant Staphylococcus aureus (MRSA) is ruled out. Participants with confirmed MRSA infection will continue to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total. arm 2: Piperacillin/tazobactam (PIP/TAZ ) administered IV as a FDC at a dosage of 4000 mg PIP/500 mg TAZ once every 6 hours for a minimum 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants will be treated empirically with 600 mg open-label linezolid administered IV every 12 hours until methicillin-resistant Staphylococcus aureus (MRSA) is ruled out. Participants with confirmed MRSA infection will continue to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.

Interventions: intervention 1: IMI/REL FDC intervention 2: PIP/TAZ FDC intervention 3: Linezolid
Intervention descriptions: intervention 1: 500 mg Imipenem, 500 mg Cilastatin and 250 mg Relebactam powder FDC provided in a single vial intervention 2: 4000 mg Piperacillin and 500 mg Tazobactam powder FDC provided in a single vial intervention 3: Open-label 600 mg Linezolid

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
NCT03583333
Document Date:           11-Nov-2020
A Multi-national Phase 3, Randomized, Double-Blind, 
Active Comparator-Controlled Clinical Trial to Study the 
Safety, Tolerability, and Efficacy of Imipenem/
Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/
Tazobactam in Subjects


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A.
(MSD).
Protocol Title: A Multi-national Phase 3, Randomized, Double-Blind, Active Comparator-
Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of 
Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in Subjects 
with Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia
Protocol Number: 016-03
Compound Number: MK-7655A
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
EudraCT NUMBER: 2018-003202-82
Approval Date:  11 November 2020
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Trial 
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
MK-7655A-016-00
15-FEB-2018
Original Protocol
MK-7655A-016-01
29-AUG-2018
The main drivers for this amendment were changes to the microbiological 
definitions at EOT and EFU as well as additional clarifications to procedures in the 
schedule of activities.
MK-7655A-016-02
18-SEP-2019
The main reason for this amendment was to change the upper age limit of 
participants from ≤75 years to ≤90 years of age due to the unmet medical need for 
treatment of HABP/VABP in the elderly population. In support of the age limit 
change, prior studies in the MK-7655A program enrolled all adults aged 18 years or 
older, and a comparable safety profile for IMI/REL was observed across all 
participants ≤90 years of age.
MK-7655A-016-03
11-NOV-2020
The main reason for this amendment were to allow for inclusion of participants 
with a gram stain result showing ‘no organism seen’ and to provide clarification for 
key inclusion/exclusion criteria and study procedures.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 03
Overall Rationale for the Amendment:
The reason for this amendment were to allow for inclusion of participants with a gram stain result showing ‘no organism seen’ and to 
provide clarification for key inclusion/exclusion criteria and study procedures.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
4.4 Beginning and End of 
Study Definition
5.1 Inclusion Criteria
8.1.1 Informed Consent
8.1.1.1 General Informed 
Consent
8.1.3 Participant 
Identification Card
8.4.1 Time Period and 
Frequency for Collecting 
AE, SAE, and Other 
Reportable Safety Event 
Information
10.1 Data Quality 
Assurance
Updated text for informed consent process
The protocol template was updated to align 
with current informed consent/assent 
procedures.
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Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(SoA)
Footnote: “f” added indicating that “If blood samples 
for chemistry and hematology safety evaluations, and 
Chest X-ray were performed within 24 hours prior to 
the EOT Visit, additional blood samples for chemistry
and hematology and Chest x-ray are not required at 
EOT.”
To clarify study procedure requirements and 
allowable windows for 
collection/completion of key procedures.
1.3 Schedule of Activities 
(SoA)
5.1 Inclusion Criteria –
Criterion 2
Notes revised to clarify that chest x-ray at 
randomization is only to be performed if prior chest x-
ray has not been performed in association with the 
current infection within 48 hours prior to
randomization. 
Added “within 48 hours prior to randomization” in 
criteria 2 to clarify the allowed window.
To clarify the allowable time window for
clinical and radiographic criteria of
HABP/VABP.
1.3 Schedule of Activities 
(SoA)
8.2.4.2 Other Lower 
Respiratory Tract Samples 
Following Randomization
Text added to notes in SOA and in 8.4.2 for Lower 
Respiratory Tract Specimen for Gram stain, Culture, 
and Susceptibility at EOT and EFU visit: “Cultures 
are not required at EOT or EFU if considered 
clinically cured (‘cure,’ ’improved,’ or ‘sustained 
cure’).”
To clarify study procedure requirements and 
allowable windows for 
collection/completion of key procedures.
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Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(SoA)
8.2.4.3 Blood Cultures
Text added to notes in SOA and in 8.4.3 for Blood 
Specimen for Culture and Susceptibility: “A culture 
obtained within 48 hours prior to the randomization 
visit is acceptable, as long as the blood cultures 
collected meet the protocol requirement, ie, 2 sets of 
blood cultures, from 2 separate venipunctures (or 1 
venipuncture and 1 catheter).”
Changed the follow-up blood culture frequency from 
“daily” to “as clinically indicated” in subjects with 
positive blood cultures at screening.
To clarify study procedure requirements and 
allowable windows for 
collection/completion of key procedures.
2.2.2. Preclinical and 
Clinical Studies
2.2.3 Ongoing Clinical 
Studies
Final information regarding MK-7655A-014 added.
MK-7655A-014 was removed as an ongoing clinical
study. MK-7655A-020 and MK-7655A-021 added as 
ongoing studies.
Updated information regarding the 
completed and ongoing clinical studies.
5.1 Inclusion Criteria –
Criterion 3
5.2 Exclusion Criteria –
Criterion 1
Changed the list of acceptable Gram stain result 
patterns to clarify that “no organism” is acceptable.
Details regarding acceptable Gram stain results were 
removed from inclusion criterion 3 and added to 
exclusion criterion 1.
To further clarify these criteria and to be 
consistent with PN014.
Details of acceptable Gram stain results 
were moved and updated to provide 
additional clarification.
5.2 Exclusion Criteria –
Criterion 6
6.5 Concomitant Therapy
Added the prohibited duration for maintenance 
glucocorticoid therapy (>40 mg/d prednisolone 
equivalent dose continuously administered for 
≥7 days).
To clarify the prohibited treatment duration.
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Section # and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria –
Criterion 15
6.5 Concomitant Therapy
Added a note to clarify that the use of valproic acid or 
divalproex sodium for seizure prophylaxis among 
subjects with no active or prior history of seizure 
disorder is acceptable for the specified uses.
Added “during treatment with linezolid” to serotonin 
re-uptake inhibitors, tricyclic antidepressants, 
serotonin 5-HT1 receptor agonists (triptans), 
monoamine oxidase inhibitors (MAOIs), meperidine 
and buspirone.
Added “dopaminergic agents (during treatment with 
linezolid)” as a prohibited medication.
Revised “concomitant systemic (IV or oral) 
antibacterial agents” to “concomitant systemic (IV, or 
oral), inhaled or intrapleural antibacterial agents.”
To clarify prohibited treatment information.
To maintain consistency with 6.5 
Concomitant Therapy.
To maintain consistency with study PN014. 
8.2.3 Microbiological 
Response
Table 8: Definitions of the 
By-Pathogen 
Microbiological Response 
Rating at the EOT Visit
Updated the response definition of ‘Superinfection’ at 
EOT, now defined as: “A lower respiratory tract 
culture grows a pathogen other than a baseline 
pathogen at the EOT visit.”
Revised footnote ‘a’ to be aligned with the updated 
definition.
To clarify definition of ‘Superinfection’ at 
EOT.
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Section # and Name
Description of Change
Brief Rationale
8.2.3 Microbiological 
Response
Table 9: Definitions of the 
By-Pathogen 
Microbiological Response 
Rating at the EFU Visit
Updated the response definition of ‘New Infection’ at 
EFU, now defined as: “A lower respiratory tract 
culture grows a pathogen other than a baseline 
pathogen at the EFU visit.”
Revised footnote ‘a’ to be aligned with the updated 
definition.
Added footnote ‘d’: “If a culture is not available at 
EFU, an assessment can be made based on a culture 
collected at the EOT visit as long as it was collected at 
least 24 hours after the end of IV therapy and before 
the EFU visit.”
To clarify the definition of ‘New Infection’ 
at EFU.
To clarify study procedure requirements and 
allowable windows for 
collection/completion of key procedures.
10.6 Appendix 6: APACHE 
II Severity of Disease 
Classification System –
APACHE II Score Form
Added footnote ‘a’ to clarify timing of collection of 
APACHE II variable during Screening: “The most 
severe value in the last 48 hours prior to a 
participant’s randomization into the study should be 
used for each variable of the APACHE II score 
calculation. The calculation of the APACHE II score 
should be captured in the patient’s medical chart or in 
a copy of the APACHE II Score form.”
Added footnote ‘b’ to clarify the temperature 
measurement: “The sponsor recommendation is to use 
rectal temperature measurement whenever possible. If 
rectal temperature is not possible, it is acceptable to 
use non-rectal temperature with no conversion as a 
substitute.”
To clarify APACHE II Score assessment.
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Section # and Name
Description of Change
Brief Rationale
Added footnote ‘c’ to clarify the oxygenation 
measurement: “It is recommended that when assessing 
the Oxygenation variable for the APACHE II 
calculation, ABG measurements should be used. If 
ABG has not been performed for a participant, then 
the APACHE II score calculation should be recorded 
as 0 for Oxygenation variable.”
Added footnote ‘d’ to clarify specific motor response 
categories: “Decerebrate for +2 points means 
extension to pain. Decorticate for +3 points means 
flexion to pain.”
Added footnote ‘e’ to clarify verbal response for 
participants who are intubated and/or 
sedated/paralyzed: “Verbal response for participants 
that are intubated and/or sedated/paralyzed: If there is 
a reliable pre-sedation GCS score or all of the 
elements of the GCS score were documented in the 
medical record - then just use the pre-sedation GCS 
score (not just the verbal response piece, but the whole 
GCS score). But if there is no reliable pre-sedation 
GCS score, then the GCS section of the Acute 
Physiology Score would just be null overall.
Investigators should note on the source documents and 
then commenting out on the APC2 eCRF that the GCS 
was not assessed.”
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Section # and Name
Description of Change
Brief Rationale
Added footnote ‘f’ to clarify assessment of the 
Chronic Health Points (CHE) Score: “The CHE score 
can only be +5, +2, or 0. These additional points are to 
be given only once and not multiple times for each 
separate condition that has been observed.”
Throughout
Minor editorial and grammatical revisions.
Minor revisions were made for clarity and 
to correct grammatical errors.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1.
Protocol Summary .....................................................................................................19
Synopsis....................................................................................................................19
Schema .....................................................................................................................22
Schedule of Activities (SoA) ...................................................................................23
2.
Introduction................................................................................................................33
Study Rationale .......................................................................................................33
Background..............................................................................................................34
Pharmaceutical and Therapeutic Background .....................................................34
Preclinical and Clinical Studies ...........................................................................35
Ongoing Clinical Studies .....................................................................................39
Information on Other Study-related Therapy ......................................................39
Comparator Therapy .....................................................................................39
Co-administration of Open-label Therapy with Linezolid for 
MRSA...........................................................................................................40
Benefit/Risk Assessment.........................................................................................41
3.
Objectives/Hypotheses and Endpoints.....................................................................42
4.
Study Design...............................................................................................................45
Overall Design .........................................................................................................45
Scientific Rationale for Study Design....................................................................46
Rationale for Endpoints .......................................................................................46
Efficacy Endpoints........................................................................................46
Safety Endpoints...........................................................................................46
Rationale for the Use of Comparator...................................................................46
Justification for Dose ..............................................................................................47
Starting Dose for This Study................................................................................47
Maximum Dose/Exposure for This Study ...........................................................49
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Rationale for Dose Interval and Study Design.....................................................49
Beginning and End of Study Definition ................................................................50
Clinical Criteria for Early Study Termination .....................................................50
5.
Study Population........................................................................................................50
Inclusion Criteria....................................................................................................50
Exclusion Criteria ...................................................................................................53
Lifestyle Considerations .........................................................................................56
Screen Failures ........................................................................................................56
Participant Replacement Strategy.........................................................................56
6.
Treatments..................................................................................................................56
Treatments Administered.......................................................................................56
Preparation/Handling/Storage/Accountability ....................................................59
Dose Preparation..................................................................................................59
IMI/REL........................................................................................................59
PIP/TAZ........................................................................................................60
Handling, Storage and Accountability.................................................................61
Measures to Minimize Bias: Randomization and Blinding.................................62
Method of Treatment Assignment .......................................................................62
Stratification..................................................................................................62
Blinding................................................................................................................62
Treatment Compliance...........................................................................................63
Concomitant Therapy.............................................................................................63
Rescue Medications and Supportive Care ...........................................................64
Dose Modification ...................................................................................................64
Treatment After the End of the Study ..................................................................64
Clinical Supplies Disclosure...................................................................................64
Standard Policies.....................................................................................................64
7.
Discontinuation of Study Treatment and Participant Withdrawal ......................65
Discontinuation of Study Treatment.....................................................................65
Participant Withdrawal From the Study..............................................................66
Lost to Follow-up ....................................................................................................66
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8.
Study Assessments and Procedures..........................................................................67
Administrative and General Procedures ..............................................................67
Informed Consent.................................................................................................67
General Informed Consent............................................................................68
Inclusion/Exclusion Criteria ................................................................................68
Participant Identification Card.............................................................................68
Medical History ...................................................................................................69
Prior and Concomitant Medications Review .......................................................69
Prior Medications..........................................................................................69
Concomitant Medications.............................................................................70
Assignment of Screening Number.......................................................................70
Assignment of Treatment/Randomization Number.............................................70
Treatment Administration....................................................................................70
Timing of Dose Administration....................................................................71
Linezolid Therapy Administration.........................................................71
Discontinuation and Withdrawal .........................................................................71
Participant Blinding/Unblinding..........................................................................72
Calibration of Equipment.....................................................................................72
Efficacy Assessments...............................................................................................73
Survival Assessment ............................................................................................73
Clinical Response.................................................................................................73
Clinical Signs and Symptoms.......................................................................75
Microbiological Response....................................................................................75
Culture and Susceptibility Testing.......................................................................77
Lower Respiratory Tract Sample Collected at Baseline...............................77
Other Lower Respiratory Tract Samples Following Randomization ...........78
Blood Cultures ..............................................................................................79
Other Relevant Culture Samples...................................................................79
Chest X-Ray.........................................................................................................79
PaO2/FiO2 or O2 Saturation...................................................................................80
Infection Source Control Review.........................................................................80
Safety Assessments..................................................................................................80
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Physical Examinations.........................................................................................81
Height and Weight ...............................................................................................81
Vital Signs............................................................................................................81
Clinical Safety Laboratory Assessments..............................................................82
APACHE II Score................................................................................................83
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events .......................................................................................83
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..................................................................83
Method of Detecting AEs, SAEs, and Other Reportable Safety Events..............85
Follow-up of AE, SAE and Other Reportable Safety Event Information............85
Regulatory Reporting Requirements for SAE .....................................................85
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs..................................................................................86
Pregnancy and Exposure During Breastfeeding ..................................................86
Events of Clinical Interest (ECIs)........................................................................86
Local Infusion Site Tolerability Monitoring........................................................87
Treatment of Overdose...........................................................................................87
Pharmacokinetics....................................................................................................88
Pharmacodynamics.................................................................................................88
Biomarkers ..............................................................................................................88
Planned Genetic Analysis Sample Collection......................................................88
Future Biomedical Research Sample Collection..................................................88
Visit Requirements..................................................................................................88
Screening..............................................................................................................88
Treatment Period..................................................................................................88
Discontinued Participants Continuing to be Monitored in the Study ..................89
Poststudy..............................................................................................................89
9.
Statistical Analysis Plan ............................................................................................89
Statistical Analysis Plan Summary........................................................................90
Responsibility for Analyses/In-house Blinding.....................................................91
Hypotheses/Estimation ...........................................................................................91
Analysis Endpoints..................................................................................................92
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Efficacy Endpoints...............................................................................................92
Safety Endpoints ..................................................................................................92
Analysis Populations...............................................................................................93
Efficacy Analysis Populations .............................................................................93
Safety Analysis Population..................................................................................94
Statistical Methods..................................................................................................94
Statistical Methods for Efficacy Analyses...........................................................95
Statistical Methods for Safety Analyses ..............................................................96
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses...............................................................................................................98
Interim Analyses .....................................................................................................98
Multiplicity ..............................................................................................................99
Sample Size and Power Calculations ....................................................................99
Subgroup Analyses..................................................................................................99
Compliance (Medication Adherence)..................................................................100
Extent of Exposure................................................................................................100
10.
Supporting Documentation and Operational Considerations.............................101
Appendix 1:  Regulatory, Ethical and Study Oversight Considerations .........101
Code of Conduct for Clinical Trials...............................................................................101
Financial Disclosure.......................................................................................................102
Data Protection...............................................................................................................103
Confidentiality of Data ..................................................................................................103
Confidentiality of Participant Records...........................................................................103
Confidentiality of IRB/IEC Information........................................................................104
Publication Policy ..........................................................................................................104
Compliance with Study Registration and Results Posting Requirements .....................104
Compliance with Law, Audit, and Debarment ..............................................................104
Data Quality Assurance .................................................................................................105
Source Documents .........................................................................................................106
Study and Site Closure...................................................................................................106
Appendix 2:  Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................107
Appendix 3:  Contraceptive Guidance and Pregnancy Testing........................108
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Definitions......................................................................................................................108
Contraception Requirements..........................................................................................108
Pregnancy Testing..........................................................................................................111
Appendix 4: Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................112
Definition of AE ............................................................................................................112
Definition of SAE ..........................................................................................................113
Additional Events Reported...........................................................................................114
Recording AE and SAE .................................................................................................114
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor.............117
Appendix 5:  Clinical Laboratory Tests..............................................................119
Appendix 6:  APACHE II Severity of Disease Classification System –
APACHE II Score Form.......................................................................................121
Appendix 7:  Clinical Pulmonary Infection Score (CPIS).................................123
Appendix 8:  Abbreviations .................................................................................124
11.
References.................................................................................................................127
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LIST OF TABLES
Table 1
Study Treatments..................................................................................................57
Table 2
Administration Dosage of IMI/REL According to Renal Function .....................60
Table 3
Recommended Dosage of PIP/TAZ in Participants According to Renal 
Function in the US Label......................................................................................61
Table 4
Definitions of the Clinical Response Rating at the OTX Visits (Day 3, 
Day 6 and Day 10 of IV Study Therapy)..............................................................73
Table 5
Definitions of the Clinical Response Rating at the EOT Visit .............................74
Table 6
Definitions of the Clinical Response Rating at the EFU Visit and Day 
28 Post-Randomization Visit................................................................................74
Table 7
Infection-Site Clinical Signs and Symptoms........................................................75
Table 8
Definitions of the By-Pathogen Microbiological Response Rating at the 
EOT Visit..............................................................................................................76
Table 9
Definitions of the By-Pathogen Microbiological Response Rating at the 
EFU Visit..............................................................................................................77
Table 10
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events............................................................................84
Table 11
Summary of Primary and Secondary Efficacy Endpoints and 
Components of a Favorable Response..................................................................92
Table 12
Summary of Analysis Strategy for Primary and Secondary Efficacy 
Endpoints..............................................................................................................95
Table 13
Analysis Strategy for Safety Parameters ..............................................................97
Table 14
Sample Size Adjustments Based on Interim Blinded Review of Day 28 
All-Cause Mortality..............................................................................................98
Table 15
Acceptable Contraceptive Methods....................................................................110
Table 16
Protocol-Required Safety Laboratory Assessments ...........................................119
Table 17
Approximate Blood Volumes Drawn by Trial Visit and Sample Types............120
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LIST OF FIGURES
          
Figure 1
Study Design.........................................................................................................22
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1. Protocol Summary
Synopsis
Protocol Title:
A Multi-national Phase 3, Randomized, Double-Blind, Active Comparator-Controlled 
Clinical Trial to Study the Safety, Tolerability, and Efficacy of 
Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in 
Subjects with Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated 
Bacterial Pneumonia
Short Title:
IMI/REL (MK-7655A) vs. PIP/TAZ for Treatment of Subjects with HABP/VABP
Objectives/Hypotheses and Endpoints:
The following objectives and endpoints will be evaluated in adult participants 
diagnosed with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated 
bacterial pneumonia (VABP):
Objective/Hypothesis
Endpoint
Primary

Objective: To determine the 
incidence rate of all-cause 
mortality through Day 28 post-
randomization associated with 
treatment with 
imipenem/cilastatin/relebactam 
(IMI/REL) compared to treatment 
with piperacillin/tazobactam 
(PIP/TAZ) in the modified 
intention-to-treat (MITT) 
population.
Hypothesis (H1): IMI/REL is non-
inferior to PIP/TAZ as measured 
by the incidence rate of all-cause 
mortality through Day 28 post-
randomization in the MITT 
population.
If non-inferiority is established, 
the following hypothesis will be 
tested: 

All-cause mortality
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Hypothesis (H2): IMI/REL is 
superior to PIP/TAZ as measured 
by the incidence rate of all-cause 
mortality through Day 28 post-
randomization in the MITT 
population.
Secondary

Objective: To evaluate favorable
clinical response (CR) rate
associated with treatment with 
IMI/REL compared to treatment 
with PIP/TAZ in the following 
visits and analysis populations:
- At the early follow-up (EFU) 
visit in the MITT population
- At the EFU visit in the clinically 
evaluable (CE) population
- At the end of treatment (EOT) 
visit in the MITT population
- At the EOT visit in the CE 
population

Favorable CR at EFU requires 
“sustained cure” or “cure” (see 
Table 6)

Favorable CR at EOT requires “cure” 
or “improved” (see Table 5)

Objective: To evaluate favorable
microbiological response (MR)
rate associated with treatment with 
IMI/REL compared to treatment 
with PIP/TAZ in the following 
visits and analysis populations:
- At the EFU visit in the 
microbiologically evaluable (ME)
population
- At the EOT visit in the 
microbiologically modified 
intention-to-treat (mMITT) 
population
- At the EOT visit in the ME 
population

Favorable MR at EFU requires 
“eradication” or “presumed 
eradication” (see Table 9)

Favorable MR at EOT requires 
“eradication” or “presumed 
eradication” (see Table 8)

Objective: To evaluate the safety 
and tolerability profile of 
IMI/REL compared 
with PIP/TAZ.

