Clinical trial NCT02493764
Conditions: Bacterial Pneumonia
Sponsor: Merck Sharp & Dohme LLC
Start date: 2015-11-24; Completion date: 2019-04-03
Enrollment: 537 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to compare treatment with a fixed-dose combination (FDC) of imipenem/relebactam/cilastatin (IMI/REL) with a FDC of piperacillin/tazobactam (PIP/TAZ) in participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP or VAPB, respectively). The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ in the incidence rate of all-cause mortality.

Detailed description:

Arms: arm 1: Imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered intravenously (IV) every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days. arm 2: Piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days.
Interventions: intervention 1: Imipenem intervention 2: Relebactam intervention 3: Cilastatin intervention 4: Piperacillin intervention 5: Tazobactam intervention 6: Linezolid
Intervention descriptions: intervention 1: Imipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days intervention 2: Relebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days intervention 3: Cilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days intervention 4: Piperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days intervention 5: Tazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days intervention 6: Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02493764  
Document Date: 
06-Sep-2018
A Phase III, 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


Product:  MK-7655A 
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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., 
WHITEHOUSE STATION, NJ, U.S.A.
This protocol amendment is applicable only to Portugal, Russia, United States.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase III, 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
IND NUMBER:  [108,754]
EudraCT NUMBER:  [2015-000246-34]
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1
Early Consent Option.......................................................................................... 15
2.1.1
Standard Consent Option .................................................................................... 15
2.1.2
Trial Diagram........................................................................................................ 16
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es) .............................................................. 17
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 17
3.2
Key Secondary Objective.................................................................................... 17
3.2.1
Other Secondary Objectives................................................................................ 17
3.2.2
Exploratory Objectives......................................................................................... 18
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
4.1
Pharmaceutical and Therapeutic Background .................................................... 19
4.1.1
Ongoing Clinical Trials....................................................................................... 21
4.1.2
Information on Other Trial-Related Therapy...................................................... 21
4.1.3
4.1.3.1
Comparator Therapy .................................................................................... 21
4.1.3.2
Co-administration of Open-label Therapy with Linezolid for MRSA......... 21
Rationale................................................................................................................ 22
4.2
Rationale for the Trial and Selected Subject Population .................................... 22
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 23
4.2.2
4.2.2.1
IMI (500 mg)/REL (250 mg) ....................................................................... 23
4.2.2.2
Comparator –PIP (4000 mg)/TAZ (500 mg) ............................................... 25
4.2.2.3
Duration of Therapy..................................................................................... 25
4.2.2.4
Rationale for the Use of Comparator........................................................... 25
Rationale for Endpoints ...................................................................................... 26
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 26
 
 
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4.2.3.1.1
Definition of Efficacy Endpoints.......................................................... 27
Survival/All-cause Mortality.......................................................... 28
4.2.3.1.1.1
Clinical Response........................................................................... 28
4.2.3.1.1.2
Microbiological Response.............................................................. 30
4.2.3.1.1.3
4.2.3.2
Safety Endpoints .......................................................................................... 33
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 34
4.2.3.4
Planned Exploratory Biomarker Research................................................... 34
4.2.3.5
Future Biomedical Research........................................................................ 34
Benefit/Risk ........................................................................................................... 34
4.3
5.0
METHODOLOGY ................................................................................................... 35
Entry Criteria........................................................................................................ 35
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 35
5.1.1
Subject Inclusion Criteria.................................................................................... 35
5.1.2
Subject Exclusion Criteria .................................................................................. 38
5.1.3
Trial Treatment(s) ................................................................................................ 41
5.2
Dose Selection/Modification .............................................................................. 43
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 43
5.2.1.1.1
IMI/REL................................................................................................ 43
5.2.1.1.2
PIP/TAZ................................................................................................ 43
Timing of Dose Administration .......................................................................... 44
5.2.2
Trial Blinding/Masking....................................................................................... 45
5.2.3
Randomization or Treatment Allocation............................................................ 45
5.3
Stratification.......................................................................................................... 45
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 46
5.5
Rescue Medications & Supportive Care............................................................. 46
5.6
Diet/Activity/Other Considerations..................................................................... 46
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 47
5.8
Subject Replacement Strategy............................................................................. 48
5.9
Beginning and End of the Trial ........................................................................... 48
5.10
Clinical Criteria for Early Trial Termination ................................................... 48
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 49
 
 
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7.0
TRIAL PROCEDURES ........................................................................................... 54
Trial Procedures ................................................................................................... 54
7.1
Administrative Procedures.................................................................................. 54
7.1.1
7.1.1.1
Informed Consent......................................................................................... 54
7.1.1.1.1
General Informed Consent.................................................................... 54
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 55
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 55
7.1.1.3
Subject Identification Card .......................................................................... 55
7.1.1.4
Medical History ........................................................................................... 55
7.1.1.5
Prior and Concomitant Medications Review ............................................... 55
7.1.1.5.1
Prior Medications.................................................................................. 55
7.1.1.5.2
Concomitant Medications..................................................................... 56
7.1.1.6
Assignment of Screening Number............................................................... 56
7.1.1.7
Assignment of Randomization Number....................................................... 56
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 57
7.1.1.9
Study Therapy Administration..................................................................... 57
7.1.1.10 Linezolid Therapy Administration............................................................... 58
Clinical Procedures/Assessments........................................................................ 58
7.1.2
7.1.2.1
APACHE II Score........................................................................................ 58
7.1.2.2
Clinical Pulmonary Infection Score (CPIS)................................................. 58
7.1.2.3
Full and Directed Physical Examinations .................................................... 58
7.1.2.4
Vital Signs.................................................................................................... 58
7.1.2.5
Height and Weight ....................................................................................... 59
7.1.2.6
Adverse Event Monitoring and Local Infusion Tolerability Monitoring .... 59
7.1.2.7
Clinical Signs and Symptoms ...................................................................... 59
7.1.2.8
Chest X-Ray................................................................................................. 60
7.1.2.9
PaO2/FiO2 OR O2 Saturation ........................................................................ 61
7.1.2.10 Infection Source Control Review................................................................. 61
Laboratory Procedures/Assessments .................................................................. 61
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 62
7.1.3.2
Culture and Susceptibility Testing............................................................... 63
7.1.3.2.1
Lower Respiratory Tract Sample Collected at Baseline....................... 63
 
 
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7.1.3.2.2
Other Lower Respiratory Tract Samples Following Randomization ... 64
7.1.3.2.3
Blood Cultures ...................................................................................... 64
7.1.3.2.4
Other Relevant Culture Samples........................................................... 65
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 65
7.1.3.3.1
Blood Collection for Plasma for REL, Imipenem, and Cilastatin ........ 65
7.1.3.4
Planned Genetic Analysis Sample Collection.............................................. 65
7.1.3.5
Future Biomedical Research........................................................................ 65
7.1.3.6
Efficacy Evaluation...................................................................................... 66
7.1.3.6.1
Survival Assessment............................................................................. 66
7.1.3.6.2
Clinical Response ................................................................................. 66
7.1.3.6.3
Microbiological Response .................................................................... 66
7.1.3.6.4
Disease-Related Complications ............................................................ 66
7.1.3.6.5
Health Resource Utilization Measures ................................................. 67
Length of Stay in Hospital ............................................................. 67
7.1.3.6.5.1
Duration of Mechanical Ventilation............................................... 67
7.1.3.6.5.2
ICU Length of Stay ........................................................................ 67
7.1.3.6.5.3
Other Procedures................................................................................................. 67
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 67
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 67
7.1.4.2
Blinding/Unblinding .................................................................................... 68
7.1.4.3
Calibration of Equipment............................................................................. 68
Visit Requirements.............................................................................................. 68
7.1.5
7.1.5.1
Screening...................................................................................................... 69
7.1.5.2
Treatment Period.......................................................................................... 69
7.1.5.3
Post-Therapy................................................................................................ 70
Assessing and Recording Adverse Events .......................................................... 70
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 71
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 71
7.2.2
Immediate Reporting of Adverse EventsAdverse Events and Incidents to the 
7.2.3
Sponsor ............................................................................................................... 72
7.2.3.1
Serious Adverse EventsAdverse Events and Incidents................................ 72
7.2.3.2
Events of Clinical Interest............................................................................ 73
 
 
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Evaluating Adverse Events ................................................................................. 74
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 77
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 77
7.3
Scientific Advisory Committee........................................................................... 77
7.3.1
Executive Oversight Committee ......................................................................... 77
7.3.2
Data Monitoring Committee ............................................................................... 77
7.3.3
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 78
Statistical Analysis Plan Summary ..................................................................... 78
8.1
Responsibility for Analyses/In-House Blinding ................................................. 80
8.2
Hypotheses/Estimation ......................................................................................... 80
8.3
Analysis Endpoints ............................................................................................... 80
8.4
Efficacy Endpoints.............................................................................................. 81
8.4.1
Safety Endpoints ................................................................................................. 81
8.4.2
Analysis Populations............................................................................................. 82
8.5
Efficacy Analysis Populations ............................................................................ 82
8.5.1
Safety Analysis Populations ............................................................................... 83
8.5.2
Statistical Methods................................................................................................ 83
8.6
Statistical Methods for Efficacy Analyses .......................................................... 83
8.6.1
Statistical Methods for Safety Analyses ............................................................. 84
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 86
8.6.3
Interim Analyses ................................................................................................... 86
8.7
Multiplicity ............................................................................................................ 88
8.8
Sample Size and Power Calculations .................................................................. 88
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 89
8.10
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 89
Investigational Product ........................................................................................ 89
9.1
Packaging and Labeling Information ................................................................. 90
9.2
Clinical Supplies Disclosure................................................................................. 90
9.3
Storage and Handling Requirements.................................................................. 90
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 90
9.5
Standard Policies................................................................................................... 91
9.6
 
 
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10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 91
Confidentiality....................................................................................................... 91
10.1
Confidentiality of Data ....................................................................................... 91
10.1.1
Confidentiality of Subject Records ..................................................................... 91
10.1.2
Confidentiality of Investigator Information........................................................ 91
10.1.3
Confidentiality of IRB/IEC Information............................................................. 92
10.1.4
Compliance with Financial Disclosure Requirements....................................... 92
10.2
Compliance with Law, Audit and Debarment ................................................... 92
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 94
10.4
Quality Management System............................................................................... 95
10.5
Data Management................................................................................................. 95
10.6
Publications ........................................................................................................... 95
10.7
11.0
LIST OF REFERENCES......................................................................................... 97
12.0
APPENDICES........................................................................................................... 99
Merck Code of Conduct for Clinical Trials........................................................ 99
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 101
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff .................................................................................... 107
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 116
APACHE II Severity of Disease Classification System – APACHE II 
12.5
Score Form .......................................................................................................... 117
Clinical Pulmonary Infection Score (CPIS) ..................................................... 119
12.6
List of Abbreviations .......................................................................................... 120
12.7
13.0
SIGNATURES......................................................................................................... 122
Sponsor's Representative ................................................................................... 122
13.1
Investigator.......................................................................................................... 122
13.2
 
 
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LIST OF TABLES
    
Table 1
Summary of Efficacy Endpoints and Components of a Favorable Response ........ 27
Table 2
Definitions of the Clinical Response Rating at the OTX Visits (Day 3, Day 6 
and Day 10 of IV Study Therapy).......................................................................... 28
Table 3
Definitions of the Clinical Response Rating at the EOT Visit ............................... 29
Table 4
Definitions of the Clinical Response Rating at the EFU Visit and Day 28 Post-
Randomization Visit............................................................................................... 30
Table 5
Definitions of the By-Pathogen Microbiological Response Rating at the EOT 
Visit ........................................................................................................................ 32
Table 6
Definitions of the By-Pathogen Microbiological Response at the EFU Visit ........ 33
Table 7
Trial Treatment ....................................................................................................... 41
Table 8
Administration Dosage of IMI/REL According to Renal Function ....................... 43
Table 9
Recommended Dosage of PIP/TAZ in Subjects According to Renal Function 
(Total PIP/TAZ dosage provided first, followed by individual components in 
parentheses ............................................................................................................. 44
Table 10 Infection-Site Clinical Signs and Symptoms.......................................................... 60
Table 11 Laboratory Tests ..................................................................................................... 62
Table 12 Evaluating Adverse Events..................................................................................... 75
Table 13 Summary of Analysis Strategy for Primary and Key Secondary Efficacy 
Endpoints................................................................................................................ 84
Table 14 Analysis Strategy for Safety Parameters ................................................................ 86
Table 15 Sample Size Adjustments based on Interim Blinded Review of Day 28 All-
Cause Mortality...................................................................................................... 87
Table 16 Product Descriptions............................................................................................... 89
 
 
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LIST OF FIGURES
Figure 1
Trial Design ........................................................................................................ 16
 
 
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SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.2.3.1.1.3
8.6.1
Microbiological Response
Statistical Methods for Efficacy 
Analyses
Added a fifth Indeterminate response 
option:  e) No specimen taken because 
subject is deemed clinically cured or 
improved.  Added/edited associated 
footnotes b and c linking this new 
indeterminate response category to 
“Presumed Eradication” in Tables 5 and 
6 
Definitions 
of 
Microbiological 
Response at the End-of-Therapy (EOT) 
and Early Follow-up (EFU) Visits, 
respectively, and added text description 
of this option for the efficacy analyses.
This update is in alignment with the way 
the data are already being collected in 
the study.
This change was made to provide 
an 
additional 
option 
of 
indeterminate 
microbiological 
response so that a “presumed 
eradication” outcome may be 
derived based on patients who are 
clinically cured or improved and 
from 
whom 
a 
respiratory 
specimen could not be obtained.  
The 
outcome 
of 
“presumed 
eradication” will be considered a 
favorable overall microbiological 
response in the efficacy analyses.  
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
2.1
5.4
7.1.1.7
8.1
Trial Design
Stratification
Assignment 
of 
Randomization 
Number
Statistical Analysis Plan Summary -
Treatment Assignment
The 
randomization 
requirement 
was 
modified to allow for “approximately” 
50% of subjects with ventilated HABP or 
VABP.
This change was made to allow 
flexibility in the number and 
proportion of ventilated HABP 
or VABP subjects randomized.
5.1.3
Subject Exclusion Criteria
Exclusion #1
Exclusion #12
Added list of acceptable Gram stain 
patterns to clarify what constitutes an 
exclusionary pattern.
Added a note clarifying that the use of 
seizure prophylaxis among patients with 
no active or prior history of seizure 
disorder is acceptable for the specified 
uses, considering Exclusion #12.  
These clarifications were added 
to better define these exclusion 
criteria.
5.5
Concomitant 
Medications/Vaccinations (Allowed 
& Prohibited)
Clarified that medications specifically 
prohibited in the protocol are not allowed 
during IV study therapy, rather than 
during the whole study.
This text was updated to align 
with current Merck standard 
protocol template.
6.0
7.1.3.3
Trial Flow Chart - Whole blood to 
obtain plasma for REL, imipenem, 
and cilastatin assay, Footnote “t”
Pharmacokinetic/ 
Pharmacodynamic Evaluations
Clarified the timing of PK sampling to 
post-“start of” Dose 3.
This text was added to clarify 
PK sample collection timing 
relative to the start of infusion.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.3.2.2
Other Lower Respiratory Tract 
Samples Following Randomization
Removed the acceptable sputum sample 
criterion for post-baseline specimens of 
“greater than 25 neutrophils on low power 
microscopy review of the Gram stain”.
This text was removed; it had 
been included in error in the 
previous protocol version.
7.1.4.2
Blinding/Unblinding
Updated 
the 
text 
on 
participant 
blinding/unblinding for blinded trials 
(IVRS/IWRS) 
using 
the 
emergency 
unblinding call center
This text was updated to align 
with 
the 
Merck 
standard 
protocol template language in 
the latest general protocol 
amendment (-014-04) for this 
study.
7.1.4.3
Calibration of Equipment
Removed 
“critical” 
throughout 
and 
deleted the list of equipment.
This text was updated to align 
with current Merck standard 
protocol template.
9.3
Clinical Supplies Disclosure
Updated the text for blinded trials 
(IVRS/IWRS) 
using 
the 
emergency 
unblinding call center with no disclosure 
envelopes provided.
This text was updated to align 
with current Merck standard 
protocol template.
8.6.1
Statistical Methods for Efficacy 
Analyses
Added specification that Cochran-Mantel-
Haenszel (CMH) weights will be used for 
efficacy analyses by baseline pneumonia 
type and APACHE II score.
This text was added to provide 
the methods to be used for the 
stratified efficacy analyses.
 