Number of participants experiencing 
adverse events (AEs)

Number of participants discontinuing 
study drug due to adverse events
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Overall Design:
Study Phase
3
Clinical Indication
Treatment for hospital-acquired/ventilator-associated 
bacterial pneumonia (HABP/VABP)
Population
Adult patients with HABP/VABP.
Study Type
Interventional
Type of Design
Multi-site parallel-group design
Type of Control
Active control without placebo
Study Blinding
Double-blind
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 31 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact. 
Number of Participants:
Approximately 270 subjects will be enrolled to obtain 270 MITT participants as 
described in Section 9.9.
Treatment Groups and Duration:
Treatment Groups
Treatment Group 1: IMI/REL administered 
intravenously (IV) as a fixed-dose combination (FDC) 
at a dosage of 500 mg IMI/250 mg REL once every 
6 hours.
Treatment Group 2: PIP/TAZ administered IV as an
FDC at a dosage of 4000 mg PIP/500 mg TAZ once 
every 6 hours.
Doses of IMI/REL and PIP/TAZ will be adjusted for 
participants with renal insufficiency.
In both treatment groups, the use of initial empiric 
treatment with open-label IV linezolid (600 mg every 
12 hours) for methicillin-resistant Staphylococcus
aureus (MRSA) infection is required and will be 
administered in an open-label fashion.
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Duration of 
Participation
Each participant will participate in the study for 
approximately 1 month from the time the participant 
provides documented informed consent through the 
final contact. After a maximum screening phase of 
2 days, each participant will be receiving assigned 
treatment for a minimum of 7 days to a maximum of 
14 days. After the end of treatment, each participant 
will be followed for 7 to 14 days. All participants must 
also have a study visit at Day 28 (up to an additional 3 
days) following randomization. The total duration for 
each participant in the study will be up to 33 days.
Study Governance:
Study Governance 
Committees
There are no governance committees in this study.
A list of abbreviations used in this document can be found in Appendix 8.
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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Schedule of Activities (SoA)
Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Participant Identification Card
X
Medical History
X
Prior or Concomitant Medication 
Review
X
X
X
X
X
X
X
X
Treatment 
Allocation/Randomization & 
Stratification
X
Penicillin Skin Test (Per local 
guidance) 
X
X
Must have a negative result prior to 
the first dose of IV study therapy. Test 
should be conducted on Screening or 
Day 1 within 72 hours prior to the IV 
study therapy with the same skin test
agent; Otherwise, should be repeated.
Administration of IV Study
Therapy
Daily (administered IV q6h)
Administered for 7 to 14 days, as 
described in Section 6.1. Refer to
Table 2 and Table 3 for dose 
adjustments based on renal 
insufficiency.
Administration of Empirical IV 
Linezolid Therapy
Daily (administered at 600 mg IV q12h)
Administered for 7 to 14 days, as 
described in Section 6.1.
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
Clinical Procedures/Assessments
APACHE II Score
X
See Appendix 6 for details
Clinical Pulmonary Infection Score 
(CPIS)
X
See Appendix 7 for details
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs (heart rate, blood 
pressure, respiratory rate, oral 
temperature)
Daily during IV study therapy
X
X
X
Assess prior to first dose of IV study 
medication on Day 1, then daily
during IV study therapy; See Section 
8.3.3
Height and Weight 
X
Assess prior to first dose of IV study 
medication
Adverse Event Monitoring
X
Daily during IV study therapy
X
X
X
See Section 8.4 for details
Local Infusion Tolerability 
Monitoring
Daily during IV study therapy
X
See Section 8.4.8 for details
Review of Clinical Signs and 
Symptoms 
of 
HABP/VABP 
Infection
Daily during IV study therapy
X
X
X
Conduct prior to first dose of IV study 
medication. See Section 8.2.2.1 for 
details.
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
Chest X-ray 
X
X
Only perform if clinically 
indicated such as for 
worsening signs/symptoms 
of pneumonia and 
verification of progression 
is clinically needed for 
diagnosis.
Xf
X
Only perform 
if clinically 
indicated (eg, 
in the setting 
of persistent 
signs and 
symptoms of 
pneumonia).
Screening: If chest x-ray performed, 
must still be performed in association 
with current infection and be within 
48 hours of randomization. If 
performed at Screening Visit, do not 
perform at randomization.
Randomization (Day 1): Perform prior 
to first dose of IV study medication; 
only perform if prior chest x-ray has 
not been performed in association with 
the current infection within 48 hours
prior to randomization. A CT scan 
obtained within 48 hours of 
randomization can be used in place of 
the baseline chest x-ray if a scout view 
or similar view can be produced. 
Days 3, 6, 10 & 28: only perform if 
clinically indicated. Post-baseline, 
chest x-rays must be used at 
subsequent visits. If CT scans are 
performed at the time of study visits 
for diagnostic purposes other than for 
HABP/VABP, the scout view or 
similar view can be used in place of 
the chest x-ray.
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
PaO2/FiO2 Ratio or O2 Saturation
Daily during IV study therapy
X
X
X
PaO2 and FiO2 measured via ABG (in 
ventilated subjects who have an 
existing arterial line) or oxygen 
saturation via pulse oximetry (in all 
other subjects) must all be measured 
on Day 1, Day 3 (OTX1), Day 6 
(OTX2), and Day 10 (OTX3, if 
applicable) of IV study therapy, and at 
the EOT, EFU, and Day 28 post-
randomization visits. On all other days 
of IV study therapy, oxygen saturation 
via pulse oximetry should be 
measured. See Section 8.2.6 for details
Infection Source Control Review
X
X
X
X
Source control includes the following: 
(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, or (c) details regarding a 
thoracentesis procedure to drain any 
accompanying pleural fluid. See 
Section 8.2.7 for details
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
Laboratory Procedures/Assessments
Blood for Hematology
X
X
X
X
Xf
Xf
X
X
Screening: Hematological parameters 
to support Inclusion/Exclusion Criteria
assessment only. Local labs drawn 
within 24 hours prior to screening are 
permissible to use to assess I/E 
criteria. Local labs drawn specifically 
for the study should occur after 
informed consent is obtained.
Visit 2: Perform prior to first dose and 
send to central safety lab (Table 16).
Visits 3-8: Perform once on each visit 
day and send to central safety lab
(Table 16). All findings must be 
recorded in the appropriate eCRFs.
Blood for Chemistry
X
X
X
X
Xf
Xf
X
X
Screening: Chemistry parameters to 
support I/E assessment only. Local 
labs drawn within 24 hours of 
screening are permissible to use to 
assess I/E criteria. Local labs drawn 
specifically for the study should occur 
after informed consent is obtained.
Visit 2: Perform prior to first dose and 
send to central safety lab (Table 16).
Visits 3-8: Perform once on each visit
day and send to central safety lab 
(Table 16).
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
HIV/HBV/HCV 
(Per 
local 
guidance)
X
Blood for Local Laboratory 
Assessment of Creatinine
X
X
X
X
X
Screening: Perform locally if 
creatinine assessment not already done 
as part of Blood for Chemistry
Visit 2: Perform prior to first dose.
Visits 3-5: Perform once on each visit 
day for the purpose of dose 
adjustments based on renal 
insufficiency by unblinded study staff
(Table 2 and Table 3)
Urine for Urinalysis
X
X
X
Perform on Screening or Day 1 on a 
mid-stream clean catch urine or 
catheter urine specimen if possible; 
Table 16
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
Serum/urine for β-human 
Chorionic Gonadotropin (β-hCG),
in women of reproductive potential 
only
X
X
Screening: Documented, local lab-
assessed, negative serum β-hCG
within 48 hours prior to enrollment 
can replace the screening assessment. 
If documentation is not available, a 
rapid urine β-hCG test may be used for 
screening; if the urine test is positive 
or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
To conduct urine testing, sites must 
have individuals certified in 
administration and interpretation of 
test and the urine test utilized must 
have sensitivity of <25 mIU/L.
Day 28: Serum pregnancy testing must 
be performed by central safety 
laboratory. 
See Appendix 3 for details.
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
Lower Respiratory Tract Specimen 
for Gram stain, Culture and 
Susceptibilityd
X
X
X
X
X
X
X
X
On either Screening or Day 1: Collect 
prior to first dose of IV study 
medication. A culture obtained within 
48 hours prior to the screening visit is 
acceptable. Microscopic examination 
of Gram-stained smears must be 
performed prior to randomization to 
ensure the adequacy of the specimen. 
The subject must be excluded from 
participating in the trial if the Gram 
stain shows the presence of Gram-
positive cocci only. See Section 
8.2.4.1 for details.
Cultures are not required at EOT or 
EFU if considered clinically cured 
(‘cure,’ ’improved,’ or ‘sustained 
cure’).
Days 3, 6, 10, & 28: only perform if 
clinically indicated. See Section 
8.2.4.2 for details.
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
Blood Specimen for Culture and 
Susceptibilitye
X
X
As clinically indicated, or if Screening or Day 1
blood culture was positive, repeat as clinically
indicated until negative on 2 consecutive 
cultures
On either Screening or Day 1: Collect 
2 sets of blood cultures, from 2
separate venipunctures (or 1 
venipuncture and 1 catheter) sites prior 
to first dose of IV study medication. A 
culture obtained within 48 hours prior 
to the randomization visit is 
acceptable, as long as the blood 
cultures collected meet the protocol 
requirement, ie, 2 sets of blood 
cultures, from 2 separate 
venipunctures (or 1 venipuncture and 
1 catheter). See Section 8.2.4.3 for 
details.
Efficacy Evaluation
Survival Assessment
X
X
Clinical Response Assessment
X
X
X
X
X
X
See Section 8.2.2
Microbiological Assessment (By-
Pathogen)
X
X
See Section 8.2.3
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Trial Period
Screening
IV Study Treatment
Post-treatment
Notes
Visit Title
Visit 1
Screening
Visit 2
Randomizatio
n
Visit 3
(OTX1)
Visit 4
(OTX2)
Visit 5a
(OTX3)
Visit 6b
(EOT)
Visit 7b
(EFU)
Visit 8b
Day 28c
Scheduled Day 
≤2 days (48 
hours) prior to 
randomization
Day 1
Day 3
Day 6
Day 10
Day 7 to 
Day 14
7 to 14 
days 
post 
EOT
Day 28 Post-
Randomizati
on
Scheduling Window
≤2 days (48 
hours) prior to 
randomization
N/A
N/A
N/A
N/A
≤24 
hours 
after 
EOT
+2 days
+3 days
I/E = Inclusion/Exclusion; PaO2 = partial pressure of oxygen in arterial blood; FiO2 = Fraction of inspired oxygen
a
OTX3 (Visit 5) is not performed if participants receive less than 10 days of IV study therapy.
b
Register completion of EOT, EFU, and Day 28 visits in IRT.
c
The Day 28 post-randomization visit may be combined with the EFU visit on a single day, as long as compliance with the visit windows is maintained for both visits. Specifically, if a participant 
receives 12 to 14 days of IV study therapy, the EFU visit may potentially be combined with the Day 28 post-randomization visit. For example, if 12 days of IV study therapy are provided, the EFU 
visit could be scheduled 16 days (14 days +2 day variance) following completion of IV study therapy, which would be 28 days (12 days of IV study therapy +16 days of follow-up) following 
randomization. It is required that for any case, the allowable visit window ranges are maintained. 
d
Obtain lower respiratory tract sample for Gram stain, culture, and susceptibility testing from infection site prior to initiation of IV study therapy for all subjects. A previously obtained culture is 
acceptable if it was obtained within 2 days (48 hours) of the screening visit. Microscopic examination of Gram-stained smears must be performed prior to randomization to ensure the adequacy of 
the specimen. The subject must be excluded from participating in the trial if the Gram stain shows the presence of Gram-positive cocci only. All culture and susceptibility should be performed at the 
local microbiology laboratory per local standards; in addition, any suspected causative bacterial pathogen must be collected and available for submission to the Central Microbiology Reference 
Laboratory. Suspected causative bacterial pathogens should also be stored at the local microbiology laboratory if possible future testing is needed. In addition, the available data from the Gram stain 
and culture specimen, including date of collection, specimen type (including method of collection), and pathogen identification (to the species level, if identified) must be collected on the 
appropriate eCRF forms.
e
Two sets of blood cultures, from 2 separate venipunctures (or 1 venipuncture and 1 catheter) sites must be collected in all subjects prior to initiation of IV study therapy. Subjects with positive 
blood cultures at screening should have follow-up blood cultures collected as clinically indicated until 2 consecutive cultures demonstrate no growth. Blood culture and susceptibility will be 
performed at the local microbiology laboratory. Per local standards; in addition, any suspected causative bacterial pathogen must be collected and available for submission to the Central 
Microbiology Reference Laboratory. Suspected causative bacterial pathogens should also be stored at the local microbiology laboratory if possible future testing is needed. Relevant culture data, 
including date of collection, specimen type (including method of collection), and pathogen identification (to the species level, if identified) must be collected on the appropriate eCRF forms.
f
If blood samples for chemistry and hematology safety evaluations, and Chest X-ray were performed within 24 hours prior to the EOT Visit, additional blood samples for chemistry and hematology 
and Chest x-ray are not required at EOT.
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2. Introduction
Study Rationale 
This regional study (PN016) is the second pivotal HABP/VABP study, to allow sufficient 
enrollment of Chinese participants and support MK-7655A registration in China. Details 
regarding specific benefits and risks for participants participating in this study may be found 
in the accompanying MK-7655 Investigators Brochure (IB) and Informed Consent 
documents.
HABP and VABP are important problems in the care of critically ill hospitalized patients 
despite advances in antimicrobial therapy, improvements in supportive care and the use of a 
wide range of preventative measures. In patients with HABP, mortality rates are significant 
and range from 12% to 22% globally [Kollef, M. H., et al 2012] [Freire, A. T., et al 2010] 
[Rubinstein, E., et al 2011]. The risk of mortality increases approximately 2-fold in patients 
with VABP and can be even higher when the lung infection is caused by multidrug-resistant 
(MDR) bacteria [Safdar, N., et al 2005]. These infections are among the most frequently 
occurring infections in intensive care units (ICUs) and account for the majority of the 
antibacterial utilization within ICUs [Freire, A. T., et al 2010]. Appropriate antibiotic therapy 
significantly improves survival for patients with HABP or VABP. In these vulnerable 
patients, additional increases in morbidity and mortality can be attributed to the empiric use 
of antimicrobial therapy that is not active against causative pathogens [Hyle, E. P., et al 
2005]. New, well-tolerated drugs with more definitive and rigorously tested dosing schemes 
showing proven activity against both susceptible and MDR bacteria without need for 
combination therapy are urgently needed, especially in patients with HABP or VABP.
IMI/REL has the potential to fulfill a significant and growing unmet medical need by 
providing a next-generation β-lactam (BL)/BLI with which to combat severe gram-negative 
bacterial infections.
A recent Asia prospective surveillance study (7 countries or regions were included: Korea, 
China, Hong Kong, Taiwan, Philippines, Thailand, Malaysia, Singapore, Indonesia) also 
showed a similar result and the most common bacterial isolates from HABP and VABP cases 
in Asian countries were Acinetobacter spp., P. aeruginosa, S. aureus, and K. pneumoniae.
Imipenem resistance rates of Acinetobacter and P. aeruginosa were 67.3% and 27.2%, 
respectively. Multidrug-resistant (MDR) rates were 82% and 42.8%, and extensively drug-
resistant rates were 51.1% and 4.9%, respectively. The multidrug-resistant rate of K. 
pneumoniae was 44.7%. The rate of oxacillin resistance among S. aureus was 82.1%. The 
all-cause mortality rate was 38.9%. All-cause mortality and pneumonia-related mortality 
rates were higher in VABP patients than those in HABP patients (52.5% in non-ICU and 
41.6% in ICU VABP patients vs 34.5% in non-ICU and 34.1% in ICU HABP patients).
Among all the isolates, Acinetobacter spp. (48.8% and 35.1%), followed by K. pneumoniae
(37.7% and 22.7%), P. aeruginosa (31% and 22.4%), and S. aureus (30.7% and 18.9%) 
contributed the highest all-cause and pneumonia-related mortality rates, respectively [Chung, 
D. R., et al 2011].
In China, HABP/VABP are the most common infections in hospital-acquired infections 
(HAI) with high mortality rates between 15.7%-66.7% [An-hua, W., et al 2014] [Ning, L., et 
al 2011] [Yuncai, Y., et al 2011]. Compared to that of HABP, the mortality for VABP is 
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around 2 times higher [Liu, Y. N., et al 2012]. Based on a China local survey, the most 
common pathogens for HABP/VABP are gram-negative bacteria, and the top 3 most 
common gram-negative pathogens are Acinetobacter baumannii, P. aeruginosa and K. 
pneumoniae. In HABP/VABP patients, the antibiotic resistance of gram-negative bacteria is 
the toughest problem in China clinical practice. ESBL-producing E.coli (55.3%) and K. 
pneumoniae (33.9%), KPC-producing gram negatives (10.8%), and MDR P. aeruginosa
(1.5%) are the most difficult to treat in HABP/VABP. Of note, the P. aeruginosa resistance 
rate to imipenem was 27.1% and to meropenem was 25.1%, according to the CHINET 2013 
survey [Fupin, H., et al 2014].
The purpose of this study is to evaluate the efficacy and safety of IMI/REL with the intention 
of demonstrating that IMI/REL is non-inferior to PIP/TAZ in the treatment of adult 
participants diagnosed with HABP or VABP. If non-inferiority is established, then 
superiority of IMI/REL compared to PIP/TAZ will be evaluated. Among 270 participants, 
there will be approximately 200 Chinese participants enrolled; this is the general requirement 
per China regulations.
The primary endpoint for this study, all-cause mortality through Day 28 post-randomization, 
was selected based upon the expected large antibacterial treatment effect on survival. In this 
study, clinical response and microbiological response will be the secondary endpoints in an 
effort to provide additional information with regard to the effect of IMI/REL versus PIP/TAZ 
in HABP/VABP participants.
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on IMI/REL.
Pharmaceutical and Therapeutic Background
Relebactam (REL, MK-7655) is a parenteral (IV), small-molecule β-lactamase inhibitor 
(BLI) which is being developed as a fixed-dose combination in a single vial with 
imipenem/cilastatin (referred to as IMI) for the treatment of infections caused by gram-
negative bacteria. Throughout this document the fixed-dose combination (MK-7655A) of 
imipenem/cilastatin (IMI) + REL will be referred to as IMI/REL.
β-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are among 
the most frequently used antimicrobial agents in clinical practice. The unrelenting 
development of resistance to β-lactam antibiotics by the production of β-lactamases is the 
most important resistance mechanism among gram-negative bacteria and poses an ongoing 
threat to the clinical utility of all β-lactams. Therefore, there is an urgent need for new BLIs 
that can be combined with existing β-lactam antibiotics to protect against hydrolysis by 1 or 
more of the 4 classes (A, B, C and D) of β-lactamase enzymes.
IMI, a potent broad spectrum β-lactam antibacterial agent from the carbapenem class, has 
been used clinically for the treatment of serious infections since 1985, and has been used 
widely in China and other Asian countries for moderate to severe infections. The bactericidal 
activity of imipenem results from inhibition of cell wall synthesis. Imipenem, when 
administered alone, is metabolized in the kidneys by dehydropeptidase I, resulting in 
relatively low levels in the urine. Cilastatin sodium is an inhibitor of this enzyme and 
effectively prevents renal metabolism of imipenem so that, when given together, adequate 
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antibacterial levels of imipenem are achieved. Imipenem is active against a broad range of 
gram-positive and gram-negative organisms and is approved for use globally in a variety of 
infections, including lower respiratory tract infections, urinary tract infections (complicated 
and uncomplicated), intra-abdominal infections, gynecologic infections, bacterial septicemia, 
bone and joint infections, skin and skin structure infections, endocarditis, and polymicrobial 
infections. The approved indications of IMI may be slightly different among approved 
countries. In China, it has been approved for the treatment of intra-abdominal infections, 
lower respiratory tract infections, gynecologic infections, septicemia, urogenital tract 
infections, bone and joint infections, skin and skin structure infections and endocarditis.
REL represents a new generation of BLIs to combat evolving clinical resistance and to 
maintain the usefulness of the β-lactam class of antibiotics. REL is an inhibitor of Ambler 
class A and class C β-lactamases and is highly potent against 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 K. pneumoniae carbapenemase (KPC) 
present in some Enterobacteriaceae, including Klebsiella strains. REL has no activity against 
the class B metallo-β-lactamases (including NDM-1, IMP, or VIM-containing strains) or 
class D β-lactamases (including OXA-producing strains).
Preclinical and Clinical Studies
Pre-clinical Studies
Preclinical data, including in vitro microbiological studies with imipenem-resistant clinical 
isolates of P. aeruginosa and KPC-producing organisms, as well as in vivo infection models 
with imipenem-resistant P. aeruginosa and K. pneumoniae, suggest that REL, in combination 
with IMI, has the potential to fulfill a significant and growing medical need by providing a 
next-generation BLI to combat severe gram-negative bacterial infections. Preclinical toxicity 
studies in rats and monkeys have demonstrated that REL is generally well-tolerated. There 
was no evidence of adverse effects of REL as a single agent on cardiovascular, central 
nervous system, and respiratory function in well-characterized preclinical safety 
pharmacology models. Toxicity of REL in combination with IMI has been evaluated for up 
to 1 month in monkeys with no adverse effects noted at 1.3 times the targeted human 
exposure of 344.4 µM.hr. Evidence of renal toxicity was observed in preclinical studies when 
MK-7655 was administered alone at levels 8 times the target human exposure. A 1-month 
intravenous toxicity study in monkeys with MK-7655 showed renal toxicity at the highest 
dose tested (225 mg/kg/day) by drug Week 4, including an increase in kidney weight and 
histomorphologic changes in the renal tubular epithelium (very slight to slight granular 
cytoplasm and very slight degeneration) that was reversible. At the mid dose (75 mg/kg/day), 
very slight to slight granular cytoplasm was observed in the renal tubular epithelium in 1 of 6 
animals; however, no clinically relevant findings associated with renal function have been 
identified in the Phase 1 studies or in the completed Phase 2 studies in humans.
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Clinical Trials
Phase 1
As of 01-Jan-2018, REL has been evaluated in approximately 265 individuals, 232 of whom 
have received at least 1 dose of REL, across 7 completed Phase 1 studies (PN001, PN002, 
PN005, PN007, PN009, PN012, and PN019). Healthy young and elderly male and female 
adults as well as patients with varying degrees of renal insufficiency have been studied, 
including patients with end-stage renal disease (ESRD) on hemodialysis.
Unblinded safety data from the Phase 1 studies have demonstrated that single and multiple 
intravenous doses of REL have been generally safe and well tolerated throughout the dose 
ranges tested. In PN001, generally mild elevations in hepatic transaminases above the upper 
limit of normal range (ULN) have been observed in the multiple-dose treatment arms in 
which REL was co-administered with IMI. Elevations were also seen in participants 
receiving IMI alone. None of the liver transaminase elevations in these participants were 
associated with clinical findings. The elevations were not dose related and were reversible 
after discontinuation of dosing. Elevations have not been observed in participants 
administered single or multiple doses in PN002, PN005, or PN007.
The pharmacokinetics of REL, imipenem, and cilastatin were evaluated following single and 
multiple doses of REL in combination with 500 mg IMI, administered every 6 hours for 7 to 
14 days in PN001 and PN002. Data from these studies demonstrated that REL exposures 
increase proportionally with dose, doses at 125 mg and above exceeding the identified REL 
PK target of AUC0-∞≥37.5 μM.hr. The pharmacokinetics of REL, imipenem, and cilastatin 
were also evaluated in renally impaired participants (PN005). Pharmacokinetic data from 
PN005 were consistent with expectations given that REL, imipenem and cilastatin are 
cleared almost entirely renally in healthy participants. The plasma clearance (CLplasma), 
terminal half-life (t1/2) and area under the concentration-time curve (AUC0-∞) all were 
significantly and similarly altered for each of these 3 analytes when comparing participants 
with renal impairment to their healthy matched participants. These data are consistent with 
the expected change in magnitude of glomerular filtration rate (GFR). In addition, in 
participants with ESRD, REL, imipenem and cilastatin were efficiently removed by 
hemodialysis. The pharmacokinetics of REL was also studied in healthy volunteers in an 
intrapulmonary lung penetration study (PN007). In PN007, the intrapulmonary 
pharmacokinetic profiles of REL and imipenem were assessed after administration of REL 
and IMI administered every 6 hours over 5 doses. Data in these participants showed 
comparable penetration of REL and imipenem into the epithelial lung fluid (ELF), with 
relative exposures (AUC0-∞in ELF compared to plasma) based on mean profiles of 43% for 
REL and 42% for IMI. 
The effect of REL on the QTc interval was assessed in PN009, which was a single-dose, 
double-blind (with respect to REL only), randomized, placebo and positive-controlled, 3-
period, balanced crossover study under fasting conditions. The pharmacokinetics of REL was 
assessed to confirm that supratherapeutic levels were achieved. Because there were no 
changes in QTcP, a relationship between REL exposure and cardiodynamic assessments was 
not performed. A single 1150-mg dose of REL in PN009 achieved AUC0-∞and a Ceoi that 
were ~4-fold higher than those observed following a single dose of 250 mg and similar to 
exposures after an identical dose in PN001.
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The PK and safety of REL was assessed in Japanese participants in PN012, which was a 
randomized, placebo-controlled, double-blind, single- and multiple-rising-dose trial of REL +
IMI in healthy Japanese male participants. The objectives of the study were to evaluate the 
safety, tolerability, and pharmacokinetics of REL and IMI. The study results indicated that 
the single-dose pharmacokinetics of REL, imipenem and cilastatin appeared to be similar 
between Japanese (PN012) and non-Japanese (PN001) participants. Also, multiple-dose 
pharmacokinetics of MK-7655 at steady-state appears to be similar between Japanese 
(PN012) and non-Japanese (PN001) participants.
Phase 2
Two Phase 2 clinical trials of IMI + REL in participants with complicated urinary tract 
infections (cUTI, PN003) and complicated intra-abdominal infections (cIAI, PN004) have 
been completed. PN003 was a randomized, double-blind, multicenter, comparative study 
evaluating the safety, tolerability, and efficacy of IMI + REL versus IMI alone in adults ≥18
years of age with cUTI. A total of 302 participants with cUTI (including pyelonephritis) were 
randomized in a 1:1:1 ratio to 1 of 3 treatment groups (1) IMI (500 mg) + REL (250 mg), (2) 
IMI (500 mg) + REL (125 mg), or (3) IMI (500 mg) alone. The results show that at 
Discontinuation of IV Therapy (DCIV) in the ME population, the proportion of participants 
with a favorable microbiological response was 95.5 % (64/67) in the MK-7655 250 mg + 
IMI group, 98.6 % (70/71) in the MK-7655 125 mg + IMI group, and 98.7 % (74/75) in the
Placebo + IMI group. Both of these comparisons indicate that treatment with either 250 mg
or 125 mg of MK-7655 + IMI is at least as effective as IMI alone with respect to 
microbiological response rate at DCIV. The proportions of participants in the ME population 
achieving a favorable microbiological response at late follow-up (LFU) visit were 68.3%
(43/63) in the MK-7655 250 mg + IMI group, 65.2% (45/69) in the MK-7655 125 mg + IMI 
group and 62.5% (45/72) in the Placebo + IMI group. The proportion was numerically higher 
for both active MK-7655 groups compared to that observed in the Placebo + IMI group. In 
general, the incidence rate of AEs observed in the active MK-7655 + IMI groups was similar 
to that observed in the Placebo + IMI group. Event of clinical interest (ECI) #1 was defined 
as a confirmed AST or ALT ≥5 X ULN. There were no statistically significant differences 
between either of the 2 MK-7655 groups versus Placebo + IMI group with respect to the 
percentage of participants meeting this definition (both p>0.05). ECI #2 was defined as an 
AST or ALT ≥3 X ULN, a total bilirubin ≥2 X ULN, and an alkaline phosphatase <2 X ULN.
No participants experienced ECI #2. The results demonstrate that both active doses of MK-
7655 + IMI are at least as effective as IMI alone with respect to microbiological response rate 
in the ME population at DCIV. Overall, both active doses of MK-7655 were generally well 
tolerated.
A Phase 2 comparator-controlled clinical trial of IMI + REL (PN004) has completed. PN004 
was a randomized, double-blind, multicenter, comparative study evaluating the safety, 
tolerability, and efficacy of IMI + REL versus IMI alone in adults with cIAI. A total of 351 
participants with cIAI were randomized in a 1:1:1 ratio to 1 of 3 treatment groups (1) IMI 
(500 mg) + REL (250 mg), (2) IMI (500 mg) + REL (125 mg), or (3) IMI (500 mg) alone in 
PN004. Data from PN004 demonstrated that both doses of IMI + REL were at least as 
effective as IMI alone with respect to clinical response rate at the discontinuation of IV study 
therapy (DCIV). Clinical response rates at DCIV were similar in participants who received 
250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior 
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to IMI alone (95.2%). The treatment groups were also similar with respect to clinical 
response at early and late follow-up, and microbiological response at all visits. Results for the 
MITT population were consistent with those obtained for the ME population. Results at later 
time points (EFU and LFU) were consistent with those observed at the DCIV time point.
Only 4.3% of participants in the MK-7655 250 mg + IMI group, 4.3% of participants in the 
MK-7655 125 mg + IMI group, and 3.5% of participants in the placebo + IMI group reported 
an AE of ALT increased; 4.3% of participants in the MK-7655 250 mg + IMI group, 4.3% of 
participants in the MK-7655 125 mg + IMI group, and 2.6% of participants in the placebo + 
IMI group reported an AE of AST increased; there were no statistically significant 
differences between either of the 2 MK-7655 + IMI groups versus the placebo + IMI group.
Overall, both doses of REL (125 mg and 250 mg) were generally well tolerated.
Phase 3
A Phase 3 study to evaluate the safety and efficacy IMI/REL in the treatment of imipenem-
resistant bacterial infection, including hospital-acquired/ventilator-associated bacterial 
pneumonia (HABP/VABP), cIAI, or cUTI (PN013) was initiated in 2015 and has been 
completed. PN013 was a double-blind, active-controlled, parallel-group, multi-site trial of 
IMI/REL compared with colistin (in the form of colistimethate sodium [CMS]) + IMI. Forty-
seven participants were randomized in a 2:1 ratio to the 2 blinded, randomized arms of the 
study: (1) IMI/REL (500 mg/250 mg) and (2) CMS (150 mg CBA, ~360 mg CMS or ~4.5 
million IU) + IMI (500 mg). In addition to the 47 randomized participants, 3 participants 
with documented imipenem- and colistin-resistant but IMI/REL-susceptible bacterial 
infections were enrolled into a third nonrandomized, unblinded/open-label treatment group 
(Treatment Group 3) to receive IMI/REL.
Results of efficacy demonstrated a 71.4% (15/21) favorable overall response for IMI/REL 
versus 70.0% (7/10) for CMS+IMI, supporting that IMI/REL is at least as effective as 
CMS+IMI for the treatment of imipenem-non-susceptible gram-negative bacterial infections.
IMI/REL was well tolerated in this critically ill population, and has a more favorable renal 
safety profile than colistin.
A Phase 3 clinical trial of IMI/REL in HABP/VABP (PN014) was initiated in the beginning 
of 2016 and has been completed. PN014 was a multi-national (excluding China), multi-
center, randomized, double-blind, active comparator-controlled clinical trial to study the 
safety, tolerability, and efficacy of IMI/REL (MK-7655A) versus PIP/TAZ in participants 
with HABP/VABP. A total of 537 participants were randomized in a 1:1 ratio to 1 of the 2 
treatment groups: (1) IMI/REL (500 mg/250 mg) administered IV as a fixed-dose 
combination, or (2) PIP/TAZ (4000 mg/500 mg) administered IV as a fixed-dose 
combination. The study design of PN014 is similar to the current study (PN016), the second 
pivotal HABP/VABP study. 
In adult participants with HABP (ventilated or nonventilated) or VABP in PN014, IMI/REL 
was non-inferior to PIP/TAZ, as assessed by the incidence rate of all-cause mortality through 
Day 28. As the non-inferiority criterion based on all-cause mortality was successfully met, 
noninferiority was also evaluated based on clinical response at the early follow-up (EFU) 
visit. IMI/REL was non-inferior to PIP/TAZ in participants with HABP/VABP, as assessed 
by the incidence rate of favorable clinical response at the EFU visit.
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Additional details regarding the preclinical, Phase 1, Phase 2, and Phase 3 clinical studies 
completed to date are summarized in the MK-7655 IB.
Ongoing Clinical Studies
There are 2 ongoing intervention trials for IMI/REL, both of which are pediatric trials. 
PN020 is a Phase 1b, open label, single dose study to evaluate the pharmacokinetics, safety 
and tolerability of MK-7655A in pediatric subjects from birth to less than 18 years of age 
with confirmed or suspected gram-negative infections. Subjects are enrolled into 1 of 5 
pediatric age cohorts:
• Cohort 1: Adolescents (age 12 to <18 years)
• Cohort 2: Older children (6 to <12 years)
• Cohort 3: Younger children (2 to <6 years)
• Cohort 4: Infants and toddlers (3 months to <2 years)
• Cohort 5: Neonates and young infants (birth to <3 months); are further divided into the 
following age sub-cohorts:
o 4 weeks to <3 months of age
o 1 to <4 weeks of age
o <1 week of age
A single IV dose of IMI/REL is administered to subjects any time after initiating standard of 
care treatment for a confirmed or suspected gram-negative bacterial infection. Enrollment in 
this study has been completed, but the final summarized data are not yet available.
PN021 is a Phase 2/3 open label, randomized, active controlled clinical study to evaluate 
safety, tolerability, efficacy and pharmacokinetics of MK-7655A in pediatric participants 
with confirmed or suspected -gram-negative bacterial infections. Subjects are enrolled into 1 
of 5 pediatric age cohorts:
• Cohort 1: Adolescents (age 12 to <18 years)
• Cohort 2: Older children (6 to <12 years)
• Cohort 3: Younger children (2 to <6 years)
• Cohort 4: Infants and toddlers (3 months to <2 years)
• Cohort 5: Neonates and young infants (birth to <3 months)
Subjects receive multiple doses of IV IMI/REL for a minimum of 5 days to a maximum of 14 
days. The first subject was randomized in this study on 09-OCT-19.
Information on Other Study-related Therapy
Comparator Therapy
Participants in the comparator arm of this trial will receive intravenous (IV) infusions of 
piperacillin/tazobactam (PIP/TAZ).
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PIP/TAZ is a combination product consisting of a penicillin-class antibacterial, piperacillin, 
and a β-lactamase inhibitor, tazobactam. It is indicated for the treatment of systemic and/or 
local bacterial infection caused by susceptible gram-negative and gram-positive bacterial 
isolates for conditions such as lower respiratory tract infections, urinary tract infections 
(complicated and uncomplicated), intra-abdominal infections, skin and skin structure 
infections, bacterial septicemia, gynecological infections, bacterial infection in patients with 
neutropenia combined with aminoglycosides antibiotics, bone and joint infections and 
polymicrobial infections in China [Chinese Package Insert 2016]. The approved indications 
of PIP/TAZ may be slightly different among other approved countries.
PIP/TAZ acts by inhibiting septum formation and cell wall synthesis of susceptible bacteria.
In the 2005 Infectious Diseases Society of America (IDSA)/American Thoracic Society 
(ATS) Guidelines for the Management of Adults with Hospital-acquired, Ventilator-
associated, and Healthcare-associated Pneumonia, PIP/TAZ is a recommended agent for 
empiric therapy for HABP/VABP. In Asian countries, PIP/TAZ is also recommended for 
empiric therapy for HABP/VABP and is widely used. In China clinical practice, PIP/TAZ is 
one of the most commonly used drugs for HABP/VABP. In a China local guideline for 
HABP [Chinese Thoracic Society, Chinese Medical Association 2002], PIP/TAZ is 
recommended for severe HABP. In a China VABP guideline [Chinese Society of Critical 
Care Medicine, Chinese Medical Assoc 2013], PIP/TAZ is also recommended for empiric 
use, and first line use in VABP patients with P. aeruginosa and extended-spectrum beta-
lactamase (ESBL)-producing isolates.
Co-administration of Open-label Therapy with Linezolid for MRSA
Beginning at randomization, all participants will receive initial empiric treatment with IV 
linezolid (600 mg q12h) for MRSA infection.
Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones. It 
is used for the treatment of infections caused by gram-positive bacteria. The in vitro
spectrum of activity of linezolid also includes certain gram-negative bacteria and anaerobic 
bacteria. Linezolid is a bacterial protein synthesis inhibitor. Its mechanism of action is 
prevention of the formation of the ribosomal initiation complex thus affecting the translation 
process. Results from time-kill studies have shown linezolid to be bacteriostatic against 
enterococci and staphylococci.
Linezolid is indicated for the treatment of the following infections caused by susceptible 
gram-positive bacteria in most approved countries: nosocomial pneumonia; community-
acquired pneumonia; complicated skin and skin structure infections, including diabetic foot 
infections, without concomitant osteomyelitis; uncomplicated skin and skin structure 
infections; vancomycin-resistant Enterococcus faecium infections [Chinese Package Insert 
2017].
Both linezolid or vancomycin are recommended for the treatment of MRSA infections when 
there is a proven or suspected infection due to MRSA, as per the IDSA/ATS guideline on the 
treatment of HABP/VABP and the IDSA guideline on treatment of MRSA infections. Of 
note, these guidelines recognize that linezolid might be preferred in certain situations, 
including (a) participants with evidence of renal insufficiency due to potential for 
vancomycin under-dosing in this patient population and the potential risk of nephrotoxicity 
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associated with vancomycin; and (b) institutions where vancomycin resistance (ie, MRSA 
isolates with vancomycin MIC ≥2 mcg/mL) is common [Kalil, A. C., et al 2016] [Liu, C., et 
al 2011]. 
Linezolid and vancomycin are also recommended for VABP patients with MRSA in the 
China VABP guideline [Chinese Society of Critical Care Medicine, Chinese Medical Assoc 
2013], while in the HABP China guideline, vancomycin is recommended (linezolid was not 
available at that time in China clinical practice), which is similar to the guidelines in other 
Asian countries.
Linezolid was compared to vancomycin for the treatment of nosocomial pneumonia due to 
MRSA in a randomized double-blind trial. In this study, the efficacy responses were 
numerically higher with linezolid than vancomycin. Overall, 58% of linezolid-treated 
participants and 47% of vancomycin-treated participants had achieved clinical cure at end of 
study. Additionally, 83% of linezolid-treated participants and 70% of vancomycin-treated 
participants had achieved clinical cure at the end of treatment. The incidence of documented 
microbiological persistence was also lower in the linezolid group, with 17% of linezolid-
treated participants and 46% of vancomycin-treated participants having a positive culture 
result for MRSA at the end of treatment. The incidence of all-cause mortality at Day 60 was 
similar between treatment groups. Although the overall incidence of adverse events was
similar in the 2 treatment groups, nephrotoxicity occurred more commonly on vancomycin 
than linezolid (18% vs. 8%, respectively) [Wunderink, R. G., et al 2012].
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.
Participants enrolled in this trial are hospitalized patients with infections requiring treatment 
with IV therapy. If randomized to receive IMI/REL, participants will receive treatment, in 
part, with an agent, IMI, recommended and commonly used for the treatment of 
HABP/VABP, and in addition can potentially benefit from treatment with the investigational 
agent REL. The combination, IMI/REL, is specifically targeted for treatment of gram-
negative imipenem-resistant infections. Participants randomized to the comparator arm will 
also receive a treatment regimen expected to be efficacious against HABP/VABP (see 
Section 4.2.2).
Although potentially more frequent than standard of care for some of the participants (ie,
moderate infections, mainly in non-ventilated participants), the study procedures described in 
Section 1.3 – Schedule of Activities (SoA) are generally typical procedures performed for 
this hospitalized patient population. Additional burden may be incurred due to visits 
following release from the hospital. However, the procedures performed at these visits are 
generally not likely to lead to significant harm (eg, blood draws, urine collection, physical 
exam, vital signs). These procedures are necessary to support a robust evaluation of the 
safety and efficacy of the investigational drug.
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and Informed Consent documents.
3. Objectives/Hypotheses and Endpoints
The following objectives and endpoints will be evaluated in adult participants diagnosed with 
HABP or VABP:
Objective/Hypothesis
Endpoint
Primary