 
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1.0
TRIAL SUMMARY
Abbreviated Title
IMI/REL (MK-7655A) vs. PIP/TAZ for Treatment of Subjects with 
HABP/VABP
Trial Phase
III
Clinical Indication
Treatment 
for 
hospital-acquired/ventilator-associated 
bacterial 
pneumonia (HABP/VABP)
Trial Type
Interventional
Type of control
Active control 
Route of administration
Intravenous
Trial Blinding
Double-blind
Treatment Groups
Treatment Group 1: Imipenem/cilastatin/relebactam (IMI/REL)
administered intravenously (IV) as a fixed-dose combination
Treatment Group 2: Piperacillin/tazobactam (PIP/TAZ) administered 
IV as a fixed-dose combination.
In both treatment groups, the use of initial empiric treatment with 
open-label IV linezolid (600 mg every 12 hours) for methicillin-
resistant S. aureus (MRSA) infection is required and will be 
administered in an open-label fashion.
Number of trial subjects
Approximately 536 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 25 
months [(~ 107 weeks) of enrollment + up to 14 days (2 weeks) of IV 
study therapy + at least 14 days (2 weeks) of follow-up = 111 weeks]
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
Subjects who are consented under the standard consent option will 
participate in the trial for approximately 28 to 31 days from the time 
the subject signs the Informed Consent Form (ICF) through the final 
contact.  After a screening visit, each subject will be receiving 
assigned treatment for approximately 7 to up to 14 days.  After the end 
of treatment each subject will be followed for 14 days. All subjects 
must also have a study visit at 28 days following randomization.  The 
total duration for each subject in the study will be up to 31 days.
Subjects who are consented under the early consent option will 
participate in the trial for approximately 42 to 45 days due to a 
prolonged screening period of up to 14 days. The total duration for 
these subjects will be up to 45 days.
A list of abbreviations used in this document can be found in Section 12.7.
Randomization Ratio
1:1 for Treatment Group 1 IMI/REL: Treatment Group 2 PIP/TAZ
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, double-blind (with in-house blinding), active-controlled, parallel-
group, multi-site trial of imipenem/cilastatin/relebactam (also known as MK-7655A; 
hereafter referred to as IMI/REL) compared with piperacillin/tazobactam (PIP/TAZ) in
subjects with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated 
bacterial pneumonia (VABP). Subjects with HABP may either be ventilated (ventilated 
HABP) or non-ventilated (non-ventilated HABP).  There are 2 consent options for this trial: 
an early consent option (Section 2.1.1) and a standard consent option (Section 2.1.2).
Approximately 536 subjects will be randomized in a 1:1 ratio to one of two 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 six 
hours. Subjects who are consented under the early consent option will have a maximum 
14-day screening period following signing of consent. Subjects who are consented under the 
standard consent option will receive study treatment after a maximum 48-hour screening 
period following signing of consent. All randomized subjects in each treatment group will 
receive a minimum of 7 days to up to a maximum of 14 days of IV study therapy.  Subjects 
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 subjects 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 post-
randomization visit will be performed in all subjects (this visit may be performed on the 
same day as the EFU visit, depending on the duration of IV study therapy).  All subjects will 
remain in the study for a total of up to 31 days after study randomization.
Since the study will enroll subjects 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.
The recommended treatment 
duration for a confirmed MRSA infection is a minimum of 7 days, with a minimum of 14 
days for MRSA bacteremia.  Empiric linezolid treatment will be stopped if the final culture
results from the baseline lower respiratory tract 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).  Approximately 50% of subjects will have ventilated
HABP or VABP. 
Safety and tolerability will be carefully monitored throughout the study by an external Data 
Monitoring Committee (eDMC).
 
 
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Early Consent Option
2.1.1
An early consent option is permitted for subjects who are considered at risk by the 
investigator for developing VABP but have not yet exhibited any or all of the clinical or 
radiographic signs or symptoms of VABP when they enter the study. Subjects who provide 
early consent must meet the following 3 early screening criteria and then have up to 2 weeks 
to fulfill all remaining inclusion and exclusion criteria and be randomized to receive study 
medication:

are 18 years or older on the day of signing informed consent (ie, Inclusion Criterion 
#1),

are anticipated to require extended intubation based on the opinion of the investigator, 
which can potentially put the subject at risk of developing VABP (ie, Inclusion 
Criterion #9), and 

understand (or have a legal representative that understands) the study procedures, 
alternative treatments available, and risks involved with the study, and voluntarily 
agree to participate by giving written informed consent for the trial (ie, Inclusion 
Criterion #7).
If these 3 early screening criteria are fulfilled and the subject goes on to develop signs and 
symptoms of pneumonia, the subject will qualify to be assessed for disease eligibility. If 
disease eligibility and all other study entry criteria are met, the subject may be randomized 
within 48 hours after meeting study entry criteria and will proceed into the study.
Standard Consent Option
2.1.2
The standard consent option is for subjects who meet all study entry criteria at the time of 
providing consent. These subjects will be randomized within 48 hours after meeting study 
entry criteria.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1
Trial Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) 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 subjects diagnosed with HABP/VABP in the modified intention-to-
treat (MITT) population.
Hypothesis: IMI/REL is non-inferior to PIP/TAZ in subjects with HABP/VABP, as 
measured by the incidence rate of all-cause mortality through Day 28 post-
randomization in the MITT population.  A non-inferiority margin of 10% will be 
used. Further details for determining non-inferiority are described in Section 8.0 
(Statistical Analysis Plan).  If non-inferiority is established, the following will be 
evaluated: IMI/REL is superior to PIP/TAZ in subjects with HABP/VABP, as 
measured by the incidence rate of all-cause mortality through Day 28 post-
randomization in the MITT population.
Secondary Objective(s) & Hypothesis(es)
3.2
Key Secondary Objective
3.2.1
1) Objective: To evaluate the efficacy of IMI/REL versus PIP/TAZ with respect to 
clinical response at the early follow-up (EFU) visit 7 to 14 days after the end of 
therapy (EOT) for subjects diagnosed with HABP/VABP in the MITT population. 
Hypothesis: IMI/REL is non-inferior to PIP/TAZ with respect to the proportion of 
subjects with a favorable clinical response at the EFU visit in subjects with 
HABP/VABP in the MITT population.  A non-inferiority margin of 12.5% will be 
used.  Further details for determining non-inferiority are described in Section 8.0 
(Statistical Analysis Plan).  If non-inferiority is established, the following will be 
evaluated: IMI/REL is superior to PIP/TAZ with respect to the proportion of subjects 
with a favorable clinical response at the EFU visit in subjects with HABP/VABP in 
the MITT population.
Other Secondary Objectives
3.2.2
1) Objective: To evaluate the safety and tolerability profile of IMI/REL vs. PIP/TAZ 
in subjects with HABP/VABP.
2) Objective: To determine the incidence rate of all-cause mortality through Day 28 
post-randomization for IMI/REL versus PIP/TAZ in subjects diagnosed with 
HABP/VABP in the microbiological modified intention-to-treat (mMITT) population.
3) Objective: To determine the incidence rate of all-cause mortality at the EFU visit for
IMI/REL versus PIP/TAZ in subjects diagnosed with HABP/VABP in the MITT 
population and mMITT population.
 
 
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4) Objective: To determine the incidence rate of all-cause mortality through Day 28 
post-randomization in subjects treated with IMI/REL versus PIP/TAZ based on 
pneumonia type (non-ventilated HABP, ventilated HABP/VABP) in the MITT 
population and mMITT population.
5) Objective:  To evaluate the efficacy of IMI/REL versus PIP/TAZ with respect to 
clinical response at the EFU visit for subjects diagnosed with HABP/VABP in the 
clinically evaluable (CE) population. 
6) Objective: To evaluate the efficacy of IMI/REL versus PIP/TAZ with respect to 
clinical response on Day 3 of IV study therapy (OTX1), Day 6 of IV study therapy 
(OTX2), Day 10 of IV study therapy (OTX3, if applicable), at the EOT visit, and at 
Day 28 post-randomization for subjects diagnosed with HABP/VABP in the MITT 
population and CE population.
7) Objective:  To evaluate the efficacy of IMI/REL versus PIP/TAZ with respect to 
microbiological response at the EOT visit and at the EFU visit for subjects diagnosed 
with HABP/VABP in the mMITT population and microbiologically evaluable (ME) 
population.
Exploratory Objectives
3.3
1) Objective: 
To summarize the pharmacokinetics of relebactam, imipenem, and 
cilastatin and to evaluate the pharmacokinetic-pharmacodynamic (PK/PD) association 
of relebactam and imipenem.
2) Objective: To determine the incidence of all-cause mortality and disease-related 
complications (e.g., development of empyema; onset of acute respiratory distress 
syndrome; bacteremia) through Day 28 post-randomization in subjects treated with 
IMI/REL versus PIP/TAZ in the MITT population.
3) Objective:  To evaluate the efficacy of IMI/REL versus PIP/TAZ with respect to the 
following key health resource utilization measures: (a) number of days spent in the 
hospital post-randomization (i.e., length of stay [LOS]) in the MITT population and 
mMITT population; (b) the number of days spent on mechanical ventilation post-
randomization for the subset of subjects with VABP and ventilated HABP in the 
MITT population and mMITT population; (c) the number of days spent in the 
intensive care unit (ICU) post-randomization for the subset of subjects with VABP 
and ventilated HABP in the MITT population and mMITT population.
4) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered.  Variation across the human genome will be analyzed for 
association with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the MK-7655 Investigator’s Brochure (IB) for detailed background information on 
MK-7655A
 
 
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Pharmaceutical and Therapeutic Background
4.1.1
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 one 
or more of the four 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.  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 
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 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. 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 a dual Ambler 
Class A/Class C BLI that is highly potent against AmpC, a common Class C β-lactamase 
encountered in many bacteria, most predominantly Pseudomonas aeruginosa. REL is also 
active against the Class A β-lactamases, including the Klebsiella 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 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 one month in monkeys with no adverse effects noted at 1.3 times the targeted human 
exposure of 344.4 uM.hr.  Evidence of renal toxicity was observed when MK-7655 was 
administered alone at levels 8 times the target human exposure; however, no clinically 
 