Objective: To determine the incidence 
rate of all-cause mortality through Day 
28 post-randomization associated with 
treatment with IMI/REL compared to 
treatment with PIP/TAZ in the modified 
intention-to-treat (MITT) population.
Hypothesis (H1): IMI/REL is non-
inferior to PIP/TAZ as measured by the 
incidence rate of all-cause mortality
through Day 28 post-randomization in 
the MITT population.
If non-inferiority is established, the 
following hypothesis will be tested: 
Hypothesis (H2): IMI/REL is superior 
to PIP/TAZ as measured by the 
incidence rate of all-cause mortality 
through Day 28 post-randomization in 
the MITT population.

All-cause mortality
Secondary

Objective: To evaluate favorable
clinical response (CR) rate associated 
with treatment with IMI/REL compared 
to treatment with PIP/TAZ in the 
following visits and analysis 
populations:
- At the early follow-up (EFU) visit 
in the MITT population
- At the EFU visit in the clinically 
evaluable (CE) population
- At the end of treatment (EOT) visit 
in the MITT population
- At the EOT visit in the CE 
population

Favorable CR at EFU requires 
“sustained cure” or “cure” (see Table 6)

Favorable CR at EOT requires “cure” or 
“improved” (see Table 5)
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Objective/Hypothesis
Endpoint

Objective: To evaluate favorable
microbiological response (MR) rate
associated with treatment with IMI/REL 
compared to treatment with PIP/TAZ in 
the following visits and analysis 
populations:
- At the EFU visit in the 
microbiologically evaluable (ME)
population
- At the EOT visit in the 
microbiologically modified 
intention-to-treat (mMITT) 
population
- At the EOT visit in the ME
population

Favorable MR at EFU requires 
“eradication” or “presumed eradication”
(see Table 9)

Favorable MR at EOT requires 
“eradication” or “presumed eradication”
(see Table 8)

Objective: To evaluate the safety and 
tolerability profile of IMI/REL 
compared with PIP/TAZ.

Number of participants experiencing 
adverse events (AEs)

Number of participants 
discontinuing study drug due to 
adverse events 
Tertiary/Exploratory

Objective: To determine the incidence 
rate of all-cause mortality associated 
with treatment with IMI/REL compared 
to treatment with PIP/TAZ in the 
following visits and analysis 
populations:
- Through Day 28 post-
randomization in the mMITT 
population
- At the EFU visit in the MITT 
population 
- At the EFU visit in the mMITT 
population

All-cause mortality 
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Objective/Hypothesis
Endpoint

Objective: To determine the incidence 
rate of all-cause mortality through Day 
28 post-randomization associated with 
treatment with IMI/REL compared to 
treatment with PIP/TAZ based on 
pneumonia type (non-ventilated HABP, 
ventilated HABP/VABP) in the 
following analysis populations:
- In the MITT population
- In the mMITT population

All-cause mortality 

Objective: To evaluate favorable
clinical response rate associated with 
treatment with IMI/REL compared to 
treatment with PIP/TAZ in the 
following visits and analysis 
populations:
- At Day 3 of IV study therapy 
(OTX1) in the MITT population and 
CE population
-At Day 6 of IV study therapy 
(OTX2) in the MITT population and 
CE population
- At Day 10 of IV study therapy 
(OTX3, if applicable) in the MITT 
population and CE population
- At Day 28 post-randomization in 
the MITT population and CE 
population.