 
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relevant findings associated with renal function have been identified in the Phase I studies or 
in the completed Phase II study in humans.  
As of 30-Nov-2017, REL has been evaluated in approximately 265 individuals, 232 of whom
have received at least one dose of REL, across seven completed Phase I 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 I 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 subjects receiving 
IMI alone.  None of the liver transaminase elevations in these subjects were associated with 
clinical findings.  The elevations were not dose related and were reversible after 
discontinuation of dosing.  Elevations have not been observed in subjects administered single 
or multiple doses in subsequent Phase I or Phase II trials.  
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 subjects (PN005).  Pharmacokinetic data from 
PN005 were consistent with expectations given that REL, imipenem and cilastatin are 
cleared almost entirely renally in healthy subjects.  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 three analytes when comparing subjects with renal 
impairment to their healthy matched subjects.  These data are consistent with the expected 
change in magnitude of glomerular filtration rate (GFR).  In addition, in subjects 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 subjects showed comparable penetration of REL and imipenem
into the epithelial lung fluid (ELF), with relative exposures (AUC0-inf in ELF compared to 
plasma) based on mean profiles of 43% for REL and 42% for IMI.  In PN009, a thorough 
QTc study in 36 healthy subjects, a supratherapeutic dose of REL did not prolong the QTcP 
interval to a clinically significant degree.
Two Phase II comparator-controlled clinical trials of IMI + REL (Protocol 003 [PN003] and 
Protocol 004 [PN004]) have been completed. Both trials were randomized, double-blind, 
multicenter, comparative studies evaluating the safety, tolerability, and efficacy of IMI + 
REL versus IMI alone in 302 adults with complicated urinary tract infection (cUTI, PN003) 
and 351 adults with complicated intra-abdominal infection (cIAI, PN004). In both trials, 
subjects were randomized in a 1:1:1 ratio to one of 3 treatment groups (1) IMI (500 mg) + 
REL (250 mg), (2) IMI (500 mg) + REL (125 mg), or (3) IMI (500 mg) + placebo.  The 
primary efficacy analysis for each study indicates that treatment with either dose of IMI + 
 
 
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REL is as effective as IMI alone as measured by the proportion of subjects with cUTI with a 
favorable microbiological response at completion of IV study therapy (DCIV, PN003) and 
the proportion of subjects with cIAI with a favorable clinical response at DCIV (PN004).
Overall, both doses of REL (125 mg and 250 mg) were generally well tolerated.
Additional details regarding the preclinical, Phase I, and Phase II clinical studies completed 
to date are summarized in the MK-7655 IB.
Ongoing Clinical Trials
4.1.2
A Phase III clinical trial of IMI/REL has recently completed enrollment, and data are 
undergoing analysis as of 30-Nov-2017. PN013 is a randomized, double-blind, comparator-
controlled study to estimate the safety and efficacy of IMI/REL versus colistin as 
colistimethate sodium (CMS) + IMI in subjects with imipenem-non-susceptible bacterial 
infections, including HABP/VABP, cIAI, and cUTI. Forty-seven subjects were randomized 
in a 2:1 ratio to receive one of the following double-blind treatments: 1) IMI/REL + placebo 
to CMS, or 2) CMS + IMI (500 mg).  In addition, 3 subjects were enrolled into a third, open-
label treatment arm in subjects with imipenem- and colistin-non-susceptible infections who 
received IMI/REL.
Information on Other Trial-Related Therapy
4.1.3
4.1.3.1
Comparator Therapy
Subjects in the comparator arm of this trial will receive intravenous (IV) infusions of 
piperacillin/tazobactam (PIP/TAZ).
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 subjects with 
moderate to severe infections caused by susceptible gram-negative and gram-positive 
bacterial isolates: (β-lactamase producing isolates of Escherichia coli, Staphylococcus 
aureus, Haemophilus influenzae), members of the Bacteriodes fragilis group (B. fragilis, B. 
ovatus, 
B.
thetaiotaomicron, 
or 
B. 
vulgatus), 
piperacillin/tazobactam-susceptible 
Acinetobacter 
baumannii, 
Haemophilus 
influenzae, 
Klebsiella 
pneumoniae, 
and 
Pseudomonas aeruginosa) for conditions such as intra-abdominal infections, skin and skin 
structure infections, female pelvic infections, community-acquired pneumonia and 
nosocomial pneumonia [1].
PIP/TAZ acts by inhibiting septum formation and cell wall synthesis of susceptible bacteria.
4.1.3.2
Co-administration of Open-label Therapy with Linezolid for MRSA
Beginning at randomization, all subjects will receive initial empiric treatment with IV 
linezolid (600 mg q12h) for methicillin-resistant S. aureus (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 
 
 
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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: 
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. [2]
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 American Thoracic Society 
(ATS)/Infectious Diseases Society of America (IDSA) guidelines on the treatment of 
HABP/VABP and the IDSA guidelines on treatment of MRSA infections.  Of note, these 
guidelines recognize that linezolid might be preferred in certain situations, including (a) 
subjects with evidence of renal insufficiency due to potential for vancomycin under dosing in 
this patient population and the potential risk of nephrotoxicity associated with vancomycin; 
and (b) institutions where vancomycin resistance (i.e., MRSA isolates with vancomycin MIC 
≥2 mcg/mL) is common. [3] [4]
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 
patients and 47% of vancomycin-treated patients had achieved clinical cure at end of study. 
Additionally, 83% of linezolid-treated patients and 70% of vancomycin-treated patients 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 patients and 
46% of vancomycin-treated patients 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 were similar in the 2 treatment 
groups, nephrotoxicity occurred more commonly on vancomycin than linezolid (18% vs. 8%, 
respectively). [5] 
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Details regarding specific benefits and risks for subjects participating in this clinical trial 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 subjects 
despite advances in antimicrobial therapy, improvements in supportive care and the use of a 
wide range of preventative measures. In subjects with HABP, mortality rates are significant
and range from 12-22% [6] [7] [8].  The risk of mortality increases approximately two-fold in 
subjects with hospital-acquired pneumonia associated with mechanical ventilation (VABP) 
and can be even higher when the lung infection is caused by multidrug-resistant (MDR) 
bacteria [9]. These infections are among the most frequently occurring infections in ICUs and 
account for a large majority of the antibacterial utilization within ICUs [6].  Appropriate 
antibiotic therapy significantly improves survival for subjects with HABP or VABP. In these 
vulnerable subjects, additional increases in morbidity and mortality can be attributed to the 
 
 
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empiric use of antimicrobial therapy that is not active against causative pathogens [10]. 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 subjects with HABP or VABP.  IMI/REL has the 
potential to fulfill a significant and growing unmet medical need by providing a next 
generation BL/BLI with which to combat severe gram-negative bacterial infections.
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 subjects 
diagnosed with HABP or VABP.
If non-inferiority is established, then superiority of 
IMI/REL compared to PIP/TAZ will be evaluated.
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, secondary endpoints will focus on the clinical response and microbiological response 
in an effort to provide additional information with regard to the effect of IMI/REL vs. 
PIP/TAZ in HABP/VABP subjects.
Rationale for Dose Selection/Regimen/Modification
4.2.2
4.2.2.1
IMI (500 mg)/REL (250 mg)
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 four-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 I 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 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, such as 250 mg administered IV once every 6 
hours, would support this evaluation.
Per the ATS/IDSA treatment guidelines for nosocomial pneumonia, a recommended IMI 
dose for HABP/VABP is 500 mg every 6 hours. [3].
In order to assess drug penetration at the site of action (pulmonary penetration), an open-
label study was conducted to evaluate the pharmacokinetics (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 subjects.  The 
intrapulmonary pharmacokinetic profiles of REL and imipenem were assessed after subjects 
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 epithelial lining fluid (ELF) 
was similar, with relative exposures (AUC0-inf 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 
 
 
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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.  
Both 125 mg and 250 mg doses of REL have been evaluated in the Phase II 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 subjects 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 4.1.1 and the MK-7655 IB for further details).  The 250 mg dose was selected 
for this study to achieve exposures above the PK target that may be required for the treatment 
of highly resistant organisms.  
As previously discussed, REL, imipenem and cilastatin are primarily renally excreted, with 
similar increases observed for each analyte in a Phase I renal insufficiency study (PN005).  
Thus, dose adjustments can be made in the same proportion for both REL and IMI, and all 
can be dosed in a fixed ratio.  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 subjects with 
renal impairment.  Depending on the individual subject’s renal function (as determined by 
actual or estimated creatinine clearance), the total daily dose of IMI/REL may be adjusted.  
The IMI package circular also includes reduced daily doses for patients with lower body 
weight.  However, the total daily dose for IMI-containing therapy (IMI/REL and IMI) for 
subjects in this study will not be adjusted for weight. This approach is consistent 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 [6] [11] [12] [13].  The few published clinical trials 
in which IMI dosage was adjusted for weight describe similar efficacy and safety [14] [15].   
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 subjects 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 
subjects with normal renal function, the dose of 250 mg REL and 500 mg IMI given every 6 
hours IV is appropriate.  For subjects 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 
 
 
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consistent percentage of subjects 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 5.2.1.1.
4.2.2.2
Comparator –PIP (4000 mg)/TAZ (500 mg) 
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 ATS/IDSA treatment guidelines [3] for nosocomial 
pneumonia. The chosen dose is routinely administered to subjects in clinical practice for this 
indication.  
4.2.2.3
Duration of Therapy
IV study therapy will be administered for a minimum of 7 days up to a maximum of 14 days. 
Of note, subjects 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 ATS/IDSA 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 [3]. If deemed clinically appropriate, subjects 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 vs. ~1 week of 
therapy [16] [17].  Lower responses and higher mortality were also recently seen following 
treatment with a shorter course of therapy (1 week of doripenem) vs. a longer course of 
therapy (10 days of IMI) in P. aeruginosa VABP cases [6].  A 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.  
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 REL.
4.2.2.4
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. 
 
 
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Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
The primary efficacy endpoint in this study is all-cause mortality at Day 28 post-
randomization in the MITT population (see Section 8.4.1).  Given the severity of illness in 
hospitalized subjects with HABP/VABP whom routinely require in-hospital treatment with 
IV antibiotics, evaluation of mortality is appropriate.  A one-month mortality endpoint has 
commonly been used for evaluation of efficacy of antibacterial therapy against HABP/VABP 
infections [6] [15] [18]. Based on the results of recently conducted trials, approximately 15% 
of subjects will die even though they receive antibacterial drug therapy for HABP/VABP 
[14] [12] [19] [15]. The goal of this trial is to demonstrate that IMI/REL is non-inferior to 
piperacillin/tazobactam (PIP/TAZ) in subjects 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 key secondary measurement for efficacy in this study is:

Clinical response for each subject evaluated at the early follow-up (EFU) visit, which 
will be performed 7 to 14 days after the end of therapy (EOT) visit.  Assessments 
will be made in the MITT population.  The evaluation of clinical response at this 
time point will provide valuable data to fully characterize the response profile of the 
test product relative to the comparator.
There are several other secondary measurements of efficacy in this study:

All-cause mortality will also be evaluated through Day 28 post-randomization in the 
mMITT population.  This mMITT population for this endpoint will add supportive 
information to the primary efficacy endpoint in the MITT population.

All-cause mortality will also be evaluated at the EFU visit in the MITT population 
and the mMITT population.

All-cause mortality will also be evaluated through Day 28 post-randomization based 
on pneumonia type (non-ventilated HABP, ventilated HABP, or VABP) in the MITT 
population and the mMITT population.

Clinical response for each subject will also be evaluated at the Day 3, Day 6, and 
Day 10 on-therapy visits (OTX1, OXT2, and OTX3 [if applicable]), at the EOT visit, 
and at Day 28 post-randomization in both the MITT and CE populations.  In 
addition, clinical response will be evaluated at the EFU visit in the CE population 
alone. 

Microbiological response for each subject will also be evaluated at the EOT and EFU 
visits in both the mMITT and ME populations. 
Other exploratory efficacy endpoints in this study include post-randomization hospital LOS, 
LOS in the ICU (for ventilated HABP and VABP subjects), and number of days spent on 
mechanical ventilation (for ventilated HABP and VABP subjects).  These additional 
endpoints will provide further information on infection-associated health outcomes important 
in estimating cost effectiveness of IMI/REL vs PIP/TAZ.  Another exploratory endpoint is 
 
 
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the pharmacokinetic evaluation of study therapy (imipenem, REL, and cilastatin).  PK/PD 
evaluations will be incorporated into IMI/REL population PK models to evaluate intrinsic 
and extrinsic factors that may impact the relationship of PK to PD.
4.2.3.1.1 Definition of Efficacy Endpoints
Refer to Table 1 for a summary favorable response by efficacy endpoint and analysis 
population.
Table 1
Summary of 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 4.2.3.1.1.1
Key 
Secondary
Clinical Response 
EFU
Sustained cure
Cure
MITT 
Section 4.2.3.1.1.2
Table 4
Other 
Secondary
All-Cause Mortality
Day 28
Survival 
mMITT
Section 4.2.3.1.1.1
All-Cause Mortality
EFU
Survival  
MITT and 
mMITT
Section 4.2.3.1.1.1
All-Cause Mortality
(non-ventilated 
HABP, ventilated 
HABP, or VABP)*
Day 28
Survival 
MITT and 
mMITT
Section 4.2.3.1.1.1
Clinical response
OTX1,
OTX2,
OTX3
Improved
MITT and CE
Section 4.2.3.1.1.2
Table 2
EOT 
Cure
Improved
Section 4.2.3.1.1.2
Table 3
EFU, 
Day 28
Sustained cure
Cure
Section 4.2.3.1.1.2
Table 4
Microbiological 
response
EOT, EFU
Eradication
mMITT and 
ME
Section 4.2.3.1.1.3
Table 5 and Table 6
Exploratory
All-cause mortality 
or  disease-related 
complications (e.g., 
empyema, onset of 
acute respiratory 
distress syndrome, 
bacteremia)
Day 28
Similar survival 
and disease-
related 
complications 
compared to 
PIP/TAZ
MITT
Section 4.2.3.1.1.1
Number of days 
spent in the 
hospital post-
randomization
NA
NA
MITT and 
mMITT
Section  7.1.3.6.5
Number of days 
spent on 
mechanical 
ventilation post-
randomization
NA
NA
MITT and 
mMITT
Section  7.1.3.6.5
Number of days 
spent in ICU post-
randomization
NA
NA
MITT and 
mMITT
Section 7.1.3.6.5
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; CE = clinically evaluable population; NA= not applicable
*Sub-group analysis of all-cause mortality will be conducted for each of the sub-groups.
 
 
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Survival/All-cause Mortality 
4.2.3.1.1.1
Survival status (i.e., whether the subject is alive or dead) through Day 28 post-randomization 
and EFU visits will be evaluated for all subjects in support of the primary and key secondary 
objectives, respectively.  
Clinical Response
4.2.3.1.1.2
Clinical response will be assessed for all subjects based on evaluation by the investigator at 
the OTX1, OTX2, OTX3 (if applicable), EOT, EFU, and Day 28 post-randomization visits.  
Based on comparison to baseline clinical signs and symptoms of the subject’s infection, the 
investigator will determine the clinical response rating at each visit as described in Table 2
(for OTX1, OTX2 and OTX3 visits, If applicable), Table 3 (for EOT visit), and Table 4 (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”. Details regarding determination of the category of clinical 
response (“favorable” or “unfavorable”) in support of relevant study endpoints are provided 
in the tables describing clinical response and in the full protocol in Section 8.2.
Table 2
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)
Subject was withdrawn for any reason before sufficient data had been 
obtained to permit evaluation for any reason; OR
c)
Extenuating circumstances (e.g., 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 #3 and Table 10 for a description of relevant clinical signs and symptoms.
 
 
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Table 3
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)
Subject was withdrawn for any reason before sufficient data had been 
obtained to permit evaluation for any reason; OR
c)
Extenuating circumstances
(e.g., 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 #3 and Table 10 for a description of relevant clinical signs and symptoms.
 
 
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Table 4
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
Subjects 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)
Subject was withdrawn for any reason before sufficient data had been 
obtained to permit evaluation of clinical response; OR
c)
Extenuating circumstances (e.g., 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 #3 and Table 10 for a description of clinical signs and symptoms.
Microbiological Response
4.2.3.1.1.3
In addition to clinical response assessments, subjects will be evaluated for microbiological 
response. Microbiological response will be evaluated separately for each lower respiratory 
tract pathogen isolated in the baseline culture (i.e., 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 local laboratory results of lower respiratory tract cultures 
collected for subjects at each of these visit, when available, relative to the pathogen(s) 
isolated at baseline/admission as described in Table 5 (for EOT visit) and Table 6 (for EFU 
visit).  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 (i.e., sample contains fewer than 10 squamous epithelial cells and greater than
25 neutrophils on low power microscopy review of the Gram stain).  
 
 
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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 (i.e., overall microbiological response for the subject 
based on the response of all pathogens present in the baseline lower respiratory tract culture) 
will be assessed as “favorable” or “unfavorable.”  For subjects from whom only one 
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 subjects from whom more than one 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 (i.e., a “favorable” overall 
microbiological response requires eradication of all baseline pathogens). 
Details regarding determination of the category of overall microbiological response outcome 
(“favorable” or “unfavorable”) in support of relevant study endpoints are provided in the 
tables describing microbiological response and in the full protocol in Section 8.4.1.
 