Favorable CR at OTX1, OTX2, or 
OTX3 requires “improved”(see Table 4)

Favorable CR at Day 28 post-
randomization requires “sustained cure” 
or “cure” (see Table 6)
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4. Study Design 
Overall Design 
This is a randomized, active-controlled, parallel-group, multi-site, double-blind trial of 
imipenem/cilastatin/relebactam (also known as MK-7655A; hereafter referred to as 
IMI/REL) compared with piperacillin/tazobactam (PIP/TAZ) in participants with hospital-
acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) 
to be conducted in conformance with Good Clinical Practices. Participants with HABP may 
either be ventilated (ventilated HABP) or non-ventilated (non-ventilated HABP).
Approximately 270 participants from around 10 countries (approximately 74% of total 
population [ie, approximately 200 participants] comes from China mainland) will be 
randomized in a 1:1 ratio to 1 of 2 treatment arms of the study: Treatment Group 1 
(IMI/REL) or Treatment Group 2 (PIP/TAZ). Both treatments will be provided as fixed-dose 
combinations, administered intravenously (IV) every 6 hours. After a maximum 48-hour 
screening period, randomized participants in each treatment group will receive a minimum of 
7 days to up to a maximum of 14 days of IV study therapy. Participants with evidence of 
concurrent bacteremia or with P. aeruginosa infection should receive 14 days of IV study 
therapy. While on IV study therapy, study visits will be performed on Day 1 (randomization), 
Day 3 (on-therapy visit #1, OTX1), Day 6 (on-therapy visit #2, OTX2), Day 10 (on-therapy 
visit #3, OTX3, if applicable) and at the end of therapy (EOT). Following the completion of 
IV study therapy, all participants will have a study visit 7 to 14 days following completion of 
therapy (at the early follow-up visit, EFU). In addition, a Day 28 (up to an additional 3 days) 
post-randomization visit will be performed in all participants (this visit may be performed on 
the same day as the EFU visit, depending on the duration of IV study therapy). All 
participants will remain in the study for a total of up to 33 days. 
Since the study will enroll participants without confirmed microbiological (culture) evidence 
of the HABP/VABP pathogen from a lower respiratory tract specimen at study entry, the use 
of initial empiric treatment with open-label IV linezolid (600 mg every 12 hours [q12h]) for 
methicillin-resistant S. aureus (MRSA) infection is required. Participants with a confirmed 
MRSA lower respiratory tract culture should receive a minimum of 7 days of therapy.
Participants with MRSA bacteremia should receive 14 days of therapy. Empiric linezolid 
treatment will be stopped if the final culture results from the baseline lower respiratory tract 
and/or blood sample do not demonstrate the presence of MRSA.
Randomization will be stratified based on pneumonia type (non-ventilated HABP vs 
ventilated HABP/VABP) and Acute Physiology and Chronic Health Evaluation II (APACHE 
II) score at baseline (<15 vs ≥15). A minimum of 25% of participants will have ventilated
HABP or VABP.
Protocol amendment MK-7655A-016-02 extended the participants’ age range from ≤75 years 
of age to ≤90 years of age due to the unmet medical need for treatment of HABP/VABP in 
the elderly population. In support of the age limit change, prior studies in the MK-7655A 
program enrolled all adults aged 18 years or older, and a comparable safety profile for
IMI/REL was observed across all participants ≤90 years of age.
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (SoA), Section 1.3. 
Details of each procedure are provided in Section 8.
Scientific Rationale for Study Design 
Rationale for Endpoints
Efficacy Endpoints
The primary efficacy endpoint in this study is all-cause mortality through Day 28 post-
randomization in the MITT population. Given the severity of illness in hospitalized 
participants with HABP/VABP whom routinely require in-hospital treatment with IV 
antibiotics, evaluation of mortality is appropriate. A 1-month mortality endpoint has 
commonly been used for evaluation of efficacy of antibacterial therapy against HABP/VABP 
infections [Freire, A. T., et al 2010] [Chastre, J., et al 2008] [West, M., et al 2003] [U.S. 
Prescribing Information 2017]. Based on the results of recently conducted trials, 
approximately 15% of participants will die even though they receive antibacterial drug 
therapy for HABP/VABP [Chastre, J., et al 2008] [Joshi, M., et al 2006] [West, M., et al 
2003] [Chastre, J., et al 2008]. The goal of this trial is to demonstrate that IMI/REL is non-
inferior to piperacillin/tazobactam (PIP/TAZ) in participants with HABP/VABP, as measured 
by the incidence of all-cause mortality through Day 28 post-randomization. If non-inferiority 
is established, then superiority of IMI/REL compared to PIP/TAZ will be evaluated.
The secondary efficacy endpoints (including clinical response and microbiological response) 
are based on the Guidance of Antibacterial Development from NMPA.
Safety Endpoints
In support of the secondary objective to evaluate the safety and tolerability profile of 
IMI/REL, the safety and tolerability of IMI/REL (as well as the safety of the comparator, 
PIP/TAZ) will be assessed by clinical evaluation of adverse events and inspection of other 
study parameters including vital signs, physical examinations, and standard laboratory safety 
tests at time points specified in Section 1.3 - SoA. Participants may be asked to return for 
unscheduled visits in order to perform additional safety monitoring.
Rationale for the Use of Comparator
PIP/TAZ is one of several empiric regimens for HABP and VABP recommended by the 
IDSA and ATS in their current treatment guidelines. It is approved for use in nosocomial 
pneumonia in the United States, EU, and other countries. Significant clinical experience, 
from both clinical trials and post-marketing data, exists for the use of PIP/TAZ in the 
treatment of HABP and VABP. It is the optimal choice for use as a comparator for IMI/REL 
as both regimens are routinely administered at an every-6-hour interval.
The chosen dose for PIP/TAZ in this study is 4500 mg (4000 mg piperacillin/500 mg 
tazobactam), administered IV once every 6 hours. This represents the currently 
recommended dose in the current IDSA/ATS treatment guidelines [Kalil, A. C., et al 2016]
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for nosocomial pneumonia. The chosen dose is routinely administered to participants in 
clinical practice for this indication.
Justification for Dose 
Starting Dose for This Study
Based on data from in vivo animal models of imipenem-resistant gram-negative infections, 
the target pharmacokinetic (PK) parameter for REL has been defined as a plasma AUC0-24hr
following 4-times daily dosing of 150 μM*hr (or an AUC0-∞≥37.5 μM*hr following single-
dose administration). Extensive PK/PD in vitro and in vivo modeling work, together with 
multiple-dose safety data for REL from the Phase 1 program, supports doses of REL 
administered IV at or above 125 mg every 6 hours. However, preclinical microbiology data 
indicate that there are some highly resistant strains of P. aeruginosa that may require higher 
concentrations of REL. To this end, it is appropriate to target a safe dose of REL that exceeds 
the anticipated PK target for common pathogens in order to appropriately cover a broader 
range of resistant bacteria. This is particularly important in HABP/VABP infections as MDR 
gram-negative organisms are more common in these infections. REL doses that are 
associated with plasma exposures exceeding the PK target of REL for common pathogens, 
such as 250 mg administered IV once every 6 hours, would support this evaluation.
A dosing regimen of IMI/REL 500mg/250 mg every 6 hours was selected for PN016 based 
on results from Phase 1 and Phase 2 trials. There were 7 Asian males enrolled in PN001;
analysis showed that the PK parameters and safety profile of these Asian participants are 
similar to non-Asian participants in PN001. Also, preliminary data from a Japanese PK study 
(PN012) show that the pharmacokinetic profiles of REL, imipenem and cilastatin in healthy 
Japanese participants are similar with historical data obtained from non-Japanese in PN001.
Per the IDSA/ATS treatment guidelines for nosocomial pneumonia, a recommended IMI 
dose for HABP/VABP is 500 mg every 6 hours [Kalil, A. C., et al 2016]. The recommended 
dose is well accepted in most countries.
Based on the China local label for TIENAM® (imipenem/cilastatin), the recommended dose 
for severe infection is 2 to 4g of imipenem per day. In China, in clinical practice, 0.5 g (0.5 g 
imipenem/0.5 g cilastatin) every 6 hours is commonly used.
In order to assess drug penetration at the site of action (pulmonary penetration), an open-
label study was conducted to evaluate the PK of REL and imipenem in the pulmonary 
epithelial lining fluid (ELF) and alveolar cells (AC) after administration of multiple doses of 
REL and IMI in 16 healthy young male or female participants. The intrapulmonary 
pharmacokinetic profiles of REL and imipenem were assessed after participants received 
multiple administrations of REL (250 mg) and IMI (500 mg) IV every 6 hours (q6h) over 
5 doses. Penetration of both REL and imipenem into the ELF was similar, with relative 
exposures (AUC0-∞in ELF compared to plasma) based on mean profiles of 43% for REL and 
42% for imipenem. Thus, given the PK target based on plasma PK was exceeded at the 
125 mg dose, this target is also projected to be met in the ELF at the selected 250 mg clinical 
dose, accounting for differences in ELF versus plasma exposure.
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Both 125-mg and 250-mg doses of REL have been evaluated in the Phase 2 clinical studies 
(PN003 and PN004). In order to inform the choice of dose for the current proposed study, 
results of an interim analysis of combined safety data from PN003 and PN004 were reviewed 
by a standing internal Data Management Committee (siDMC). The interim analysis included 
an evaluation of the safety and tolerability of the 250-mg dose of REL given in combination 
with IMI in comparison to the control regimen (IMI alone) and in comparison to the 125-mg 
dose of REL + IMI. The analysis was performed after 50% of planned participants across 
PN003 and PN004 (N=331) were followed through the early follow-up visit (5 to 9 days 
following completion of study therapy). The data from the interim analysis supported the use 
of a 250-mg dose of REL with IMI. The safety profile of the 250-mg dose is further 
supported by unblinded data from PN004 which showed that the safety and tolerability 
profile of the 250-mg dose was similar to the 125-mg dose of REL as well as to IMI alone 
(See Section 2.2.2 and the MK-7655 IB for further details). The 250-mg dose was selected 
for this study to achieve exposures above the PK target for common pathogens that may be 
required for the treatment of highly resistant organisms.
The total daily dose in PN016 is adjusted based on renal function. Relebactam, imipenem, 
and cilastatin are primarily renally excreted. In a Phase 1 renal insufficiency trial (PN005), 
changes in renal clearance and exposures with changing renal function were similar for both 
IMI and REL, supporting their coadministration across all the spectrum of renally impaired 
population, with dose adjustments made in the same proportion for both IMI and REL. IMI 
and REL will be provided together in a single vial as a fixed-dose combination product in 
this study. Dose adjustment is required in participants with renal impairment. Depending on 
the individual participant’s renal function (as determined by actual or estimated creatinine 
clearance), the total daily dose of IMI/REL may be adjusted. Unlike the Phase 2 trials
(PN003 and PN004) but similar to the other Phase 3 trials (PN013 and PN014), the total 
daily dose in this study (PN016) is not adjusted based on weight. Population PK-based 
simulations were conducted to evaluate the impact of removal of weight-based adjustments 
for IMI, and the results were supportive of dose adjustments based solely on renal function.
This approach is consistent with the current TIENAM® and PRIMAXIN®
(imipenem/cilastatin) labels (updated in January 2016 and December 2016, respectively), as 
well as with general clinical practice and other recent clinical trials using IMI as a 
comparator. For example, clinical trials for HABP/VABP published since 2006 have 
administered IMI at standard dosages without an adjustment for weight. Efficacy rates in 
these trials have ranged from ~60% to 80% without significant toxicity [Kollef, M. H., et al 
2012] [Ramirez, J., et al 2013] [Joshi, M., et al 2006] [Schmitt, D. V., et al 2006]. The few 
published clinical trials in which IMI dosage was adjusted for weight describe similar 
efficacy and safety [Freire, A. T., et al 2010] [Chastre, J., et al 2008]. Furthermore, weight is 
already a component of calculated creatinine clearance, used for determination of renal 
function and need for dose adjustment, thus raising the theoretical concern of under-dosing in 
participants with low body weight. Population PK-based simulations were conducted to 
evaluate the impact of removal of weight-based adjustments for IMI. Results of these 
simulations indicate that in individuals of lower weight, exposures of IMI/REL are 
significantly lower than those in higher weight ranges when doses are adjusted based on 
weight, and are supportive of dose adjustments based solely on renal function, as has been 
described above in clinical practice. Specifically, simulation results indicate that in 
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participants with normal renal function, the dose of 250-mg REL and 500-mg IMI given 
every 6 hours IV is appropriate. For participants with mild renal insufficiency, the dose 
should be reduced to 200-mg REL and 400-mg IMI given every 6 hours IV; for moderate 
renal insufficiency, 150-mg REL and 300-mg IMI given every 6 hours IV; and for severe 
renal insufficiency, 100-mg REL and 200-mg IMI given every 6 hours IV. These doses result 
in a consistent percentage of participants achieving the PK targets for both REL and IMI 
across the range of weights and creatinine clearances, and maintain exposures in a range 
demonstrated to be safe and well-tolerated for both IMI and REL. The specific dosing 
guidelines are included in Section 6.
Maximum Dose/Exposure for This Study
No dose modifications are planned for this study aside from dose reductions for renal 
insufficiency. Therefore, the maximum dose for this study will be 500 mg IMI/250 mg REL 
every 6 hours.
Rationale for Dose Interval and Study Design
Blinded IV study therapy will be administered for a minimum of 7 days up to a maximum of 
14 days. Of note, participants with evidence of concurrent bacteremia or with P. aeruginosa 
infection should receive 14 days of treatment. The duration of therapy is consistent with 
practice guidelines and data from clinical trials.
Guidelines published by IDSA/ATS 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 [Kalil, A. C., et al 2016]. If deemed clinically appropriate, participants may 
receive up to 14 days of treatment 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]. 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.
Based on the most recent China data, the new China VABP guideline (published in 2013) 
recommended shorter treatment durations for VABP overall (7 to 10 days for most of the 
cases, and a longer duration for immunocompromised patients or those with infections 
caused by MDR pathogens) compared with the recommended duration of therapy in an older 
HABP guideline published in 2002 (recommended 14 to 28 days for E.coli, K. pneumonia, 
P. aeruginosa).
Preclinical toxicology data for REL support administration of study therapy for up to 14 days 
in this study. Refer to the MK-7655 IB for more detailed information on preclinical toxicity 
studies of REL.
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Open-label treatment with linezolid for a confirmed MRSA infection is recommended for a 
minimum of 7days. Participants with MRSA bacteremia should receive 14 days of therapy.
Empiric linezolid treatment will be stopped if the final culture results from the baseline lower 
respiratory tract and/or blood sample do not demonstrate the presence of MRSA.
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws from the study or is lost to follow-up (ie, 
the participant is unable to be contacted by the investigator).
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5. Study Population
Male/Female participants with HABP/VABP between the ages of 18 and 90 years (inclusive)
will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Require treatment with IV antibiotic therapy for HABP or VABP.
NOTE: 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 2 days (48 hours) or within 7 days after discharge from a hospital stay of 
at least 2 days (48 hours) duration (includes patients institutionalized in a skilled 
nursing or other long-term care facility). Of note, such participants may or may not 
require mechanical ventilation (ventilated HABP and non-ventilated HABP). 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 2 days (48 hours). 
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2. Fulfill the clinical and radiographic criteria described below within 48 hours prior to 
randomization, with onset of criteria occurring after more than 2 days (48 hours) of 
hospitalization or within 7 days after discharge from a hospital (for HABP) or at least 
2 days (48 hours) after mechanical ventilation (for VABP):
(a) Participant has at least one of the following clinical features: 

New onset or worsening pulmonary symptoms or signs, 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 participant is breathing room air at standard atmosphere 
pressure, 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
(b) Participant has at least one of the following signs:

Documented fever (body temperature ≥38 degrees Celsius) 

Hypothermia (body temperature ≤35 degrees Celsius)

Total peripheral white blood cell (WBC) count ≥10,000 cells/cubic millimeter 
(mm3) 

Leukopenia with total WBC ≤4,000 cells/mm3

Greater than 15 percent immature neutrophils (bands) noted on peripheral 
blood smear 
AND
(c) Participant has a chest radiograph showing the presence of a new or 
progressive infiltrate(s) suggestive of pneumonia.
3. Have an adequate baseline (at or within 2 days [48 hours] of screening) lower 
respiratory tract specimen obtained for Gram stain and culture.
NOTE: Microscopic examination of Gram-stained smears must be performed prior to 
randomization to ensure the adequacy of the specimen. The low-power microscopic 
view of the Gram stain can be used to ascertain the quality of the respiratory 
specimen which helps to ensure that the respiratory specimen sent for culture does not 
represent oropharyngeal contamination. For specimens obtained by direct sampling of 
the lower respiratory tract (ie, sampling via bronchoalveolar lavage [BAL], mini BAL 
or protected brush specimen [PBS]), no predefined requirements are required to 
ascertain the quality of the respiratory specimen. However, for specimens not 
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obtained by direct sampling of the lower respiratory tract, such as those obtained by 
expectorated sputum, an adequate lower respiratory tract specimen is defined as 
having fewer than 10 squamous epithelial cells and greater than 25 neutrophils per 
low power field of Gram stains (white blood cell [WBC] counts of greater than 25 per 
low power field of Gram stains are acceptable in place of neutrophils). 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.
4. Have an infection known or thought to be, in the opinion of the investigator, caused 
by microorganisms susceptible to the IV study therapy.
5. Agree to allow any bacterial isolates obtained from protocol-required specimens 
related to the current infection to be provided to the Central Microbiology Reference 
Laboratory for study-related microbiological testing and long-term storage.
Demographics
6. Be between 18 to 90 (inclusive) years of age on the day of signing informed consent.
NOTE: Adults are the intended study population for this protocol. Participants under 
the age of legal consent per a specific country’s regulation should be excluded from 
participation in this study.
Male participants:
7. A male participant must agree to use contraception as detailed in Appendix 3 of this 
protocol from the time of providing informed consent through completion of the 
study and refrain from donating sperm during this period.
Female participants:
8. A female participant is eligible to participate if she is not pregnant (see Appendix 3), 
not breastfeeding, and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 from 
the time of providing informed consent through completion of the study.
Informed Consent
9. The participant (or legally acceptable representative if applicable) has provided
documented informed consent/assent for the study.
Note: As allowable by local regulations in Russia, the consent may be provided by a 
council of healthcare professionals for deciding on the possibility of inclusion of a 
patient in the clinical study or signed by an authorized designee per local regulations 
or requirements, including but not limited to independent physicians qualified to 
provide consent for patients who are unable to provide consent for themselves. In 
these circumstances, special care must be taken to ensure consent is consistent with 
all local laws and regulations and that patients (if/when they are able to provide 
consent for themselves) or their Legally Acceptable Representative (when available) 
are reconsented.
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Additional Criteria
10. If a penicillin skin test is required by local clinical practice, the participant must have 
a negative skin test result for allergy to penicillin before receipt of first dose of IV 
study therapy.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a baseline lower respiratory tract specimen Gram stain that shows the presence of 
gram-positive cocci only.
•
NOTE: For example, the following Gram stain patterns are acceptable:
• only gram-negative organisms;
• only gram-positive rods;
• a mixture of gram-positive and gram-negative organisms;
• a mixture of gram-positive cocci and gram-positive rods; or
• no organisms seen on Gram stain
2. Has confirmed or suspected community-acquired bacterial pneumonia (CABP).
3. Has confirmed or suspected pneumonia caused by Mycoplasma, Chlamydia, or 
Legionella, or of viral, fungal, or parasitic etiology.
4. 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.
5. Has a carcinoid tumor or carcinoid syndrome.
6. Has active immunosuppression, defined as either receiving immunosuppressive 
medications or having a medical condition associated with immunodeficiency.
Including but not limited to: (1) HIV (AIDS or CD4 <200 cell/mm³),
(2) Chemotherapy was performed within 6 weeks before randomization,
(3) Immunosuppressive therapy, including maintenance glucocorticoid therapy
(>40 mg/d prednisolone equivalent dose continuously administered for ≥7 days), (4) 
Neutrophilic granulocyte absolute count <500/mm³.
NOTE: Short-term treatment with systemic (IV or oral) steroids of <1 week duration 
(eg, treatment for an acute asthma exacerbation or acute skin condition) is allowed.
Topical steroids for the treatment of skin conditions are also allowed.
7. The participant is expected to die during the 7- to 14-day treatment period, despite 
adequate antibiotic therapy.
8. Has a concurrent condition or infection that, in the investigator’s judgment, would 
preclude evaluation of therapeutic response (eg, active tuberculosis, cystic fibrosis, 
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granulomatous disease, a disseminated fungal infection, invasive fungal pulmonary 
infection or endocarditis).
9. Has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious 
reaction to any of the following:

any β-lactams (including PIP/TAZ, carbapenems, cephalosporins, or other β-
lactam agents)

β-lactamase inhibitors (eg, tazobactam, sulbactam, clavulanic acid, avibactam)
NOTE: Participants with a history of mild rash to penicillins or other β-lactams may 
be enrolled and closely monitored, and this should be judged by investigators.
10. Has a history of a seizure disorder which has required ongoing treatment with anti-
convulsive therapy or prior treatment with anti-convulsive therapy within the last 
3 years.
11. Is currently undergoing hemodialysis or peritoneal dialysis.
12. Has a history or current evidence of any condition, therapy, laboratory abnormality, 
or other circumstance that, in the opinion of the investigator, might confound the 
results of the study, interfere with the participant’s participation for the full duration 
of the study, or pose additional risk in administering the study drugs to the 
participant.
Note: patients with a history of allergy to linezolid or any oxazolidinones are required 
to be assessed under this exclusion criterion for severity of the allergy or potential 
hypersensitivity that would require exclusion from the study as judged by the
investigator.
13. A WOCBP who has a positive urine pregnancy test at screening.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required; a WOCBP who has a positive serum pregnancy test will be 
excluded.
Prior/Concomitant Therapy
14. Has received effective antibacterial drug therapy with known coverage of pathogens 
that cause HABP/VABP for a continuous duration of more than 48 hours during the 
previous 72 hours.
Exceptions:

Participants who have failed prior antibiotic therapy for the current episode of
HABP/VABP (ie, have persistent/worsening signs and/or symptoms of
HABP/VABP at screening which are still present despite at least 48 hours on the
prior antibacterial regimen), provided the prior respiratory or blood culture did not 
grow only S. aureus (methicillin-susceptible S. aureus [MSSA] or methicillin-
resistant S. aureus [MRSA]).