 
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Table 5
Definitions of the By-Pathogen Microbiological Response Rating at the EOT 
Visit
Microbiological 
Responsea,b,c
Response Definition
Eradication
A lower respiratory tract culture taken at the EOT visitd shows eradication
of the pathogen found at study entry.
Persistencee
A lower respiratory tract culture taken at the EOT visitd grows the
pathogen found at study entry.
Superinfection
An infection-site culture grows a pathogen other than a baseline pathogen 
during the course of IV study therapy OR emergence during IV study 
therapy of a new pathogen at a distant sterile site along with worsening 
signs and symptoms of infection.
Indeterminate
a)
Follow-up culture is not available at the EOT visitd due to subject
death or withdrawal from study; OR
b)
Available microbiological data are incomplete; OR
c)
Extenuating circumstances (e.g., a major protocol violation) preclude
microbiological assessment;  OR
d)
Any other circumstance which makes it impossible to define the 
microbiological response
e)
No specimen taken because subject is deemed clinically cured or 
improved
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 which was not identified at baseline, the microbiological 
response rating should be recorded as “superinfection” for any new/emergent pathogen isolated after initiation 
of IV study therapy.
b. The response of “No specimen taken because subject is deemed clinically cured or improved” will be 
considered to be “presumed eradication”.
c. A favorable by-pathogen microbiological response at EOT requires “eradication” or “presumed eradication”
(i.e., Indeterminate - No specimen taken because subject is deemed clinically cured or improved) of the 
baseline pathogen.
d. 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.
e. If a subject is discontinued from IV study therapy due to clinical failure (i.e., unfavorable clinical response), 
but persistence of the admission pathogen is not confirmed by culture results or no culture is obtained at the 
time of clinical failure, the admission pathogen will be presumed to have persisted.
 
 
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Table 6
Definitions of the By-Pathogen Microbiological Response at the EFU Visit
Microbiological 
Responsea,b,c
Response Definition
Eradication
A lower respiratory tract culture taken at the EFUd visit shows eradication 
of the pathogen found at study entry.
Persistence
A lower respiratory tract culture taken at the EFU visit grows the
pathogen found at study entry.
New Infection
A pathogen, other than an original microorganism found at baseline is 
present in the lower respiratory tract specimen  any time after IV study 
therapy is finished; OR
A pathogen is isolated from a distant sterile site after IV study therapy has 
been completed.  
Recurrence
A lower respiratory tract specimen grows the baseline pathogen taken any 
time after documented eradication. 
Indeterminate
a)
Follow-up culture is not available at the EFU visit due to subject
death or withdrawal from study; OR
b)
Available microbiological data are incomplete; OR
c)
Extenuating circumstances (e.g., a major protocol violation) preclude
microbiological assessment;  OR
d)
Any other circumstance which makes it impossible to define the 
microbiological response
e)
No specimen taken because subject is deemed clinically cured or 
improved
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 which was not identified at baseline, the microbiological 
response rating should be recorded as “new infection” for any new/emergent pathogen isolated after initiation 
of IV study therapy.
b. The response of “No specimen taken because subject is deemed clinically cured or improved” will be 
considered to be “presumed eradication”.
c. A favorable by-pathogen microbiological response at EFU visit requires “eradication” or “presumed 
eradication” (i.e., Indeterminate - No specimen taken because subject is deemed clinically cured or improved)
of the baseline pathogen.
d. 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 subject had fully resolved clinical symptoms/signs of the index infection at the EFU visit.
4.2.3.2
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 the Trial Flow Chart.  Adverse events are graded and 
recorded according to Section 7.2.  Subjects may be asked to return for unscheduled visits in 
order to perform additional safety monitoring.  
 
 
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4.2.3.3
Pharmacokinetic Endpoints
At the time points specified in the Trial Flow Chart (Section 6.0), whole blood samples will
be collected for determination of plasma concentrations of REL, imipenem, and cilastatin.  
These samples will support further evaluation of the pharmacokinetic profiles of these drugs
by confirming that subjects achieve expected exposures, and will also aid in further 
assessment of the clinical relationship between IMI and REL plasma concentrations and 
efficacy. 
4.2.3.4
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research.  This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation.  If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
4.2.3.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA specimens collected for 
future biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects enrolled in this trial are hospitalized patients with infections requiring treatment 
with IV therapy.  If randomized to receive IMI/REL, subjects 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. 
 
 
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The combination, IMI/REL, is specifically targeted for treatment of gram-negative 
imipenem-resistant infections.  Subjects randomized to the comparator arm will also receive 
a treatment regimen expected to be efficacious against HABP/VABP (see Section 4.2.2 and 
4.2.2.1).  
Although potentially more frequent than standard of care, the study procedures described in 
Section 6.0 (Trial Flow Chart) 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 (e.g., 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.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying MK-7655A Investigators Brochure (IB) and 
Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male and female subjects who are at least 18 years of age and have been diagnosed with 
either hospital-acquired (HABP) or ventilator-associated bacterial pneumonia (VABP) will 
be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. be ≥ 18 years of age on the day of signing informed consent.
NOTE: Adults are the intended study population for this protocol.  Subjects under the 
age of legal consent per a specific country’s regulation should be excluded from 
participation in this study.
2. require treatment with IV antibiotic therapy for hospital-acquired bacterial pneumonia 
(HABP) or ventilator-associated bacterial pneumonia (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 subject after being hospitalized for more 
than 48 hours or within 7 days after discharge from a hospital stay of at least 48 
hours duration (includes patients institutionalized in a skilled nursing or other long-
term care facility). Of note, such subjects 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 
 
 
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occurring in a subject already receiving mechanical ventilation via an endotracheal 
tube for a minimum of 48 hours. 
3. fulfill the clinical and radiographic criteria described below, with onset of criteria 
occurring after more than 48 hours of hospitalization or within 7 days after discharge 
from a hospital (for HABP) or at least 48 hours after mechanical ventilation (for 
VABP):
(a)
Subject has at least one of the following clinical features: 

New onset or worsening pulmonary symptoms or signs, such as cough, dyspnea, 
tachypnea (e.g., respiratory rate greater than 25 breaths per minute), expectorated  
sputum production, or requirement for mechanical ventilation

Hypoxemia [e.g., a partial pressure of oxygen less than 60 millimeters of mercury 
while the subject is breathing room air, as determined by arterial blood gas 
(ABG) or worsening of the ratio of the partial pressure of oxygen to the fraction 
of inspired oxygen (PaO2/FiO2)]

Need for acute changes in the ventilator support system to enhance oxygenation, 
as determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes 
in the amount of positive end-expiratory pressure 

New onset of suctioned respiratory secretions
AND
(b)
Subject has at least one of the following signs:

Documented fever (e.g., body temperature ≥ 38 degrees Celsius) 

Hypothermia (e.g., core body temperature ≤35 degrees Celsius)

Total peripheral white blood cell (WBC) count ≥ 10,000 cells/cubic millimeter 
(mm3) 

Leukopenia with total WBC ≤4,500 cells/mm3

Greater than 15 percent immature neutrophils (bands) noted on peripheral blood 
smear 
AND
(c)
Subject has a chest radiograph showing the presence of a new or 
progressive infiltrate(s) suggestive of bacterial pneumonia
4. have an adequate baseline (at or within 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 [the ONLY direct sampling techniques accepted in the 
study are the following 3 methods:  i.e., sampling via bronchoalveolar lavage (BAL), 
 
 
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mini BAL or protected brush specimen (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, an adequate lower respiratory tract specimen is defined as 
having fewer than 10 squamous epithelial cells and greater than 25 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.
5. have an infection known or thought to be, in the opinion of the investigator, caused 
by microorganisms susceptible to the IV study therapy.
6. 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, long-term storage, and other 
future testing.
7. understand (or have a legal representative that understands) the study procedures, 
alternative treatments available, and risks involved with the study, and voluntarily 
agree to participate by giving written informed consent for the trial.  The subject may 
also provide consent for Future Biomedical Research.  However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
8. meet one of the following categories:
a) The subject is a male who is not of reproductive potential.  A male subject who is 
not of reproductive potential is defined as a male whom is not sexually active or has 
undergone a successful vasectomy.  A successful vasectomy is defined as: (1) 
microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years 
ago with no resultant pregnancy despite sexual activity post-vasectomy.
NOTE: A male subject who is not of reproductive potential is eligible without 
requiring the use of contraception.
OR
b) the subject is a female who is not of reproductive potential. Female subjects 
meeting at least one of the following criteria are considered not of reproductive 
potential (1) women age > 50 years AND no menses for >12 months OR 
FSH >40 mIU/mL; (2) women age > 45 years AND no menses for >18 months OR 
FSH >40 mIU/mL; (3) women with documented congenital/acquired condition that 
prevents childbearing; OR (4) women with documented total abdominal hysterectomy 
(TAH) and/or bilateral salpingo-oophorectomy (BSO).
NOTE: A female subject who is not of reproductive potential is eligible without 
requiring the use of contraception.
OR
c) the subject is a female or a male who is of reproductive potential and agrees to 
avoid becoming pregnant or impregnating a partner from the time of consent through 
completion of the study by complying with one of the following:  (1) practice 
abstinence† from heterosexual activity OR (2) use (or have their partner use) 
 
 
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acceptable contraception during heterosexual activity.  Acceptable methods of 
contraception are‡:
Single method (one of the following is acceptable):
•
non-hormonal intrauterine device (IUD)
•
vasectomy of a female subject’s male partner

male condom or female condom (cannot be used together)
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)
•
contraceptive sponge (nulliparous women only) 
†True abstinence (relative to heterosexual activity) starting from the time of consent 
through completion of the study: abstinence is in line with the preferred and usual 
lifestyle of the subject and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g., abstinence only on certain calendar days, 
abstinence only during ovulation period, use of symptom-thermal method, is of post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
For Early Consenting Option ONLY
9. is anticipated to require extended intubation based on the opinion of the investigator,
which puts the subject at risk of developing VABP.  Subject must have been 
intubated for at least 48 hours prior to developing signs and symptoms of pneumonia 
in order to qualify for assessment of disease eligibility at ≤48 hours prior to 
randomization.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
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).
 
 
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3. has confirmed or suspected pneumonia 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. 
NOTE: Short-term treatment with systemic (IV or oral) steroids of <1 week duration 
(e.g., treatment for an acute asthma exacerbation or acute skin condition) is allowed.  
Topical steroids for the treatment of skin conditions are also allowed.  
7. is expected to survive < 72 hours.
8. has a concurrent condition or infection that, in the investigator’s judgment, would 
preclude evaluation of therapeutic response (e.g. active tuberculosis, cystic fibrosis, 
granulomatous disease, a disseminated fungal infection, invasive fungal pulmonary 
infection or endocarditis).  
NOTE: Subjects in whom fungal pathogens are isolated are eligible for participation 
provided that treatment of the fungus is not planned.
9. has received effective antibacterial drug therapy for the index infection of 
HABP/VABP for a continuous duration of more than 24 hours during the previous 72 
hours.
NOTE: Subjects are only allowed to have received such antibacterial agents for up to 
24 hours prior to study treatment.  
Exceptions:

Subjects who have failed prior antibiotic therapy for the current episode of 
HABP/VABP (i.e., have persistent/worsening signs and/or symptoms of 
HABP/VABP at screening which are still present despite >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 (e.g., low dose erythromycin or polymyxin) or to eradicate 
C. difficile (oral vancomycin or fidaxomicin).
10. has a history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious 
reaction to any of the following:

any penicillin (including PIP/TAZ, carbapenems, cephalosporins, or other 
β-lactam agents)
 
 
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
β-lactamase inhibitors (e.g.,
tazobactam, sulbactam, clavulanic acid, 
avibactam)  
NOTE: Subjects with a history of mild rash to penicillins or other β-lactams may be 
enrolled and closely monitored.
11. is a female who is pregnant or is expecting to conceive (or is a male partner of a 
female who is expecting to conceive), is breastfeeding, or plans to breastfeed prior to 
completion of the study. 
12. 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.
NOTE:  Among patients with no active or prior history of seizure disorder, it is 
acceptable to use non-valproate anticonvulsants for mood disorders, behavior 
disturbance, or to prevent seizures following stroke, neurosurgery, or head trauma
(See Exclusion #13).
13. 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)

serotonin re-uptake inhibitors, tricyclic antidepressants, or serotonin 5-HT1 
receptor agonists (triptans) 

monoamine oxidase inhibitors (MAOIs) (or has used MAOIs during the 2 weeks 
prior to screening)

meperidine 

buspirone 

concomitant systemic (IV or oral) antibacterial agents in addition to those 
designated in the study treatment groups 
NOTE: As the study will enroll subjects 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 methicillin-resistant S. aureus (MRSA) infection is required.
The 
recommended treatment duration for a confirmed MRSA infection is a minimum 
of 7 days, with a minimum of 14 days for MRSA bacteremia.  Empiric linezolid 
treatment will be stopped if the final culture results from the baseline lower 
respiratory tract sample do not demonstrate the presence of MRSA.

Concomitant systemic (IV or oral) antifungal or antiviral therapy for the index 
infection of HABP/VABP.
 
 
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14. 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
15. is currently undergoing hemodialysis or peritoneal dialysis.
16. 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 subject’s participation for the full duration of the 
study, or pose additional risk in administering the study drugs to the subject.
17. 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 30 days 
prior to screening or is anticipated to participate in such a clinical study during the 
course of this trial.
18. has previously participated in this study at any time.
19.is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Treatment(s)
5.2
The blinded IV study therapies to be used in this trial are outlined below in Table 7.
Table 7
Trial Treatment
Druga
Dose/Potencyb
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Periodc
Use
Treatment Group 1 (N=268)
Imipenem/ 
relebactam
(IMI/REL)
Imipenem/relebactam
500 mg/250 mg
Every 6 hours
IV
7 to 14 days
Experimental
Treatment Group 2 (N=268)
Piperacillin/
tazobactam
(PIP/TAZ)
Piperacillin/ 
tazobactam
4000 mg/500 mg
Every 6 hours
IV
7 to 14 days
Active -
Comparator
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 subjects with renal insufficiency (Please reference Table 8 and 
Table 9 in Section 5.2.1.1). 
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.
 
 
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The first dose of prescribed study therapy should be administered at the Day 1 visit. The 
Unblinded Study Pharmacist (or qualified designee) will contact the IVRS/IWRS for 
assignment of the study therapy to be administered.  Sites should not call IVRS/IWRS for 
drug administration until the subject has met all entry criteria for the study and ready to be 
randomized.  Randomized subjects in each treatment group will receive a minimum of 7 days 
to up to a maximum of 14 days of intravenous (IV) study therapy.  Of note, subjects with 
evidence of concurrent bacteremia or with P. aeruginosa involvement should receive 14 days
of IV study therapy.
Detailed dosing guidelines, including dose selection and timing of dose administration, are 
outlined in Section 5.2.1 and Section 5.2.2, respectively. 
Co-administration of Open-label Therapy with Linezolid:
As the study may enroll subjects 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 methicillin-resistant S. aureus (MRSA) infection is 
required.
The recommended treatment duration for a confirmed MRSA infection is a 
minimum of 7 days, with a minimum of 14 days for MRSA bacteremia.  Empiric linezolid 
treatment will be stopped if the final culture results from the baseline lower respiratory tract 
sample do not demonstrate the presence of MRSA.  Linezolid will be given open-label in 
both treatment groups.  Linezolid will not be provided 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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
 
 
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Dose Selection/Modification  
5.2.1
5.2.1.1
Dose Selection (Preparation)
5.2.1.1.1 IMI/REL
The chosen dose for IMI/REL in subjects with normal renal function is IMI/REL 500mg/250
mg administered IV as an FDC once every 6 hours.  For subjects with renal insufficiency
or whose creatinine clearance changes during treatment with study therapy, the dose 
must be adjusted by the Unblinded Study Pharmacist (or qualified designee) based 
upon the degree of renal function impairment, as determined by the estimated or actual 
creatinine clearance.  Subjects should be carefully monitored for renal function during IV 
treatment.  Dose adjustments are included in Table 8.
Table 8
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 subject who has a creatinine clearance of 50 mL/min should receive 
a 300/150 mg q6h dose of IMI/REL according to the table.
Creatinine clearance in mL/min may be calculated from serum creatinine concentration by 
the following 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.
5.2.1.1.2 PIP/TAZ
Subjects 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 six hours, resulting in a daily total of 
18.0 g (16.0 g PIP/2.0 g TAZ).  For subjects with renal insufficiency or whose creatinine 
clearance changes during treatment with study therapy, the dose must be adjusted by 
the Unblinded Study Pharmacist (or qualified designee) based upon the degree of renal 
function impairment, as determined by the estimated or actual creatinine clearance.
Subjects should be carefully monitored for renal function during IV treatment. The 
recommended daily doses for subjects with renal impairment per the US product label are 
included in Table 9.  
NOTE: Assuming there are no market shortages, country requirements for local sourcing of 
comparator, or any additional sourcing issues, the study is planning on using an EU central 
source for the comparator throughout the life of the study. According to the EU product 
label, the recommended dosing for subjects with renal insufficiency (based on creatinine 
clearance) is based on the adjustment of the frequency of administration of PIP/TAZ from 
 
 
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every 6 hours to every 8 or every 12 hours (depending on creatinine clearance value) while 
maintaining the dose of PIP/TAZ the same.  This would require the need to include placebo-
matching infusion of IV normal saline to maintain study blind between treatment groups.  
The additional fluid overload to these critically ill subjects and the additional resources and 
operational challenges for healthcare personnel at the site would make the study unfeasible.  
As a result, dosing of PIP/TAZ in this study should be administered per Table 9 below based 
on the US product information.
Table 9
Recommended Dosage of PIP/TAZ in Subjects According to Renal Function 
(Total PIP/TAZ dosage provided first, followed by individual components in parentheses
Creatinine clearance 
(mL/min)
PIP/TAZ Dosea for Nosocomial Pneumonia
> 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 subject 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.
Creatinine clearance in mL/min may be calculated from serum creatinine concentration by 
the following 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.
Timing of Dose Administration
5.2.2
As shown in Table 8 and Table 9, the dose of IMI/REL and PIP/TAZ may need to be 
adjusted based on the subject’s renal function.  The frequency of administration will not 
change.  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 
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. 
Additional details for preparation and administration of study drug are provided in a separate 
Pharmacy Manual.
 