Prior therapy with a non-absorbed antibiotic therapy used for gut decontamination 
(eg, low dose erythromycin or polymyxin) or to eradicate Clostridium difficile
(oral vancomycin or fidaxomicin).
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15. Is anticipated to be treated with any of the following medications during the course of 
study therapy:

valproic acid or divalproex sodium (or has used valproic acid or divalproex 
sodium in the 2 weeks prior to screening)
NOTE: The exclusion of participants with valproic acid or divalproex sodium use 
in the 2 weeks prior to screening is only applicable to participants with a history 
of a seizure disorder. This criterion does not apply to participants who do not have 
a history of a seizure disorder and had previously received valproic acid or 
divalproex sodium for prophylactic purposes.

serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor 
agonists (triptans) (during treatment with linezolid)

monoamine oxidase inhibitors (MAOIs) (during treatment with linezolid or has 
used MAOIs during the 2 weeks prior to screening)

meperidine (during treatment with linezolid)

buspirone (during treatment with linezolid)

dopaminergic agents (during treatment with linezolid)

concomitant systemic (IV or oral), inhaled, or intrapleural antibacterial agents in 
addition to those designated in the study treatment groups
NOTE: As the study will enroll participants without confirmed microbiological 
(culture) evidence of the HABP/VABP pathogen on a lower respiratory tract 
specimen at study entry, the use of initial empiric treatment with open-label IV 
linezolid for MRSA infection is required. The recommended treatment duration 
for a confirmed MRSA infection is a minimum of 7 days. Participants with 
MRSA bacteremia should receive 14 days of therapy. Empiric linezolid treatment 
will be stopped if the final culture results from the baseline lower respiratory tract 
and/or blood sample do not demonstrate the presence of MRSA.

concomitant systemic (IV or oral) antifungal or antiviral therapy for the index 
infection of HABP/VABP

traditional Chinese medicine or herbal medicine
Prior/Concurrent Clinical Study Experience
16. Is currently participating in, or has participated in, any other clinical study involving 
the administration of investigational or experimental medication (not licensed by 
regulatory agencies) at the time of the presentation or during the previous 90 days 
prior to screening or is anticipated to participate in such a clinical study during the 
course of this trial.
17. Has previously participated in this study at any time.
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Diagnostic Assessments
18. Has an estimated or actual creatinine clearance of <15 mL/min at screening, based on 
the findings of local laboratory values. Creatinine clearance in mL/min may be 
calculated from serum creatinine concentration by the Cockcroft-Gault (C-G) 
equation:
Creatinine clearance (Males) = 
(weight in kg) X (140 minus age)
(72) X (creatinine in mg/dL)
Creatinine clearance (Females) = 
0.85 X the value obtained using the formula
above
19. 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.
Lifestyle Considerations
There are no dietary or activity restrictions in this study, except as medically indicated.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events (AEs) or serious adverse 
events (SAEs) meeting reporting requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
6. Treatments
Study treatment is defined as any investigational treatment(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 treatment(s) provided by the Sponsor] will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Treatments Administered
The study treatments to be used in this study are outlined below in Table 1 Study Treatments.
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Table 1
Study Treatments
Study Treatment 
Name
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Imipenem/
cilastatin/relebactam
(IMI/REL)a
Powder for 
Constitution
MK-7655A 
(REL) 
250 mg
Imipenem 
500mg
Cilastatin 
500mg
Imipenem
/cilastatin 500 
mg/
relebactam
250 mgb
once every 
6 hours
IV infusion
Visits 2 through 
6 (7 to 14 
days)c,d
Experimental
IMP
Provided 
centrally by the 
Sponsor 
Piperacillin/
tazobactam
(PIP/TAZ)a
Powder for 
Reconstitution
Piperacillin / 
Tazobactam 
4g / 0.5g
4000 mg 
piperacillin/ 
500 mg 
tazobactamb
once every 
6 hours
IV infusion
Visits 2 through 
6 (minimum of 
7 days, 
maximum of 
14 days)c,d
Active 
comparator
IMP
Provided 
centrally by the 
Sponsor
Linezolid
Single-use, 
ready-to-use 
infusion bag
Linezolid 
600 mg
600 mg every 
12 hours
IV infusion
Visits 2 through 
6 (minimum of 
7 days if MRSA 
in lower 
respiratory tract, 
minimum of 14 
days if MRSA in 
blood)e
Open-label 
therapy for 
MRSA
NIMP
Provided 
centrally by the 
Sponsor. May 
be sourced 
locally by trial 
site, subsidiary
or designee with 
Sponsor 
approval
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Study Treatment 
Name
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Definition Investigational Medicinal Product (IMP) and Non- Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
a
IMI/REL and PIP/TAZ are each provided as a fixed-dose combination (FDC) in a single vial. IMI/REL also includes 500 mg of cilastatin within the FDC.
b
Adjustments to dosage of IMI/REL or PIP/TAZ are required for participants with renal insufficiency (Please reference Table 2 and Table 3 in Section 
6.2.1). 
c
IV study therapy should be administered for a minimum of 168 hours (7 full days). Seven full days of therapy corresponds to 28 doses of IMI/REL 
(Treatment Group 1) and PIP/TAZ (Treatment Group 2) for every 6 hours (q6h). The total duration of IV study therapy should not exceed 14 days.
d
Participants with evidence of concurrent bacteremia or with P. aeruginosa should receive 14 days of IV study therapy.
e
Treatment duration for a confirmed MRSA infection is a minimum of 7 days. Participants with MRSA bacteremia should receive 14 days of therapy.
Empiric linezolid treatment will be stopped if the final culture results from the baseline lower respiratory tract and/or blood samples do not demonstrate 
the presence of MRSA.
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All supplies indicated in Table 1 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements. 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 treatment.
Co-administration of Open-label Therapy with Linezolid
As the study may enroll participants without confirmed microbiological (culture) evidence of 
the HABP/VABP pathogen on a lower respiratory tract specimen at study entry, the use of 
initial empiric treatment with IV linezolid for MRSA infection is required. The 
recommended treatment duration for a confirmed MRSA infection is a minimum of 7 days.
Participants with MRSA bacteremia should receive 14 days of therapy. Empiric linezolid 
treatment will be stopped if the final culture results from the baseline lower respiratory tract
and/or blood sample do not demonstrate the presence of MRSA. Linezolid will be given 
open-label in both treatment groups. Linezolid will be provided by the Sponsor, or locally by 
the trial site, subsidiary or designee if approved by the Sponsor.
Preparation/Handling/Storage/Accountability
Dose Preparation
All IV study therapy will be reconstituted and administered according to the details provided 
in a separate Pharmacy Manual. An unblinded study staff (eg, pharmacist or qualified 
designee) at the study site will be responsible for preparing the IV study therapy for this 
study; this individual(s) must not be involved in any of the safety and efficacy evaluations of 
the study participants. Due to a visual difference in the appearance of study treatment 
solutions, the infusion bags will be covered with an opaque sleeve by the unblinded study
staff (eg, pharmacist or qualified designee) to ensure that other study personnel and all 
participants remain blinded to clinical material assignments.
IMI/REL
The chosen dose for IMI/REL in participants with normal renal function is IMI/REL 
500 mg/250 mg administered IV as an FDC once every 6 hours. For participants with renal 
insufficiency or whose creatinine clearance changes during treatment with study 
therapy, the dose must be adjusted by the unblinded study staff (eg, pharmacist or 
qualified designee) based upon the degree of renal function impairment, as determined 
by the estimated or actual creatinine clearance. Participants should be carefully monitored 
for renal function during IV treatment. Dose adjustments are included in Table 2.
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Table 2
Administration Dosage of IMI/REL According to Renal Function
Creatinine Clearance (mL/min)
IMI/RELa
≥90 
500/250 mg q6h
<90 to ≥60 
400/200 mg q6h
<60 to ≥30 
300/150 mg q6h
<30 to ≥15 
200/100 mg q6h
a
IMI/REL is provided as a single vial in a fixed-dose combination; therefore, the dose for each 
component will be adjusted equally during preparation. For example, a participant who has a creatinine 
clearance of 50 mL/min should receive a 300/150 mg q6h dose of IMI/REL according to the table.
PIP/TAZ
Participants in Treatment Group 2 will receive piperacillin/tazobactam (PIP/TAZ) as an FDC 
at a dosage of 4500 mg (4000 mg PIP/500 mg TAZ) every 6 hours, resulting in a daily total 
of 18.0 g (16.0 g PIP/2.0 g TAZ). For participants with renal insufficiency or whose 
creatinine clearance changes during treatment with study therapy, the dose must be 
adjusted by the unblinded study staff (eg, pharmacist or qualified designee) based upon 
the degree of renal function impairment, as determined by the estimated or actual 
creatinine clearance. Participants should be carefully monitored for renal function during IV 
treatment. The recommended daily doses for participants with renal impairment per the US 
product label are included in Table 3.
NOTE: Dose adjustment for renal impairment may be different in labels from different 
countries, eg in the China local label, the dose adjustment for renal impairment is a little bit 
different from that in the US label for nosocomial pneumonia patients, while the 
recommended total daily dose is identical. In China clinical practice, for renal impairment 
nosocomial pneumonia patients, the dose adjustment is either to decrease the dose frequency 
(China label) or to decrease the single dose (US label) [U.S. Prescribing Information 2017].
Based on the PK/PD profile description of PIP/TAZ in the China label, there are no 
significant differences in steady-state serum concentration between the 2 different dose 
regimens, ie, 2.25 g q6h and 4.5 g q6h. The t1/2 in renal impairment patients will increase 
with the decrease of creatinine clearance. Also based on the compound profile, for PIP/TAZ, 
as with other beta-lactam antibiotics, T >MIC is the PK parameter associated with efficacy, 
which should still be achieved by the more frequent dosing interval with lower dose in the 
renal dose adjustment in the US label. As a result, to get the best product profile of PIP/TAZ 
and keep double-blind fashion, the dosing regimen in this study will be based on the US label 
in renal impairment nosocomial pneumonia patients.
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Table 3
Recommended Dosage of PIP/TAZ in Participants According to Renal Function 
in the US Label
Creatinine clearance
(mL/min)
PIP/TAZ dosea for nosocomial pneumonia patients recommended 
in US labelb
>40
4500 mg (4000 mg PIP/500 mg TAZ) q6h
40 to >20
3375 mg (3000 mg PIP/375 mg TAZ) q6h
<20 to >15
2250 mg (2000 mg PIP/250 mg TAZ) q6h
a
PIP/TAZ is provided as a single vial in a fixed-dose combination; therefore, the dose for each 
component will be adjusted equally during preparation. For example, a participant who has a creatinine 
clearance of 30 mL/min should receive a 3375 mg dose (3000 mg PIP/375 mg TAZ) according to the 
table.
b
The dosing regimen will be based on the US label in renally impaired participants in this study.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments 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 treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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 
treatments in accordance with the protocol and any applicable laws and regulations.
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Measures to Minimize Bias: Randomization and Blinding
Method of Treatment Assignment 
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study treatment arms. Participants will be assigned 
randomly in a 1:1 ratio to IMI/REL (Treatment Group 1; N=135) or PIP/TAZ (Treatment 
Group 2; N= 135), respectively.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Pneumonia type at baseline: non-ventilated HABP vs ventilated HABP/VABP
2. APACHE II score at baseline: <15 vs ≥15
Participants will be stratified by factors (as noted above) that are most likely to impact 
mortality outcomes. This will be done in order to balance treatment assignment within each 
stratum level and for increased efficiency of the statistical analysis.
In addition, the randomization will be controlled by quotas built into the IRT such that a 
minimum of 25% of randomized participants are in the ventilated HABP/VABP stratum.
Blinding 
A double-blinding technique will be used. IMI/REL and PIP/TAZ will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or unblinded qualified study site 
personnel. The participant and the investigator who is involved in the study treatment 
administration or clinical evaluation of the participants are unaware of the group 
assignments.
Study therapy supplies will be provided in an open-label fashion to the sites; hence an 
unblinded study staff (eg, pharmacist or qualified designee) at the study site will be 
responsible for preparing the IV study therapy for this study; this individual(s) must not be 
involved in any safety or efficacy evaluations of the study participants and needs to consult 
the most current renal function prior to dispensing each dose. Due to a visual difference in 
the appearance of study treatment solutions, the infusion bags will be covered with an opaque 
sleeve by the unblinded study staff (eg, pharmacist or qualified designee) to ensure that other 
study personnel and all participants remain blinded to clinical material assignments. The 
intravenous line (through which the infusion is administered) does not require opaque 
covering since the differences between the clinical materials are not visually distinguishable 
within the tubing. Once each infusion bag is properly prepared and masked with an opaque 
sleeve, the study therapy will be administered by qualified trial site personnel. The personnel 
involved in the administration of the study infusion treatment should be unaware of the 
treatment group assignments. The participant, the investigator and Sponsor personnel or 
delegate(s) who are involved in the treatment or clinical evaluation of the participants are 
unaware of the group assignments.
As the study may enroll participants without confirmed microbiological (culture) evidence of 
the HABP/VABP pathogen on a lower respiratory tract specimen at study entry, participants 
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will receive treatment with open-label IV linezolid for MRSA infection beginning at 
randomization.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
Treatment Compliance
Administration of trial medication will be performed by the blinded qualified trial site 
personnel.
Interruptions from the protocol specified treatment totaling ≥4 doses of IV study therapy 
during the first 7 days of therapy OR ≥4 doses of IV study therapy during Days 8 to 14 of 
therapy require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on participant management.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during IV study therapy. If there is a clinical indication for any medication or vaccination
specifically prohibited, discontinuation from study treatment may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant's primary physician. However, the decision to continue the participant on 
study treatment requires the mutual agreement of the investigator, the Sponsor and the 
participant.
The following concomitant medications/therapies are not permitted during IV study therapy:
1. Immunosuppressive agents (>40 mg/d prednisolone equivalent dose continuously 
administered for ≥7 days) (including chemotherapy
NOTE: Short-term treatment with systemic (IV or oral) steroids of <7 days duration (eg, 
treatment for an acute asthma exacerbation or acute skin condition) is allowed. Topical 
steroids for the treatment of skin conditions are also allowed.
2. Valproic acid or divalproex sodium
3. Serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor 
agonists (triptans)(during treatment with linezolid)
4. MAOIs (during treatment with linezolid and the 2 weeks prior to screening)
5. Meperidine (during treatment with linezolid)
6. Buspirone (during treatment with linezolid)
7. Dopaminergic agents (during treatment with linezolid)
8. Non-study systemic (IV or oral), inhaled, or intrapleural antibacterial treatments
NOTE: As noted in Section 6.1, the use of initial empiric treatment with IV linezolid for 
MRSA infection is required. The recommended treatment duration for a confirmed 
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MRSA infection is a minimum of 7 days. Participants with MRSA bacteremia should 
receive 14 days of therapy. Empiric linezolid treatment will be stopped if the final culture 
results from the baseline lower respiratory tract and/or blood sample do not demonstrate 
the presence of MRSA.
9. Systemic (IV or oral) antifungal or antiviral therapy for the index infection of 
HABP/VABP
10. Traditional Chinese Medicine or herbal medicine
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
Dose Modification 
No dose modifications are planned for this study.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This study is blinded but supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study treatment 
identity (name, strength or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind participants and to unmask study treatment identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic treatment allocation/randomization system (IRT) should be used in 
order to unblind participants and to unmask study treatment identity. The Sponsor will not 
provide random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
Standard Policies
For studies using Controlled Substances, all Federal, State, Province, Country, etc. 
regulations must be adhered to in regard to the shipping, storage, handling and dispensing of 
controlled substances. Additionally, the investigator should have the appropriate controlled 
drug license(s) as mandated by Federal, State, Province, Country, etc. laws in which the 
study is being conducted.
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7. Discontinuation of Study Treatment and Participant Withdrawal
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment. Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 1.3 and Section 8.10.3.
Participants may discontinue study treatment at any time for any reason or be discontinued
from the study treatment at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study treatment by the investigator 
or the Sponsor if study treatment is inappropriate, the study plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study treatment discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study treatment 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 treatment.
o
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary or through the emergency unblinding call center.
o
Any of the following post-baseline elevations in liver transaminase levels:

In participants without baseline transaminase elevations:
o
ALT or AST ≥8 X ULN.
o
ALT or AST ≥3 X ULN, accompanied by total bilirubin >2 X ULN OR INR 
>1.5.
o
ALT or AST ≥3 X ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever (defined as body temperature ≥38.0°C), 
rash, and/or eosinophilia (>5%).

In participants with baseline transaminase elevations:
o
Further increase in transaminases to ≥8 X ULN (with at least 50% increase 
from transaminase values collected at randomization [Day 1]) that is not 
anticipated from their underlying medical condition.
o
ALT or AST ≥3 X ULN (with at least 50% increase from transaminase values 
collected at randomization [Day 1]) and new onset of clinical signs and 
symptoms of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever (defined as body temperature ≥38.0°C), rash, and/or eosinophilia (>5%).
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o
Clinically significant worsening of liver function associated with further 
transaminase elevations in a participant with abnormal transaminase levels 
already meeting the above criteria (ie, ≥8X ULN [with at least 50% increase 
from transaminase values collected at randomization (Day 1)]; ALT or AST 
≥3 X ULN [with at least 50% increase from transaminase values collected at 
randomization (Day 1)] and new onset of clinical signs and symptoms listed) at 
baseline
o
A post-baseline decline in estimated or actual creatinine clearance to a value of less than 
15 mL/min.
o
The participant requires initiation of hemodialysis or peritoneal dialysis.
o
The participant has a confirmed positive serum pregnancy test.
o
A physician investigator feels it is in best interest of the participant to discontinue for any 
reason, including, but not limited to, the need for alternative non-study antibacterial 
therapy. If while on study medication isolates are found to be resistant to 
piperacillin/tazobactam and the patient is not improving clinically, the patient should be 
discontinued from study medication in order to initiate appropriate alternative treatment. 
Consultation with the Sponsor physician is encouraged.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
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 treatment 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.
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.
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
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.

Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant. The missing data for the participant will be managed 
via the prespecified statistical data handling and analysis guidelines.
8. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed approximately 100 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating in this clinical. If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
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investigator or qualified designee must ensure the appropriate documented informed consent 
is in place.
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant (or their 
legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF and any written information provided to the 
participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s 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 form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
As allowable by local regulations in Russia, the consent may be provided by a council of 
healthcare professionals for deciding on the possibility of inclusion of a patient in the clinical 
study or signed by an authorized designee per local regulations or requirements, including 
but not limited to independent physicians qualified to provide consent for patients who are 
unable to provide consent for themselves. In these circumstances, special care must be taken 
to ensure consent is consistent with all local laws and regulations and that patients (if/when 
they are able to provide consent for themselves) or their Legally Acceptable Representative
(when available) are reconsented.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain study site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
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Card immediately after the participant provides documented informed consent. At the time of 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
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 eCRF.
Any history of prior HABP or VABP episodes or conditions that may predispose a 
participant to the development of a pulmonary infection 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.
A full evaluation of the current primary diagnosis (HABP/VABP) will also be performed.
The details of the HABP/VABP diagnosis will be documented separately on the appropriate 
eCRF(s).
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 14 days before starting the trial.
Following a diagnosis of HABP/VABP and prior to the receipt of first dose of IV study
therapy, participants may receive no more than 48 hours’ worth (for example, >2 dose of a 
once-daily antibiotic, >4 doses of a twice-daily antibiotic) of active non-study antibiotic 
therapy in the 72 hours preceding the first dose of IV study therapy for treatment of the 
current index infection.
Participants who have failed prior antibiotic therapy for the current episode of HABP/VABP
(ie, have persistent/worsening signs and symptoms at the time of screening) may be
considered for enrollment provided the prior antibiotic was given for at least 48 hours before
a diagnosis of clinical failure was made and the prior respiratory or blood culture did not
grow only S. aureus (methicillin-susceptible S. aureus [MSSA] or methicillin-resistant 
S. aureus [MRSA]). For such participants, the baseline lower respiratory tract culture must be 
obtained while the participant is on the failing antibiotic therapy and before the participant
receives the first dose of IV study therapy. Following collection of the baseline lower 
respiratory tract culture, only IV study therapy is permitted in these participants.
Participants receiving prior therapy with a non-absorbed antibiotic used for gut 
decontamination (ie, low dose erythromycin or polymyxin) or to eradicate C. difficile (oral 
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vancomycin or fidaxomicin) are eligible for enrollment, irrespective of duration of prior 
antibacterial therapy.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
Since the study will enroll participants without confirmed microbiological (culture) evidence 
of the HABP/VABP pathogen from a lower respiratory tract specimen at study entry, the use 
of initial empiric treatment with open-label IV linezolid (600 mg q12h) for MRSA infection 
is required. The recommended treatment duration for a confirmed MRSA infection is a 
minimum of 7 days. Participants with MRSA bacteremia should receive 14 days of therapy.
Empiric linezolid treatment will be stopped if the final culture results from the baseline lower 
respiratory tract and/or blood sample do not demonstrate the presence of MRSA.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization or treatment 
allocation. Each participant will be assigned only one screening number. Screening numbers 
must not be re-used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Rescreening of an individual participant for enrollment is not expected to occur commonly.
However, any participant who is screened multiple times will retain the original screening 
number assigned at the initial screening visit. Specific details on the screening visit 
requirements (screening/rescreening) are provided in Section 8.10.1.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
Administration of study medication will be witnessed by the investigator and/or study staff.
The first dose of prescribed study therapy should be administered at the Day 1 visit (detailed 
procedures please refer to Section 1.3 – SoA). The unblinded study staff (eg, pharmacist or 
qualified designee) will contact the IRT for assignment of the study therapy to be 
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administered. Sites should not call the IRT for drug administration until the participant has 
met all entry criteria for the study and is ready to be randomized.
Timing of Dose Administration
The frequency of administration will be every 6 hours, regardless of dose adjustments for 
renal insufficiency (Table 2 and Table 3). Each infusion should be administered within 60 
minutes of the scheduled dose. 
IMI/REL (Treatment Group 1) and PIP/TAZ (Treatment Group 2) should be administered by 
the blinded investigator and/or blinded trial staff over 30 minutes ±10 minutes. The study 
therapy must NOT be administered simultaneously through the same infusion line/lumen
with any other drugs (including IV non-study drugs). If another IV drug is required either 
prior to or after study drug and only 1 line/lumen is available, an appropriate volume of 
saline flush must be used between IV infusions.
IV study therapy should be administered for a minimum of 7 full days to up to a maximum of 
14 days. Participants with evidence of concurrent bacteremia or with P. aeruginosa infection 
should receive 14 days of IV study therapy.
Additional details for preparation and administration of study drug are provided in a separate 
Pharmacy Manual.
Linezolid Therapy Administration
Since the study will enroll participants without confirmed microbiological (culture) evidence 
of the HABP/VABP pathogen from a lower respiratory tract specimen at study entry, the use 
of initial empiric treatment with open-label IV linezolid (600 mg q12h) for MRSA infection 
is required. The recommended treatment duration for a confirmed MRSA infection is a 
minimum of 7 days. Participants with MRSA bacteremia should receive 14 days of therapy.
Empiric linezolid treatment will be stopped if the final culture results from the baseline lower 
respiratory tract and/or blood sample do not demonstrate the presence of MRSA.
Each infusion should be administered within 60 minutes of the scheduled dose. Linezolid 
should be administered by the blinded investigator and/or blinded trial staff over 30 to 120
minutes ±10 minutes. Linezolid therapy can be administered concomitantly with IV study 
therapy, at those time points where there is administration overlap; however, the IV study 
therapy and IV linezolid therapy must NOT be administered simultaneously through the 
same infusion line/lumen.
Discontinuation and Withdrawal
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Day 28 visit should be performed (at the time of withdrawal). Any AEs
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which are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
Overall survival status at Day 28 post-randomization or later will be assessed among all 
participants according to procedures outlined in the ICF. 
Participant Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND THE PARTICIPANT UNLESS 
NECESSARY.
For emergency situations where the investigator or delegate needs to identify the drug used 
by a participant and/or the dosage administered, he/she will contact the emergency 
unblinding call center by telephone and make a request for emergency unblinding. As 
requested by the investigator or delegate the emergency unblinding call center will provide 
the information to him/her promptly and report unblinding to the Sponsor. Prior to contacting 
the emergency unblinding call center to request unblinding of a participant’s treatment 
assignment, the investigator or delegate should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study drug, the reason thereof, etc., in the 
medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. 
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator/delegate 
and/or nonstudy treating physician must be discontinued from study drug, but should 
continue to be monitored in the study.
Additionally, the investigator must go into the IRT system and perform the unblind in the 
IRT system to update drug disposition. In the event that the emergency unblinding call center 
is not available for a given site in this study, the IRT system should be used for emergency 
unblinding in the event that this is required for participant safety.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
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Documentation of equipment calibration must be retained as source documentation at the 
study site.
Efficacy Assessments 
Survival Assessment
For each participant, survival status (ie, whether the participant is alive or dead) will be 
assessed at Day 28 post-randomization to support the primary endpoint of all-cause mortality 
at Day 28. Results of the assessment, including date and cause of death if relevant, will be 
recorded on the appropriate eCRF.
Clinical Response
Clinical signs and symptoms of infection (eg, cough, dyspnea, fever, etc.) will be assessed at 
visits specified in Section 1.3 - SoA in support of determination of a clinical response rating 
for each participant. A detailed list of disease-specific signs and symptoms in support of 
evaluation of the clinical response rating are included in Section 8.2.2.1, Table 7.
Based on comparison to baseline clinical signs and symptoms of the participant’s infection, 
the investigator will determine and record the clinical response rating at each visit as 
described in Table 4 (for OTX1, OTX2, and OTX3 visits), Table 5 (for EOT visit), and 
Table 6 (for EFU and Day 28 post-randomization visits).
The clinical response rating determined by the investigator at each visit will be categorized as 
“favorable” or “unfavorable,” as described in the footnote of each table describing clinical 
response.
Table 4
Definitions of the Clinical Response Rating at the OTX Visits (Day 3, Day 6 and 
Day 10 of IV Study Therapy)
Clinical Responsea
Response Definition
Improved
The majority of pre-therapy signs and symptomsb of the index infection have 
improved or resolved (or returned to "pre-infection status") 
Persistence
Little apparent response to IV study therapy in pre-study signs and symptomsb of the 
index infection(s): persistence of the majority of or all pre-therapy signs and 
symptoms.
Progression
Worsening of response while on IV study therapy in pre-study signs and symptomsb
of the index infection(s): progression of the majority of or all pre-therapy signs and 
symptoms.
Indeterminate
Study data are not available for evaluation of clinical response for any reasons at the 
OTX1, OTX2 or OTX3 visit, 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 for any reason; OR
c)
Extenuating circumstances (eg, a major protocol violation) preclude 
classification as "improved," "persistence,” or “progression;” OR
d)
Death occurred during the study period and the index infection was clearly 
noncontributory.
a
A favorable clinical response at OTX1, OTX2, or OTX3 requires an assessment of “improved”.
b 
Refer to Inclusion Criterion #2 for a description of relevant clinical signs and symptoms.
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Table 5
Definitions of the Clinical Response Rating at the EOT Visit
Clinical Responsea
Response Definition
Cure
All pre-therapy signs and symptomsb of the index infection have resolved (or 
returned to "pre-infection status") AND no additional antibiotic therapy is 
required for the index infection.
Improved
The majority of pre-therapy signs and symptomsb of the index infection have 
improved or resolved (or returned to "pre-infection status") AND no additional 
antibiotic therapy is required.
Failure
No apparent response to IV study therapy in pre-study signs and symptomsb of the 
index infection: persistence or progression of the majority of or all pre-therapy 
signs and symptoms.
Indeterminate
Study data are not available for evaluation of clinical response for any reasons at 
the EOT visit, 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 for any reason; OR
c)
Extenuating circumstances (eg, a protocol violation) preclude classification as 
"cure," "improved," or "failure;" OR
d)
Death occurred during the study period and the index infection was clearly 
noncontributory.
a
A favorable clinical response at EOT requires an assessment of “cure” or “improved”.
b
Refer to Inclusion Criterion #2 for a description of relevant clinical signs and symptoms.
Table 6
Definitions of the Clinical Response Rating at the EFU Visit and Day 28 Post-
Randomization Visit
Clinical Responsea,
Response Definition
Sustained Cure
All pre-therapy signs and symptomsb of the index infection have resolved (or 
returned to "pre-infection status") with no evidence of resurgence AND no additional 
antibiotic therapy was required for the index infection.
Cure
All pre-therapy signs and symptomsb of the index infection have resolved (or 
returned to "pre-infection status") AND no additional antibiotic therapy is required 
for the index infection.
Failure
No apparent or insufficient response to IV study therapy in pre-study signs and 
symptoms of the index infection: persistence, progression, or improvement (without 
full resolution) of all pre-therapy signs and symptomsb
Relapse
Participants with a favorable clinical response (cure or improved) at the EOT visit 
have worsening signs and symptomsb of the index infection by the EFU or Day 28 
post-randomization visit.
Indeterminate
Study data are not available for evaluation of efficacy for any reasons, 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, a major protocol violation) preclude 
classification as "sustained cure," "failure," or "relapse;" OR
d)
Death occurred during the study period and the index infection was clearly 
noncontributory.
a
A favorable clinical response at EFU or Day 28 post-randomization 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 Inclusion Criterion #2 for a description of clinical signs and symptoms.
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Clinical Signs and Symptoms
A detailed diagnosis as well as relevant clinical information associated with the 
HABP/VABP diagnosis including clinical signs and symptoms, radiographic and laboratory 
characteristics related to the participant’s infection will be reviewed and documented on the 
appropriate eCRFs at time points specified in Section 1.3 – SoA.
In particular, clinical signs and symptoms specific to the index infection for this study are 
based predominantly on criteria outlined in Inclusion Criterion #2 (Section 5.1) and are 
summarized in Table 7 below. Presence or absence of these symptoms will be recorded daily 
while on IV study therapy and at visits as specified in Section 1.3 – SoA. Intensity of signs 
and symptoms will also be graded by the investigator as mild, moderate, or severe (see 
Appendix 4). Collection at randomization (Visit 2) should be performed prior to initiation of 
IV study therapy.
Table 7
Infection-Site Clinical Signs and Symptoms
Infection Site
Clinical Signs and Symptoms
HABP/VABP

Cough

Dyspnea

Tachypnea (eg, respiratory rate greater than 25 breaths per minute)

Expectorated sputum production

Requirement for mechanical ventilation

New onset of suctioned respiratory secretions

Chills/rigors

Chest pain or chest tenderness

Fever (body temperature ≥38 degrees Celsius)

Hypothermia (body temperature ≤35 degrees Celsius)
Microbiological Response
Microbiological response will be evaluated separately for each lower respiratory tract 
pathogen isolated in the baseline culture (ie, by-pathogen). The by-pathogen response rating 
determined by the investigator will be assessed based on local laboratory results. 
A by-pathogen microbiological response rating will be determined by the investigator at 
EOT, and EFU visits based on the results of lower respiratory tract cultures collected for 
participants at each of these visits relative to the pathogen(s) isolated at baseline/admission as 
described in Table 8 (for EOT visit) and Table 9 (for EFU visit). As described in 
Section 8.2.4, lower respiratory tract 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).
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The overall microbiological response (ie, overall microbiological response for the participant
based on the response of all pathogens present in the baseline lower respiratory tract culture) 
will be assessed as “favorable” or “unfavorable,” as described in the tables describing 
microbiological response. For participants from whom only 1 pathogen is isolated in the 
baseline lower respiratory tract culture, the overall microbiological response assessment will 
be based on the microbiological response rating for that pathogen. For randomized 
participants from whom more than 1 baseline pathogen is isolated in the baseline lower 
respiratory tract culture, the overall microbiological response outcome will be based on 
microbiological culture results for all pathogens (ie, a “favorable” overall microbiological 
response requires eradication of all baseline pathogens). 
Antibiotic susceptibility results from the Central Microbiology Lab, as well as 
microbiological response, will be summarized by pathogen. The by-pathogen 
microbiological response rating determined by the investigator at each EOT and EFU visits 
will be utilized to categorize the overall microbiological response.
Table 8
Definitions of the By-Pathogen Microbiological Response Rating at the EOT 
Visit
Microbiological 
Responsea,b
Response Definition
Eradication
A lower respiratory tract culture taken at the EOT visitc shows eradication of the 
pathogen found at study entry.
Presumed Eradication
No specimen taken because subject is deemed clinically cured or improved.
Persistenced
A lower respiratory tract culture taken at the EOT visitc grows the pathogen 
found at study entry.
Superinfection
A lower respiratory tract culture grows a pathogen other than a baseline 
pathogen at the EOT visit.c
Indeterminate
a)
Follow-up culture is not available at the EOT visitc due to participant death 
or withdrawal from study; OR
b)
Available microbiological data are incomplete; OR
c)
Extenuating circumstances (eg, a major protocol violation) preclude 
microbiological assessment; OR
d)
Any other circumstance which makes it impossible to define the 
microbiological response
a
A microbiological response rating must be completed separately for each pathogen isolated at baseline. If a 
new/emergent pathogen is identified at this visit that was not identified at baseline, the microbiological response 
rating should be recorded as “superinfection.”
b
A favorable by-pathogen microbiological response at EOT requires “eradication” or “presumed eradication” of the 
baseline pathogen.
c
If a culture is not available at EOT, an assessment at this visit can be made from the last available culture which 
was collected after at least 72 hours of IV study therapy.
d
If a participant is discontinued from IV study therapy due to clinical failure (ie, unfavorable clinical response), but 
persistence of the baseline pathogen is not confirmed by culture results or no culture is obtained at the time of 
clinical failure, the baseline pathogen will be presumed to have persisted.
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Table 9
Definitions of the By-Pathogen Microbiological Response Rating at the EFU Visit
Microbiological 
Responsea,b
Response Definition
Eradication
A lower respiratory tract culture taken at the EFUc visit shows eradication of the 
pathogen found at study entry.
Presumed Eradication
No specimen taken because subject is deemed clinically cured or improved.
Persistence
A lower respiratory tract culture taken at the EFU visit grows the pathogen 
found at study entry.
New Infection
A lower respiratory tract culture grows a pathogen other than a baseline 
pathogen at the EFU visit.d
Recurrence
A lower respiratory tract specimen grows the baseline pathogen taken at EFU 
visit after documented eradication. 
Indeterminate
a)
Follow-up culture is not available at the EFU visit due to participant death 
or withdrawal from study; OR
b)
Available microbiological data are incomplete; OR
c)
Extenuating circumstances (eg, a major protocol violation) preclude 
microbiological assessment; OR
d)
Any other circumstance which makes it impossible to define the 
microbiological response
a
A microbiological response rating must be completed separately for each pathogen isolated at baseline. If a 
new/emergent pathogen is identified at this visit that was not identified at baseline, the microbiological response 
rating should be recorded as “new infection.” 
b
A favorable by-pathogen microbiological response at EFU visit requires “eradication” or “presumed eradication” of 
the baseline pathogen.
c
If a culture is not available at EFU, 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 end of IV therapy and before the EFU visit and provided the 
participant had fully resolved clinical symptoms/signs of the index infection at the EFU visit.
d        If a culture is not available at EFU, an assessment can be made based on a culture collected at the EOT visit as long 
as it was collected at least 24 hours after the end of IV therapy and before the EFU visit.
Culture and Susceptibility Testing
Lower Respiratory Tract Sample Collected at Baseline
A lower respiratory tract sample will be obtained at baseline for Gram stain, culture and 
susceptibility testing from infection site prior to initiation of IV study therapy for all 
participants. A previously obtained culture is acceptable if it was obtained within 2 days (48 
hours) of the screening visit. Culture and susceptibility should be performed at the local 
microbiology laboratory.
Microscopic examination of Gram-stained smears must be performed prior to randomization 
to ensure the adequacy of the specimen and to exclude participants with gram-positive cocci 
only detected. For specimens obtained by direct sampling of the lower respiratory tract (ie, 
sampling via BAL, mini BAL or PBS), no predefined requirements are required to ascertain 
the quality of the respiratory specimen. However, for specimens not obtained by direct 
sampling of the lower respiratory tract, such as those obtained by expectorated sputum, the 
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low-power microscopic view of the Gram stain can be used to ascertain the quality of the 
respiratory specimen which 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 per low power field of Gram stains is an example of an 
adequate expectorated/suctioned sputum specimen; white blood cell [WBC] counts of greater 
than 25 per low power field of Gram stains are acceptable in place neutrophils). 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 Gram stain and culture at the local microbiology 
laboratory according to recognized methods and per each laboratory's standard procedures.
In addition to local laboratory testing, a pure isolate of any suspected causative 
bacterial pathogen(s) must be submitted to the Central Microbiology Reference 
Laboratory. Suspected causative bacterial pathogens should also be stored at the local 
laboratory for possible future testing.
The available data from the Gram stain and culture specimen, including date of collection, 
specimen type (including method of collection), and pathogen identification (to the species 
level, if identified) must be collected on the appropriate eCRF forms.
Additional details regarding bacterial specimen collection, processing, handling, and 
shipment will be provided by the Sponsor in a separate microbiology laboratory manual.
Other Lower Respiratory Tract Samples Following Randomization
Culture from the lower respiratory tract site, including susceptibility testing of any identified 
pathogens on culture, should also be performed at the EOT and EFU visits as outlined in 
Section 1.3 – SoA; cultures are not required at EOT or EFU if subjects is considered 
clinically cured (‘cure,’ ‘improved’ or ‘sustained cure).’ Lower respiratory tract 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).
In addition, at other times during the study, lower respiratory tract samples may also be 
collected if there is clinical or laboratory evidence of persistence or progression of the 
infectious process (including persistent fever, elevated white blood cell 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).
All culture and susceptibility should be performed at the local microbiology laboratory 
following the same standard procedures as used for the baseline lower respiratory tract 
sample. In addition, a pure isolate of any suspected causative bacterial pathogen(s) must 
be submitted to the Central Microbiology Reference Laboratory. Suspected causative 
bacterial pathogens should also be stored at the local laboratory for possible future 
testing, if needed.
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The available data from the Gram stain and culture specimen, including date of collection, 
specimen type (including method of collection), and pathogen identification (to the species 
level, if identified) must be collected on the appropriate eCRF forms.
Additional details regarding bacterial specimen collection, processing, handling, and 
shipment will be provided by the Sponsor in a separate microbiology laboratory manual.
Blood Cultures
On either Screening or Day 1, two sets of blood cultures, from 2 separate venipunctures (or 1 
venipuncture and 1 catheter) sites must be collected in all participants prior to initiation of IV 
study therapy. A culture obtained within 48 hours prior to the randomization visit is 
acceptable, as long as the blood cultures collected meet the protocol requirement, ie, 2 sets of 
blood cultures, from 2 separate venipunctures (or 1 venipuncture and 1 catheter). Participants 
with positive blood cultures at screening should have follow-up blood cultures collected as 
clinically indicated until 2 consecutive cultures demonstrate no growth. Follow-up blood 
cultures in participants with no evidence of bacteremia (ie, positive blood cultures) at study 
entry should also be performed, at the investigator discretion, as clinically indicated.
Blood culture and susceptibility will be performed at the local microbiology laboratory 
according to recognized methods and per each laboratory's standard procedures. In addition,
any suspected causative bacterial pathogen must be collected and available for submission to
the Central Microbiology Reference Laboratory. Suspected causative bacterial pathogens
should also be stored at the local microbiology laboratory if possible future testing is needed.
Relevant culture data, including date of collection, specimen type (including method of 
collection), and pathogen identification (to the species level, if identified) must be collected 
on the appropriate eCRF forms.
Other Relevant Culture Samples
During the study, other pulmonary samples, including pleural fluid or direct lung samples, or 
samples from other distant sites of infection may also be collected if there is clinical or 
laboratory evidence of persistence or progression of the infectious process (including 
persistent fever, elevated white blood cell count, or significant changes in the participant’s 
clinical condition). In general, for any pulmonary procedure, specimens should also be 
collected at any time of surgical or drainage procedure (if required).
In these situations, relevant culture data, including 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.
Chest X-Ray
A baseline chest x-ray should be performed in all participants prior to initiation of IV study 
therapy on the Day 1 (Randomization) visit and at other visits as specified in Section 1.3 -
SoA. A baseline chest x-ray at randomization is not required if a prior chest x-ray was 
performed in association with the current infection within 2 days (48 hours) of 
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randomization. CT scans obtained within 48 hours of randomization can be used in place of 
the baseline chest x-ray if a scout view or similar view can be produced. A CT scan obtained 
at the Screening Visit is acceptable for entry if local clinical practice requires a CT scan for 
HABP/VABP diagnosis. Post-baseline, chest x-rays must be performed at subsequent visits,
as indicated in the SoA. Scout view data from CT scans performed for non-study purposes 
can be used in place of chest x-ray assessments post-baseline.
Chest x-ray results at baseline (prior to initiation of IV study therapy) and at indicated 
follow-up visits including a description, location, and extent of infiltrates or consolidation 
must be documented on the appropriate eCRF(s). The presence of a pleural effusion and 
other abnormalities associated with disease-related complications should also be noted on the 
appropriate eCRF(s).
PaO2/FiO2 or O2 Saturation
PaO2 and FiO2 should be measured by arterial blood gas (ABG) determination and oxygen 
saturation should be determined by pulse oximetry or by ABG.
For ventilated participants who have an existing arterial line in place, PaO2 and FiO2 should 
be measured by ABG on Day 1, Day 3 (OTX1), Day 6 (OTX2), and Day 10 (OTX3, if 
applicable) of IV study therapy, and at the EOT, EFU, and Day 28 post-randomization visits.
On all other days while on IV study therapy, oxygen saturation via pulse oximetry should be 
measured daily.
For non-ventilated participants or ventilated participants who do not have an existing arterial 
line in place, oxygen saturation via pulse oximetry should be measured daily while on IV 
study therapy and at the EOT, EFU, and Day 28 post-randomization visits.
All measured values for PaO2, FiO2, or oxygen saturation should be documented on the 
appropriate eCRFs.
Infection Source Control Review
Information related to infection source control must be collected for all participants at the 
visits specified in Section 1.3 – SoA.
Source control includes the following: (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, or 
(c) details regarding a thoracentesis procedure to drain any accompanying pleural fluid.
Relevant information regarding infection source control should be documented on the 
appropriate eCRF.
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
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the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
All physical examinations must be performed by the principal investigator or sub-
investigator (physician, physician assistant or nurse practitioner).
A full physical examination, performed at randomization, includes the following 
assessments: general appearance, head, eyes, ears/nose/throat, neck, lymph nodes, skin, 
lungs, heart, abdomen, musculoskeletal, and neurologic evaluations. Breast, rectal, and 
genitourinary/pelvic exams should be performed when clinically indicated. If a physical 
examination was performed within 72 hours prior to screening, those results can be recorded 
and a repeat physical examination is not required. Any abnormal or clinically significant 
findings from the physical examinations must be recorded on the appropriate eCRF.
After the initial full physical examination, a physical examination targeted to the 
participant’s illness and complaints will be performed at subsequent visits as specified in 
Section 1.3 –SoA.
Height and Weight
The participant’s height and weight should be measured prior to initiation of IV study 
therapy at the randomization (Day 1) visit. Collection at randomization (Visit 2) should be 
performed prior to initiation of IV treatment.
Vital Signs
Vital signs should be collected daily while on IV study therapy and at other time points/visits 
as specified in Section 1.3 – SoA. Collection at randomization (Visit 2) should be performed 
prior to initiation of IV therapy.
For this study, vital signs include heart rate (HR), blood pressure (BP), respiratory rate (RR), 
and oral temperature. Participants should be resting in a seated or semi-recumbent position 
for at least 10 minutes prior to having vital sign measurements obtained. For participants who 
are intubated and cannot sit up, HR, BP, and RR may be taken in a supine or semi-recumbent 
position. Oral temperatures should be taken, but if oral is not possible, tympanic, rectal, or 
axillary methods are acceptable.
Any abnormal or clinically significant vital signs findings must be recorded on the 
appropriate eCRF.
     
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Clinical Safety Laboratory Assessments
Refer to Appendix 5 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
case report form (CRF). The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 5, 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 1 day after the last dose of study treatment, 
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. 
Laboratory Monitoring for Liver Function
Participants’ liver function should be closely monitored during the study execution, please 
refer to Section 7.1 (Discontinuation of Study Treatment) for details regarding liver function 
monitoring.
Local Laboratory Monitoring for Renal Function
Safety laboratory results from the central laboratory will likely not be available in a timely 
fashion to impact on an individual participant’s medical management. Therefore, additional 
laboratory tests required for adequate medical management of individual study participants 
should be obtained as indicated by the primary physician and submitted to the local 
laboratory for testing in the medically appropriate timeframe.
Specifically, for the purpose of monitoring an individual participant’s renal function in “real 
time,” a creatinine assessment should be performed at the local laboratory on Days 1, 3, 6, 
and 10 (if applicable) during IV study therapy in addition to the chemistry safety panel 
performed at the central laboratory. For participants with renal insufficiency or whose 
creatinine clearance changes during treatment with study therapy (refer to Table 2 and 
Table 3 in Section 6.2.1), the dose of study drug must be adjusted based upon the degree 
of renal function impairment as determined by the estimated or actual creatinine 
clearance.
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Results of these local laboratory tests must be documented in the appropriate eCRF.
Laboratory abnormalities resulting in an adverse event or dose adjustment should also be 
collected on the appropriate eCRF. Any laboratory test abnormality that emerged during 
study therapy and was considered by the investigator to be an adverse event or event of 
clinical interest should be repeated until the abnormal value has normalized, stabilized, or 
returned to baseline.
APACHE II Score
Severity of illness in this study will be determined by APACHE II score at screening [Knaus, 
W. A., et al 1985]. See Appendix 6 for details regarding the calculation of this score. Results 
of APACHE II score calculations must be entered on the appropriate eCRF(s).
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs, and other reportable safety events for outcome according to Section 8.4.3.
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 before treatment allocation/randomization must be reported by 
the investigator 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 treatment allocation/randomization through the Day 28 post-randomization 
visit, all AEs, SAEs and other reportable safety events must be reported by the investigator. 
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a
death, at any time after a participant has been discharged from the study, and he/she 
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considers the event to be reasonably related to the study treatment 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.
Table 10
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Time Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Consent to 
Randomization/ 
Allocation
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
After the Protocol 
Specified Follow-up 
Period
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential drug-
induced liver 
injury (DILI)
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
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Type of Event
Time Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Consent to 
Randomization/ 
Allocation
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
After the Protocol 
Specified Follow-up 
Period
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
Overdose
Not applicable
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
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 AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
Cancer and Overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 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 towards the safety of 
participants and the safety of a study treatment 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 treatment under clinical 
investigation. All AEs will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R2) Guidelines for GCP.
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●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Events of Clinical Interest (ECIs)
Selected nonserious and serious adverse events are also known as ECIs and must be reported 
to the Sponsor.
Events of clinical interest for this study include: 
1.
an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
2.
a confirmed (ie, verified by repeat testing) elevated AST or ALT laboratory value 
that is greater than or equal to 5 X ULN as a result of within-protocol-specific 
testing or unscheduled testing.
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NOTE: In participants with pre-existing elevations in transaminase values, only a further 
elevation that is not anticipated from an underlying medical condition will be considered 
an ECI. These events may require an additional evaluation for an underlying etiology.
The trial site guidance for assessment and follow up of these criteria can be found in the 
Investigator Trial File Binder.
3.
An overdose of Sponsor’s product, as defined in Section 8.5 – Treatment of 
Overdose, that is not associated with clinical symptoms or abnormal laboratory 
results.
Local Infusion Site Tolerability Monitoring
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. All events should be documented on the appropriate eCRF.
Treatment of Overdose
In this study, an overdose in IV study therapy is defined as (1) administration of a total daily 
dose of IMI/REL in excess of 4 g (IMI) or 2 g (REL) OR (2) administration of a total daily 
dose of PIP/TAZ greater than 16 g (PIP) and 2 g (TAZ).
In this study, an overdose in linezolid is defined as administration of a total daily dose of 
linezolid in excess of 1200mg.
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.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a non-serious adverse event, unless other serious 
criteria are met. This must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious adverse event using the terminology “accidental or intentional 
overdose without adverse effect.” This must be reported by the investigator within 5 calendar 
days of learning of event to the Sponsor either by electronic media or paper.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
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Pharmacokinetics
PK parameters will not be evaluated in this study.
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
Biomarkers
Biomarkers are not evaluated in this study.
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
Future Biomedical Research Sample Collection 
Future biomedical research samples will not be collected in this study.
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
Screening
Approximately 2 days (48 hours) prior to treatment allocation/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.
Rescreening of an individual participant for enrollment is not expected to occur commonly.
Screening procedures may be repeated in some circumstances but only after consultation
with the Sponsor.
Treatment Period
IV study therapy should be administered for a minimum of 7 full days to up to a maximum of 
14 days. Participants with evidence of concurrent bacteremia or with P. aeruginosa 
infections should receive 14 days of IV study therapy.
For participants who receive 7 to 9 days of IV study therapy, Day 10 (OTX3 [Visit 5]) will 
not be completed. Assessments and procedures while on IV study therapy will be completed 
at the indicated times and intervals as per Section 1.3 – SoA. The EOT visit for participants 
who receive 7 to 9 days of therapy will be completed within 24 hours after the last dose of IV 
study therapy on Day 7, Day 8, or Day 9 followed by the subsequent post-treatment visits as 
indicated in Section 1.3 – SoA.
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Participants receiving IV study therapy through Day 10 and up to Day 14 will complete all 
OTX visits (OTX1 on Day 3, OTX2 on Day 6, and OTX3 on Day 10). Assessments and 
procedures while on IV study therapy will be completed at the indicated times and intervals 
as per Section 1.3 – SoA. The EOT visit will be completed within 24 hours after the last dose 
of IV study therapy on Day 10, 11, 12, 13, or 14 followed by the subsequent post-treatment 
visits as indicated in Section 1.3 – SoA. Participants who end treatment on Day 10 will have 
a combined OTX3 and EOT visit. All procedures required for each visit must be completed 
for the combined visit. Procedures that are common to both visits would only be assessed 
once.
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study treatment prior to completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits.
Poststudy
An EFU visit (7 to 14 days after the cessation of IV study therapy [ie, 7 to 14 days after 
EOT]) and a Day 28 post-randomization visit must be completed for each participant.
Depending on the total duration of IV study therapy, the EFU and Day 28 post-
randomization visit may be combined into a single visit. These visits may only be combined 
as long as compliance with the protocol-specified visit windows is maintained for both visits.
Specifically, if a participant receives 12 to 14 days of IV study therapy, the EFU visit may 
potentially be combined with the Day 28 post-randomization visit. For example, if 12 days of 
IV study therapy are provided, the EFU visit could be scheduled 16 days (14+2) following 
completion of therapy which would be 28 days (12 days of IV therapy +16 days of follow-
up) following randomization. It is required that for any case, the allowable visit window 
ranges are maintained and all procedures required for each visit must be completed for the 
combined visit.
9. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes are made to primary and/or secondary 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be 
amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, but prior to unblinding, 
will be documented in a supplemental SAP (sSAP) and referenced in the Clinical Study 
Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in the 
CSR.
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Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A randomized, double-blind (with in-house blinding), active-controlled, 
parallel-group, multi-site, trial of IMI/REL compared with PIP/TAZ in 
participants with HABP or VABP.
Treatment Assignment
This study will randomize participants in a 1:1 ratio to the 2 treatment 
arms of the study (Group 1: IMI/REL and Group 2: PIP/TAZ).
Randomization will be stratified by: 1) pneumonia type at baseline (non-
ventilated HABP vs. ventilated HABP/VABP) and 2) APACHE II score 
at baseline (<15 vs. ≥15). In addition, randomization will be controlled 
such that a minimum of 25% of randomized participants are in the VABP 
or ventilated HABP strata.
A double-blind/masking technique will be used. IMI/REL and PIP/TAZ 
will be dispensed in a blinded fashion by an unblinded study staff (eg,
pharmacist or qualified designee). Due to a visual difference in the 
appearance of study treatment solutions, the infusion bags will be covered 
with an opaque sleeve by the unblinded study staff (eg, pharmacist or 
qualified designee) to ensure that other study personnel and all 
participants remain blinded to clinical material assignments. The 
personnel involved in the administration of the study infusion treatment 
should be unaware of the treatment group assignments. The participant, 
the investigator and Sponsor personnel or delegate(s) who are involved in 
the treatment or clinical evaluation of the participants are unaware of the 
group assignments.
Analysis Populations
Primary Efficacy Analysis: modified intention-to-treat (MITT) population 
(defined as all randomized participants who receive at least 1 dose of IV 
study therapy and do not have the presence of gram-positive cocci only
on baseline Gram stain).
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Incidence of all-cause mortality through Day 28 post-randomization
Statistical Methods for Key 
Efficacy Analyses
For the primary hypothesis (mortality), IMI/REL will be compared to 
PIP/TAZ using the stratified Miettinen and Nurminen method with the 
Cochran-Mantel-Haenszel (CMH) weighting. IMI/REL will be 
considered non-inferior (NI) to PIP/TAZ if the upper bound of the 2-sided 
95% confidence interval for the difference in incidence between the 
treatment groups (IMI/REL minus PIP/TAZ) is less than 12.5%. If non-
inferiority is established, then superiority of IMI/REL compared to 
PIP/TAZ will be evaluated at the α=0.025 (1-sided) level.
For secondary endpoints, point estimates and 2-sided 95% confidence 
intervals will be calculated using the same stratified Miettinen and 
Nurminen method as described above.
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and Tier 2) 
will be provided for between-treatment differences in the percentage of 
participants with events; these analyses will be performed using the 
Miettinen and Nurminen method.
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Interim Analyses
A blinded review of the aggregate mortality rate will be ongoing during the 
study. The impact of the blinded aggregate rate on the assumptions 
underlying the power/sample size calculation will be formally assessed by 
the Sponsor when approximately 75% of the planned sample size (N=202) 
have completed 28 days of follow-up or sooner if enrollment or event rates 
are occurring faster than anticipated. If Day 28 all-cause mortality is higher 
than the 15% assumed in the power calculation, consideration will be given 
to increasing the sample size.
There are no plans to conduct a formal interim analysis of unblinded 
efficacy data in the study.
Multiplicity
A sequential testing approach will be employed on the primary efficacy
endpoint.
Sample Size and Power 
The planned sample size of 135 participants per group will provide 80% 
power to reject the null hypothesis that the true difference in all-cause 
mortality exceeds the NI margin of 12.5% assuming true rates for both 
the control and experimental regimens of 15% (1-tailed alpha of 2.5%).
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures.
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in IRT.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
For the primary hypothesis, IMI/REL will be considered non-inferior (NI) to PIP/TAZ if the 
upper bound of the 2-sided 95% confidence interval (CI) for the difference in incidence 
between the treatment groups (IMI/REL minus PIP/TAZ) is less than 12.5%. The 12.5% NI 
margin is selected based on the estimated treatment effect from the random effect meta-
analysis of all-cause mortality by the FDA. Specifically, the all-cause mortality rate with
effective treatment is 20% with a 95% upper confidence bound of 23%, and the lower bound 
of the all-cause mortality of inadequate/delayed treatment is 52%; therefore, the treatment 
effect is almost 29% (52%-23%=29%). Based on this estimate, the treatment effect has been 
conservatively set to be 25%, and the NI margin is set to be its half, ie, 12.5%. If non-
inferiority is established, then a subsequent test will be performed to determine whether or 
not IMI/REL is superior to PIP/TAZ (ie, the upper bound of the 2-sided 95% CI for the 
difference in incidence between the treatment groups is less than 0%).
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Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
Efficacy Endpoints
A full description of the efficacy measures is provided in Section 8.2, and primary and 
secondary efficacy endpoints are summarized in Table 11.
IV study therapy will be administered for a minimum of 7 days up to a maximum of 14 days 
(see Section 4.3.3). The duration of therapy will be summarized by treatment group for the 
overall population. In addition, the impact of any difference in duration of therapy on the 
treatment group comparisons will be assessed.
Table 11
Summary of Primary and Secondary Efficacy Endpoints and Components of a 
Favorable Response
Objective
Endpoint
Timing
Favorable 
Response
Analysis 
Population
References
(Section/Table)
Primary 
Endpoint 
All-Cause 
Mortality
Day 28 
Survival 
MITT
Section 8.2.1
Secondary 
Endpoint
Clinical 
Response 
EOT, EFU
EOT (Cure or 
Improved)
EFU (Cure or 
Sustained Cure)
MITT and 
CE 
Section 8.2.2
Table 5 and Table 6
Microbiological 
Response
EOT, EFU
EOT (Eradication
or Presumed 
Eradication)
EFU (Eradication
or Presumed 
Eradication)
mMITT
and ME
Section 8.2.3
Table 8 and Table 9
Abbreviations: CE=clinically evaluable population; Day 28=Day 28 post-randomization; EFU=early follow-up visit; EOT=end of 
therapy visit; MITT=modified intention to treat population; mMITT=microbiological modified intention to treat population; NA=not 
applicable
Safety Endpoints
A description of safety measures is provided in Section 8.3. The analysis of safety endpoints 
will follow a tiered approach. For this protocol, the following are pre-specified events of 
interest (Tier 1 events).
1. An elevated AST or ALT laboratory value that is greater than or equal to 3 X ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 
2 X ULN and, at the same time, an alkaline phosphatase laboratory value that is less 
than 2 X ULN, as a result of within-protocol-specific testing or unscheduled testing.
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It will not be counted as a Tier 1 event if the preceding conditions were present at 
randomization (Day 1).
2. A confirmed (ie, verified by repeat testing) elevated AST or ALT laboratory value 
that is greater than or equal to 5 X ULN as a result of within-protocol-specific testing 
or unscheduled testing. It will not be counted as a Tier 1 event if the preceding 
conditions were present at randomization (Day 1).
The broad clinical and laboratory adverse event (AE) categories, consisting of the percentage 
of participants with any AE, a drug-related AE, a serious AE, an AE which is both drug 
related and serious, who discontinued IV study therapy due to an AE, and who discontinued 
IV study therapy due to a drug-related AE, will be considered Tier 2 endpoints.
Analysis Populations
Efficacy Analysis Populations
The modified intention-to-treat (MITT) population will serve as the primary population for 
efficacy analyses in this study. The MITT population is defined as all randomized 
participants who receive at least 1 dose of IV study therapy and do not have the presence 
of -positive cocci only on baseline Gram stain.
The microbiological modified intention-to-treat (mMITT) population is the secondary 
population for efficacy analyses. The mMITT population is defined as all randomized 
participants who receive at least 1 dose of IV study therapy and do not have gram-positive 
cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as 
the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial 
activity.
The clinical-evaluable (CE) and microbiological-evaluable (ME) populations will serve as 
additional analysis populations for the some of the secondary and exploratory efficacy 
endpoints. The CE population is a subset of the MITT population who also meet the 
following criteria:

Meet important diagnostic criteria for entry into the study, 

Have no significant deviation from the protocol that could impact the assessment of 
efficacy,

Receive the minimum duration of IV study therapy, ie, 7 days, and

Have an efficacy assessment at the time point of interest.
The CE population does not require a positive baseline culture for a bacterial pathogen 
identified as the cause of HABP/VABP against which IMI/REL has been shown to have 
antibacterial activity.
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The ME population is a subset of the CE population who also meet the following criteria:

Have a baseline bacterial pathogen identified as the cause of HABP/VABP against 
which IMI/REL has been shown to have antibacterial activity, and 

Have results from a lower respiratory tract culture obtained at the indicated time 
point.
The final determination on major protocol deviations, and thereby the composition of the CE 
and ME populations, will be made prior to the final unblinding of the database and will be 
documented in a separate memo.
Participants will be included in the treatment group to which they are 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 – Statistical Methods.
Safety Analysis Population
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized participants who received at least 
1 dose of IV study therapy. Participants will be included in the treatment group 
corresponding to the IV study therapy they actually received for the analysis of safety data 
using the ASaT population. For most participants this will be the treatment group to which 
they are randomized. Participants who take incorrect study therapy for the entire treatment 
period will be included in the treatment group corresponding to the study therapy actually 
received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of IV 
study therapy is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required. 
For the analysis of pre-specified events of interest (Tier 1 events) described above in Section 
9.4.2, participants will be excluded from specific analyses if the conditions defining the event 
were present at randomization (Day 1).
Statistical Methods
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error rate control strategy are described in Section 9.8 - Multiplicity. Nominal p-
values will be computed for other efficacy analyses, but should be interpreted with caution 
due to potential issues of multiplicity, sample size, etc. Unless otherwise stated, all statistical 
tests of efficacy endpoints will be conducted at the α=0.025 (1-sided) level.
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Statistical Methods for Efficacy Analyses
The analysis of between-treatment differences in the incidence (or percentage of participants) 
with binary events will be performed using the stratified Miettinen and Nurminen method 
(1985) [Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method. The 
analyses will be stratified by: 1) pneumonia type at baseline (non-ventilated HABP vs. 
ventilated HABP/VABP), and 2) APACHE II score at baseline (<15 vs. ≥15), with the 
Cochran-Mantel-Haenszel (CMH) weighting.
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 study therapy due to lack of efficacy (ie, withdrawals 
with subsequent non-study antibiotic therapy) will be considered as “failures” with 
respect to clinical response at the time of discontinuation and all subsequent time 
points.

Participants discontinuing IV study therapy due to lack of efficacy will be presumed 
to have persistence for the microbiological response at the time of discontinuation and 
all subsequent time points.
The primary and secondary endpoints, primary and secondary analysis population, and 
statistical methods that will be employed for the efficacy analyses are presented in 
Table 12. Since a favorable clinical response at EOT requires an assessment of “cure” or 
“improved”, an assessment of “indeterminate” would be considered a failure to achieve a 
favorable clinical response. Since a favorable clinical response at EFU 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 EOT and EFU requires an assessment of “eradication” or 
“presumed eradication”, an assessment of “indeterminate” would be considered a failure to 
achieve a favorable microbiological response.
Table 12
Summary of Analysis Strategy for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
(Description, Time point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary:
Incidence of all-cause mortality 
through Day 28 post-randomization.
NI comparison of IMI/REL to 
PIP/TAZ using 12.5% margin
Stratified M&Na
MITTb
M=Fc
Secondary:
Percentage of participants achieving 
a favorable clinical response at EFU. 
Stratified M&Na
MITTb
M=Fc
Percentage of participants achieving 
a favorable clinical response at EOT. 
Stratified M&Na
MITTb
M=Fc
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Endpoint/Variable
(Description, Time point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Percentage of participants achieving 
a favorable clinical response at EFU.
Stratified M&Na
CEe
DAOd
Percentage of participants achieving 
a favorable clinical response at EOT.
Stratified M&Na
CEe
DAOd
Percentage of participants achieving 
a favorable microbiological response 
at EOT. 
Stratified M&Na
mMITTf
M=Fc
Percentage of participants achieving 
a favorable microbiological response 
at EFU. 
Stratified M&Na
MEg
DAOd
Percentage of participants achieving 
a favorable microbiological response 
at EOT. 
Stratified M&Na
MEg
DAOd
a  M&N is Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] stratified by pneumonia type at baseline (non-
ventilated HABP vs. ventilated HABP/VABP) and APACHE II score (<15 vs. ≥15).
b  MITT population includes all randomized participants who receive at least 1 dose of IV study therapy and do not have the presence of 
gram-positive cocci only on baseline Gram stain.
c  M=F is missing=failure.
d  DAO=data as observed.
e  CE population is a subpopulation of MITT population who also meet the following criteria: 1) Meet important diagnostic criteria for 
entry into the study; 2) Have no significant deviation from the protocol that could impact the assessment of efficacy; 3) Receive the 
minimum duration of IV study therapy; and 4) Have an efficacy assessment at the time point of interest.
f  mMITT population includes all randomized participants who receive at least 1 dose of IV study therapy and do not have
gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP 
against which IMI/REL has been shown to have antibacterial activity.
g  ME population is a subpopulation of CE population who also meet the following criteria: 1) have a baseline bacterial pathogen 
identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and 2) Have results
from a lower respiratory tract culture obtained at the indicated time point.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach Table 13. The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse events of special 
interest that are identified a priori constitute “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% confidence intervals 
provided for between-group comparisons. Other safety parameters will be considered Tier 2 
or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% confidence 
intervals provided for between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters. p-values (Tier 1 only) and 95% confidence 
intervals (Tier 1 and Tier 2) will be provided for between-treatment differences in the 
percentage of participants with events; these analyses will be performed using the Miettinen 
and Nurminen method (1985), an unconditional, asymptotic method. Since the stratification 
factors (pneumonia type at baseline and APACHE II score at baseline) are not considered to 
be related to safety endpoints, they will not be included as stratification factors in the safety 
analyses.
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Adverse events (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory and vital signs parameters that are not pre-specified as Tier 1 endpoints 
will be classified as belonging to "Tier 2" or "Tier 3," based on the number of events 
observed. Membership in Tier 2 requires that at least 4 participants in any treatment group 
exhibit the event; all other adverse events and predefined limits of change will belong to 
Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse events and 
predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital signs parameters 
that are not pre-specified as Tier 1 endpoints will be considered Tier 3 safety parameters.
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format.
Table 13
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Elevated AST or ALT ≥3 X ULN and
elevated total bilirubin ≥2 X ULN and 
alkaline phosphatase <2 X ULN
X
X
X
A confirmed elevated AST or ALT ≥5 X ULN
X
X
X
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Discontinuation due to Drug-Related AE
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 
participants in 1 of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 
participants in all of the treatment groups)
X
Change from Baseline Results (Labs, Vital 
Signs)
X
†
Adverse Event references refer to both Clinical and Laboratory AEs.
‡
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
Abbreviations: PDLC=Pre-Defined Limit of Change; SOC=System Organ Class; X=results will be provided.
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Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened, randomized, and the 
primary reason for discontinuation will be displayed. Demographic variables, baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables.
Interim Analyses
There are no plans to conduct a formal interim analysis of unblinded efficacy data in the 
study.
An internal blinded sample size re-estimation will be conducted as described in the following 
paragraph.
Blinded review of the aggregate Day 28 all-cause mortality rate (referred to as the mortality 
rate for the remainder of this section) will be ongoing during the study. The impact of the 
mortality rate on the assumptions underlying the power/sample size calculation will be 
formally assessed when approximately 75% (N=202) of the planned sample size (N=270) 
have completed 28 days of follow-up or sooner if enrollment or event rates are occurring 
faster than anticipated. If the observed overall mortality rate is higher than the 15% assumed 
in the power calculation, consideration will be given to increasing the overall sample size as 
outlined in Table 14. If the observed mortality rate is less than 15%, the overall sample size 
will be maintained at the planned N=270 and power for this endpoint/hypothesis will exceed 
80%. The maximum sample size will not exceed N=380 (190 per group) regardless of the 
observed overall mortality rate. The accruing database will not be officially locked for this 
blinded sample size re-estimation; however, all data relating to the assessment of mortality 
will be cleaned and all queries resolved before the formal assessment of the mortality rate. As 
this sample size re-estimation will be done in a blinded fashion, there is no impact on type 1 
error rates.
Table 14
Sample Size Adjustments Based on Interim Blinded Review of Day 28 All-Cause 
Mortality
Observed Mortality 
Rate (%) †
Power Based on Original 
Sample Size (N=270)
Revised 
Sample Size ‡
Percent Increase from 
Original Sample Size
16%
78.3%
282
4.4%
17%
76.6%
294
8.9%
18%
74.9%
306
13.3%
19%
73.3%
318
17.8%
20%
71.9%
328
21.5%
21%
70.5%
340
25.9%
22%
69.2%
350
29.6%
23%
67.9%
360
33.3%
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Observed Mortality 
Rate (%) †
Power Based on Original 
Sample Size (N=270)
Revised 
Sample Size ‡
Percent Increase from 
Original Sample Size
24%
66.8%
370
37.0%
25%
65.7%
380
40.7%
†
This is the aggregate Day 28 all-cause mortality rate expressed as a percent and rounded to the 
nearest integer value.
‡
Calculated to provide 80% power based on the observed mortality rate
Multiplicity
A sequential testing approach will be employed on the primary efficacy endpoint (incidence 
of Day 28 all-cause mortality). The non-inferiority will be evaluated first using 1-sided 
α=0.025 level. If non-inferiority is met, the superiority will be evaluated using α=0.025, 1-
sided.
Sample Size and Power Calculations
This study will randomize participants in a 1:1 ratio to the 2 treatment arms of the study 
(Group 1: IMI/REL and Group 2: PIP/TAZ), in order to obtain approximately 270
participants who meet the criteria for inclusion in the modified intention-to-treat (MITT) 
population. A sample size of 135 participants per group will provide 80% power to reject the 
null hypothesis that the true difference in all-cause mortality exceeds the NI margin of 
12.5%, assuming true rates for both the control and experimental regimens of 15% (1-tailed 
alpha of 2.5%).
Another way to assess the precision of a non-inferiority trial is to consider the maximum 
observed difference that would just meet the criterion for non-inferiority (in this case, an 
upper bound of the 2-sided 95% CI for the difference in all-cause mortality [IMI/REL minus 
PIP/TAZ] that is just less than 12.5%). This maximum observed difference will increase as 
the observed mortality in the control group decreases. For example, an observed difference of 
2.3 percentage points will just meet the criterion for non-inferiority given an observed 
mortality of 20.7% (28/135) in the control group and 23% (31/135) in the experimental 
group. An observed difference of 3.7 percentage points will just meet the criterion for non-
inferiority given an observed mortality of 10.4% (14/135) in the control group and 14.1% 
(19/135) in the experimental group.
Subgroup Analyses
To assess the consistency of the treatment effect across various subgroups, the estimate of the 
between-group treatment effect (with a nominal 95% CI) for the Day 28 all-cause mortality 
(MITT population) will be estimated within each category of the following classification 
variables (assessed prior to or at the point of randomization) if there are at least 25 
participants in each subgroup in each treatment group:

Age category (<65, ≥65 years)

Gender (female, male)

Country (China, other countries/regions)
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
Stratification variable: Pneumonia type at baseline (non-ventilated HABP, ventilated 
HABP/VABP)

Stratification variable: APACHE II score at baseline (<15, ≥15)

Concurrent bacteremia (Y, N)
Compliance (Medication Adherence)
Considering this is an IV study on hospitalized participants conducted by 
investigators/nurses, it is expected to follow the protocol strictly without compliance issues.
Any non-compliance dosage will be monitored and recorded for discussion.
Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics.
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10.
Supporting Documentation and Operational Considerations
Appendix 1: Regulatory, Ethical and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (e.g., 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 (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials which are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full 
control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial.
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-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
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conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care. 
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have access to 
confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review to identify potentially eligible participants.
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 (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices. 
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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 
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Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which 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.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
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 in 
order to verify worksheet/CRF data. By signing the consent form, the participant agrees to 
this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
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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.
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 International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other 
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generally accepted standards of GCP); and all applicable federal, state and local laws, rules 
and regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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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 participant’s 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. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’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 may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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Appendix 2: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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Appendix 3:  Contraceptive Guidance and Pregnancy Testing
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required.
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol-defined time frame in Section 5.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
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●
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
○
The following are not acceptable methods of contraception:
▪
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM).
▪
Male and female condom cannot be used together.
○
A combination of male condom with either cap, diaphragm or sponge with 
spermicide are considered acceptable, but not highly effective, birth control methods.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 15 consistently and correctly during the 
protocol-defined time frame in Section 5.1.
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Table 15
Acceptable Contraceptive Methods
Highly Effective Contraceptive Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only contraceptive implantb, c 

Intrauterine hormone-releasing system (IUS)b

Intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause). This is a 
highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. A 
spermatogenesis cycle is approximately 90 days. Note: Documentation of 
azoospermia can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing ) hormonal contraceptionb, c
o
Oral 
o
Intravaginal 
o
Transdermal 
o
Injectable

Progestogen-only hormonal contraceptionb, c
o
Oral 
o
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 treatment. 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 With a 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
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Notes: 

Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.

The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM).
-
Male and female condom should not be used together (due to risk of failure with friction).
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly). 
b
If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period. IUS is a 
progestin-releasing IUD.
c
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation.
d
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods.
Pregnancy Testing
WOCBP should only be included after a negative pregnancy test has been confirmed at 
screening. Prior documentation of a negative serum β-hCG within 2 days (48 hours) of 
enrollment is acceptable for women of reproductive potential. If documentation is not 
available, a rapid urine β-hCG test may be used for screening; if the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. To conduct urine 
testing, sites must have individuals certified in administration and interpretation of test and 
the urine test utilized must have sensitivity of <25 mIU/L.
Additional serum pregnancy testing will be performed at the Day 28 post-randomization 
visit.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
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 treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment 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 
treatment 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 
of study treatment without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to Section 8.4.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is diagnosed 
prior to the use of an MSD product and is documented in the patient’s medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
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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 one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events Reported
Additional events which require reporting 
●
In addition to the above criteria, AEs meeting either of the below criteria, although 
not serious per ICH definition, are reportable to the Sponsor.
●
Is a cancer;
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the AE
CRFs/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant 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.
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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: 
●
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. (for pediatric studies, 
awareness of symptoms, but easily tolerated)
●
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. (for pediatric studies, definitely acting like something is 
wrong)
●
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric studies, extremely distressed or unable to do usual activities).
Assessment of causality
●
Did the Sponsor's product cause the AE?
●
The determination of the likelihood that the Sponsor's product caused the AE will 
be provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form, ensures that a medically qualified assessment of 
causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the test 
product and the AE based upon the available information
●
The following components are to be used to assess the relationship between 
the Sponsor's product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more 
likely the Sponsor's product caused the AE:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to studies with investigational 
medicinal product)?
●
Likely Cause:  Is the AE not reasonably explained by another etiology such 
as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
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factors
●
Dechallenge: Was the Sponsor's product discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor's product; (3) the study is a single-dose drug study); or (4) 
Sponsor's product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
study?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death 
or permanent disability, or (2) the study is a single-dose drug study); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF 
RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL 
POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR, AND IF REQUIRED, THE IRB/IEC.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor's product is reasonable. 
The AE is more likely explained by the Sponsor's product than by another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
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onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product. (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one 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.
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool. 
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form. 
●
Reference Section 8.4.1 for reporting time requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.
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●
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 Trial File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
●
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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Appendix 5: Clinical Laboratory Tests 

The tests detailed in Table 16 will be performed by the central laboratory, with the 
exception of the rapid urine β-hCG test and HIV/HBV/HCV assessment (if 
HIV/HBV/HCV testing is required per local policy).

As described in Section 8.3.4, for the purpose of monitoring an individual 
participant’s renal function in “real time,” a creatinine assessment should be 
performed at the local laboratory on Days 1, 3, 6, and 10 (if applicable) during IV 
study therapy in addition to the chemistry safety panel performed at the central 
laboratory. The local laboratory results 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 16
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human 
chorionic gonadotropin 
(β-hCG)
Hemoglobin
Alkaline phosphatase
Glucose
Rapid urine β-hCG
Platelet count
Alanine aminotransferase 
(ALT)
Protein
HIV/HBV/HCV (Per 
local guidance)
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Microscopic exam, if 
abnormal results are 
noted 
Bicarbonate
Calcium
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin
Direct Bilirubin, if total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Blood Urea Nitrogen
Investigators must document their review of each laboratory safety report.
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Table 17
Approximate Blood Volumes Drawn by Trial Visit and Sample Types
Screening
IV Study Treatment
Post-Treatment
Trial Visit
V1 
Screening
V2 
Randomization
V3 
OTX1
V4 
OTX2
V5 
OTX3
V6 
EOT
V7 
EFU
V8
Day 28
Blood 
Parameter
Approximate Blood Volume (mL)
Hematology
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
Serum/ 
Plasma 
Chemistry
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
Serum 
ß-hCGa
3.5
3.5
Local 
Laboratory 
Assessment 
of Creatinineb
2.0
2.0
2.0
2.0
2.0
Culture and 
Susceptibility
40
As clinically indicated (40 mL per assessment)
Expected 
Total (mL)c,d
11.0
47.5
7.5 or 47.5
if culture 
and 
susceptibility 
testing 
clinically 
indicated
7.5 or 47.5
if culture 
and 
susceptibility 
testing 
clinically 
indicated
7.5 or 47.5
if culture 
and 
susceptibility 
testing 
clinically 
indicated
5.5 or 45.5
if culture 
and 
susceptibility 
testing 
clinically 
indicated
5.5 or 45.5
if culture 
and 
susceptibility 
testing 
clinically 
indicated
9.0
a For female subjects of childbearing potential only; to be conducted only if prior documentation (within 48 hours of 
enrollment) of a negative β-hCG unavailable and if rapid urine β-hCG test result is positive or cannot be confirmed as 
negative. Further guidance can be found in appendix 3 of the protocol.
b Not needed at screening visit if performed at screening Blood for Chemistry assessment.
c Additional blood samples may be collected in support of evaluation for an underlying etiology throughout the study. The 
trial site guidance for assessment and follow up of these criteria can be found in the Investigator Trial File Binder. 
Depending on the results of initial testing, additional blood volumes could range from approximately 8.5 mL up to 
approximately 92.0 mL and could include HIV and/or Hepatitis testing.
d Blood cultures will be collected in all subjects prior to initiation of IV study therapy. Subjects with positive blood cultures 
at screening should have follow-up blood cultures collected daily until 2 consecutive blood cultures demonstrate no 
growth. Blood cultures will be performed at the local microbiology laboratory according to recognized methods and per 
each laboratory’s standard procedures and isolates sent to the central microbiology laboratory.
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Appendix 6: APACHE II Severity of Disease Classification System – APACHE II Score Form
A. Acute Physiology Scorea:
HIGH ABNORMAL RANGE
LOW ABNORMAL RANGE
PHYSIOLOGIC VARIABLE
+4
+3
+2
+1
0
+1
+2
+3
+4
1
Temperature rectal (oC)b
□
≥41
□
39-40.9
□
38.5-38.9
□
36.0-38.4
□
34-35.9
□
32-33.9
□
30-31.9
□
≤29.9
2
Mean arterial pressure (mmHg)=
(2 x diastolic + systolic)/3
□
≥160
□
130-159
□
110-129
□
70-109
□
50-69
□
≤49
3
Heart rate (ventricular response)
□
≥180
□
140-179
□
110-139
□
70-109
□
55-69
□
40-54
□
≤39
4
Respiratory rate (nonventilated or ventilated)
□
≥50
□
35-49
□
25-34
□
12-24
□
10-11
□
6-9
□
≤5
5
Oxygenationc
A-aDO2 or PaO2 (mm Hg)
a)FiO2≥0.5:record A-aDO2
□
≥500
□
350-499
□
200-349
□
<200
b)FiO2<0.5:record only PaO2
□
>70
□
61-70
□
55-60
□
<55
6
Arterial pH (*If no ABGs record Serum HCO3 
below)
□
≥7.7
□
7.6-7.69
□
7.5-7.59
□
7.33-7.49
□
7.25-7.32
□
7.15-7.24
□
<7.15
7
Serum sodium (mMol/L)
□
≥180
□
160-179
□
155-159
□
150-154
□
130-149
□
120-129
□
111-119
□
≤110
8
Serum potassium (mMol/L)
□
≥7
□
6-6.9
□
5.5-5.9
□
3.5-5.4
□
3-3.4
□
2.5-2.9
□
<2.5
9
Serum creatinine (mg/dL) 
Double point for acute renal failure
□
≥3.5
□
2-3.4
□
1.5-1.9
□
0.6-1.4
□
<0.6
10
Hematocrit (%)
□
≥60
□
50-59.9
□
46-49.9
□
30-45.9
□
20-29.9
□
<20
11
White blood count (total/mm3) (in 1000’s)
□
≥40
□
20-39.9
□
15-19.9
□
3-14.9
□
1-2.9
□
<1
12
Glasgow Coma Scale 
Enter 15 minus actual GCS –see calculations in 
table below
15-GCS =
A
Total Acute Physiology Score (APS)
Sum of the 12 individual variable points =
*
Serum HCO3(venous-mMol/L)
(Not preferred, use if no ABGs)
□
≥52
□
41-51.9
□
32-40.9
□
22-31.9
□
18-21.9
□
15-17.9
□
<15
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APACHE II Severity of Disease Classification System
Glasgow Coma Score (GCS)
(circle appropriate response)
Eyes open (E)
4 - spontaneously
3 - to verbal command
2 - to painful stimul
1 - no response
Motor response (M)
6 - to verbal command
5 - localizes to pain
4 - withdraws to pain
3 - decorticated
2 - decerebrated
1 - no response
Verbal - Response (V)e
5-oriented and controversed
4-confused and disoriented
3-inappropriate words
2-incomprehensible sounds
1-no response
GLASGOW COMA SCORE† = E + M + V
†  Participants scoring 3 or 4 have an 85% chance of dying or remaining vegetative, while scores above 11 
indicate 5 to 10% likelihood of death or vegetative state and 85% chance of moderate disability or good 
recovery. Intermediate scores correlate with proportional chances of participants recovering.
B. Age Points
Age
Points
≤44
0
45-54
2
55-64
3
65-74
5
≥75
6
Age points = _________
C. Chronic Health Points (CHE)f
If any of the 5 CHE categories is answered with yes give +5 points for nonoperative or emergency 
postoperative participants, or +2 points for elective postoperative participants
Liver - Cirrhosis with Portal Hypertension (PHT) or encephalopathy
Cardiovascular –NYHA Class IV angina or at rest or with minimal self-care activities
Pulmonary -chronic hypoxemia or hypercapnia or polycythemia or pulmonary hypertension >40 mm Hg
Kidney -chronic peritoneal or hemodialysis
Immune -immune compromised host
Chronic Health Points=________
APACHE-II Score is sum of A+B+C
APS points
A _______
Age points
+B _______
Chronic Health Points+C _________
Total APACHE-II Score=________
Adapted From: [Knaus, W. A., et al 1985]
a.
The most severe value in the last 48 hours prior to a participant’s randomization into the study should be used for each variable of the 
APACHE II score calculation. The calculation of the APACHE II score should be captured in the patient’s medical chart or in a copy 
of the APACHE II Score form.
b.
The sponsor recommendation is to use rectal temperature measurement whenever possible. If rectal temperature is not possible, it is 
acceptable to use non-rectal temperature with no conversion as a substitute.
c.
It is recommended that when assessing the Oxygenation variable for the APACHE II calculation, ABG measurements should be used. 
If ABG has not been performed for a participant, then the APACHE II score calculation should be recorded as 0 for Oxygenation 
variable.
d.
Decerebrate for +2 points means extension to pain. Decorticate for +3 points means flexion to pain.
e.
Verbal response for participants that are intubated and/or sedated/paralyzed: If there is a reliable pre-sedation GCS score or all of the 
elements of the GCS score were documented in the medical record - then just use the pre-sedation GCS score (not just the verbal 
response piece, but the whole GCS score). But if there is no reliable pre-sedation GCS score, then the GCS section of the Acute 
Physiology Score would just be null overall. Investigators should note on the source documents and then commenting out on the
APC2 eCRF that the GCS was not assessed.
f.
The CHE score can only be +5, +2 or 0. These additional points are to be given only once and not multiple times for each separate 
condition that has been observed.
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Appendix 7: Clinical Pulmonary Infection Score (CPIS)
PARAMETER
SCORE
Temperature (oC)
≥36.5 and ≤38.4
≥38.5 and ≤38.9
≥39.0 or <36.5
0
1
2
White Blood Cell (WBC) Count (X 109/L)
≥4,000 and ≤11,000
<4,000 or >11,000
<4,000 or >11,000 & band forms ≥50%
0
1
2
Lower Respiratory Tract Sample/Tracheal Secretions
No or minimal sputum/secretions
Non-purulent sputum/secretions
Purulent sputum/secretions
0
1
2
PaO2/FiO2*
Not ventilated to allow assessment
>240 or evidence of ARDS**/pulmonary contusion
≤240 and no evidence of ARDS**/pulmonary contusion
0
0
2
Chest Radiograph at Study Entry
No infiltrate
Diffuse (or patchy) infiltrate
Localized infiltrate
0
1
2
* Ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen.
** ARDS is defined as a PaO2/FiO2 ≤200, PAOP ≤18mmHg, and acute bilateral infiltrates
Source:  Modified from[Zilberberg, M. D. 2010]
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Appendix 8: Abbreviations
Abbreviation
Definition
ABG
arterial blood gas
AE
adverse event
AIDS
Acquired Immune Deficiency Syndrome
ALT
alanine aminotransferase
APACHE
Acute Physiology and Chronic Health Evaluation 
ASaT
All Subjects as Treated
AST
aspartate aminotransferase
ATS
American Thoracic Society
AUC0-∞
area under the concentration-time curve from time zero to infinity
AUC0-24hr
area under the concentration-time curve from time zero to 24 hours
BAL
bronchoalveolar lavage
β-hCG
β-human chorionic gonadotropin
BL
β-lactam
BLI
β-lactamase inhibitor 
BP
blood pressure
CABP
community-acquired bacterial pneumonia
CD4
cluster of differentiation 4
CE
clinically evaluable
Ceoi
concentration at the end of infusion
CFR
Code of Federal Regulations
C-G
Cockcroft-Gault
CI
confidence interval
cIAI
complicated intra-abdominal infection
CLplasma
plasma clearance
CMS
colistimethate sodium
CPT
Common Protocol Template
CSR
clinical study report
cUTI
complicated urinary tract infection
DCIV
discontinuation of iv therapy
DNA
deoxyribonucleic acid
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data capture
EFU
early follow-up
ELF
epithelial lung fluid
EOT
end of therapy; end of treatment
ESBL
extended-spectrum beta-lactamase
ESRD
end-stage renal disease
EU
European Union
FDAAA
Food and Drug Administration Amendments Act
FDC
fixed-dose combination
FiO2
fraction of inspired oxygen
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GCS
Glasgow Coma Score
GFR
glomerular filtration rate
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Abbreviation
Definition
HABP
hospital-acquired bacterial pneumonia
HAI
hospital-acquired infections
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICU
intensive care unit
IDSA
Infectious Diseases Society of America
IEC
Independent Ethics Committee
IMI
imipenem/cilastatin
IMI/REL
fixed-dose combination of imipenem/cilastatin/relebactam
IMI + REL
imipenem/cilastatin co-administered with relebactam (ie, from 
separate vials)
IMP
investigational medicinal product
INR
international normalized ratio
IRB
Institutional Review Boards
IRT
Interactive Response Technology
IUD
intrauterine device
IV
intravenous (parental)
KPC
Klebsiella pneumoniae carbapenemase 
LAM
lactational amenorrhea method
LFU
late follow-up
MAOI
monoamine oxidase inhibitors
MDR
multi-drug resistant
ME
Microbiologically evaluable
mg
milligram 
MIC
minimum inhibitory concentration
MITT
modified intention-to-treat
mMITT
microbiological modified intention-to-treat
MRSA
methicillin-resistant S. aureus
MSD
Merck & Co, Inc. (Merck Sharp & Dohme outside the US)
MSSA
methicillin-susceptible S. aureus
NI
non-inferior
NIMP
non-investigational medicinal product
NMPA
National Medical Products Administration (China)
OTX
on-therapy
PaO2
partial pressure of oxygen
PaO2/FiO2
ratio of partial pressure of oxygen to the fraction of inspired oxygen
PBS
protected brush specimen
PD
pharmacodynamic
PDLC
pre-defined limit of change
PIP
piperacillin
PK
pharmacokinetic
q6h
every 6 hours
q12h
every 12 hours
QTc
corrected QT interval
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Abbreviation
Definition
QTcP
population-specific corrected QTc
REL
relebactam
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event
SAP
Statistical Analysis Plan
siDMC
standing internal Data Management Committee
SoA
Schedule of Activities
SOC
system organ class
TAZ
tazobactam
t1/2
terminal half-life 
ULN
upper limit of normal
US
United States
VABP
ventilator-associated bacterial pneumonia
WBC
white blood cell
WOCBP
women of childbearing potential
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Product:  MK-7655A 
130
Protocol/Amendment No.:  016-03 
MK-7655A-016-03 Final Protocol
11-Nov-2020
Confidential
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