 
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Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used.  IMI/REL and PIP/TAZ will be dispensed in 
a blinded fashion by an unblinded pharmacist or qualified trial site personnel.  Study therapy 
supplies will be provided in an open-label fashion to the sites; hence an Unblinded Study 
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.  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 Pharmacist (or qualified designee) to ensure that other study personnel and 
all subjects 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.  See Section 7.1.4.2, (Blinding/Unblinding), for a description of the method of 
unblinding a subject during the trial, should such action be warranted.
The subject, the 
investigator and Sponsor personnel or delegate(s) who are involved in the treatment or 
clinical evaluation of the subjects are unaware of the group assignments.
As the study may enroll subjects without confirmed microbiological (culture) evidence of the 
HABP/VABP pathogen on a lower respiratory tract specimen at study entry, subjects will 
receive treatment with open-label IV linezolid for methicillin-resistant S. aureus (MRSA) 
infection beginning at randomization.
Randomization or Treatment Allocation
5.3
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 2 randomized treatment arms.  Subjects will 
be assigned randomly in a 1:1 ratio to IMI/REL (Treatment Group 1; N=268) or PIP/TAZ
(Treatment Group 2; N=268).
Stratification
5.4
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
Subjects 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.
 
 
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Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during time periods specified by this protocol for that medication or vaccination.  If there is a 
clinical indication for any medication or vaccination specifically prohibited during time 
periods specified by this protocol for that medication or vaccination, discontinuation from 
trial therapy or vaccination 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 subject's primary physician.  
However, the decision to continue the subject on trial therapy or vaccination schedule 
requires the mutual agreement of the investigator, the Sponsor and the subject.
The following concomitant medications/therapies are not permitted during IV study therapy: 
1. Immunosuppressive agents
NOTE: Short-term treatment with systemic (IV or oral) steroids of <1 week duration
(e.g., 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 (during treatment with study drug and the 2 
weeks prior to screening)
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. Non-study systemic (IV or oral) antibacterial treatments
NOTE: As noted in Section 5.2, 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, with a minimum of 14 days for 
MRSA bacteremia.  Empiric linezolid treatment will be stopped if the final culture 
results from the baseline lower respiratory tract sample do not demonstrate the 
presence of MRSA.
8. Systemic (IV or oral) antifungal or antiviral therapy for the index infection of 
HABP/VABP
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
There are no dietary or activity restrictions in this study, except as medically indicated.
 
 
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Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.
In this trial, a subject may discontinue from IV study therapy but should continue to 
participate in the regularly scheduled activities, as long as the subject does not withdraw 
consent.  Discontinuation from IV study therapy is permanent.  Once a subject has 
discontinued IV study therapy, even though he/she continues to be monitored in the trial, 
he/she shall not be allowed to begin treatment again.
A subject must be discontinued from IV study therapy (but should continue to be monitored 
in the trial) for any of the following reasons:
1. Any of the following post-baseline elevations in liver transaminase levels:
     In subjects without baseline transaminase elevations:
ALT or AST ≥8 X ULN
ALT or AST ≥3 X ULN, accompanied by total bilirubin > 2 X ULN OR INR 
> 1.5
ALT or AST ≥3 X ULN with the appearance of fatigue, nausea, vomiting,
right upper quadrant pain or tenderness, fever (defined as oral or tympanic 
temperature ≥38.0°C [≥100.4°F]) rash, and/or eosinophilia (>5%)
     In subjects with pre-existing transaminase elevations: 
Further increase in transaminases to ≥8X ULN [with at least 50% increase 
from transaminase values collected at randomization (Day 1)] that is not 
anticipated from their underlying medical condition
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 
 
 
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tenderness, fever
(defined as oral or tympanic temperature ≥38.0°C 
[≥100.4°F]), rash, and/or eosinophilia (>5%)
Clinically significant worsening of liver function associated with further 
transaminase elevations in a subject with abnormal transaminase levels 
already meeting the above criteria (i.e., ≥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.
NOTE: The subject will discontinue from study therapy, but will continue to 
participate in the study and will be assessed according to all study planned study 
procedures through the final study visit and will be evaluated for blood chemistry and 
hematology (including, at minimum, ALT, AST, alkaline phosphatase, bilirubin 
(direct + indirect) and creatine phosphokinase) until values return to within normal 
range. The trial site guidance for assessment and follow up of liver function test 
(LFT) elevations can be found in the Investigator Trial File Binder.
2. A post-baseline decline in estimated or actual creatinine clearance to a value of 
less than 15 mL/min.
3. The subject requires initiation of hemodialysis or peritoneal dialysis.
4. The subject has a confirmed positive serum or urine (sensitivity of < 25 mIU/L is
required if using urine test) pregnancy test.
5. A physician investigator feels it is in best interest of the subject to discontinue for 
any reason, including, but not limited to, the need for alternative non-study 
antibacterial therapy.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last trial visit, discontinues from the trial or is 
lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
Clinical Criteria for Early Trial Termination
5.11
The clinical trial 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 trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening
IV Study Treatment
Post-treatment
Visit Title:
Visit 1
Visit 2
Randomization/
Initiation of 
Therapy
Visit 3
On 
Therapy #1
(OTX1)
Visit 4
On 
Therapy #2
(OTX2)
Visit 5
On 
Therapy #3
(OTX3)
Visit 6 a
End of 
Treatment 
(EOT)
Visit 7 a
Early 
Follow-Up 
(EFU)
Visit 8 a
Day 28b
Early Consent 
Option
Standard 
Consent Option
Scheduled Day 
Day -14 to 
-1
Day -2 
to -1
Day -2 to -1
Day 1
Day 3
Day 6
Day 10
Anytime 
from Day 7 
to Day 14c
7 to 14 
days post 
EOT
Day 28 Post-
Randomization
Scheduling Window: 
≤ 2 weeks 
prior to 
randomiz-
ation
≤ 48 hours 
prior to 
randomiz-
ation
≤ 48 hours 
prior to 
randomization
N/A
N/A
N/A
N/A
≤ 24 hours 
after last 
dose of IV 
study 
therapy
+ 2 days
+ 3 days
Administrative Procedures
Informed Consent (Early Consent Option)
X
Informed Consent (Standard Consent 
Option)
X
Informed Consent for Future Biomedical 
Research d (optional)
X
X
Inclusion/Exclusion Criteria 
(Early Consent Option)
Assess Inclusion Criteria #1, 7, 9e
X
Assess Inclusion Criteria #2, 3, 4, 5, 6, 8
X
Assess All Exclusion Criteria
X
Inclusion/Exclusion Criteria 
(Standard Consent Option)
Assess All Inclusion/Exclusion Criteria
X
Subject Identification Card
X
X
Medical History
X
X
Prior or Concomitant Medication Review
X
X
X
X
X
X
X
X
X
Treatment Allocation/Randomization & 
Stratification
X
Administration of IV Study Therapy c
Daily (administered IV q6h)
Administration of Empirical IV Linezolid 
Therapyf
Daily (administered at 600 mg IV q12h)
Clinical Procedures/Assessments
APACHE II Score g
X
X
Clinical Pulmonary Infection Score (CPIS)g
X
X
Full Physical Examination
X
 
 
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Trial Period:
Screening
IV Study Treatment
Post-treatment
Visit Title:
Visit 1
Visit 2
Randomization/
Initiation of 
Therapy
Visit 3
On 
Therapy #1
(OTX1)
Visit 4
On 
Therapy #2
(OTX2)
Visit 5
On 
Therapy #3
(OTX3)
Visit 6 a
End of 
Treatment 
(EOT)
Visit 7 a
Early 
Follow-Up 
(EFU)
Visit 8 a
Day 28b
Early Consent 
Option
Standard 
Consent Option
Scheduled Day 
Day -14 to 
-1
Day -2 
to -1
Day -2 to -1
Day 1
Day 3
Day 6
Day 10
Anytime 
from Day 7 
to Day 14c
7 to 14 
days post 
EOT
Day 28 Post-
Randomization
Scheduling Window: 
≤ 2 weeks 
prior to 
randomiz-
ation
≤ 48 hours 
prior to 
randomiz-
ation
≤ 48 hours 
prior to 
randomization
N/A
N/A
N/A
N/A
≤ 24 hours 
after last 
dose of IV 
study 
therapy
+ 2 days
+ 3 days
Directed Physical Examination
X
X
X
X
X
X
Vital Signs (heart rate, blood pressure, 
respiratory rate, oral temperature)h
Daily during IV study therapy
X
X
X
Heighti
X
Weighti
X
Adverse Event Monitoring j
X
X
X
Daily during IV study therapy
X
X
X
Local Infusion Tolerability Monitoring j
Daily during IV study therapy
X
Review of Clinical Signs and Symptoms of 
HABP/VABP Infection k
Daily during IV study therapy
X
X
X
Chest X-ray l
X
X
X
X
PaO2/FiO2 Ratio or O2 Saturationm
Daily during IV study therapy
X
X
X
Infection Source Control Review n
X
X
X
X
Laboratory Procedures/Assessments
Blood for Hematology o
X
X
X
X
X
X
X
Blood for Chemistryo
X
X
X
X
X
X
X
Blood for Local Laboratory Assessment of 
Creatininep
X
X
X
X
Urine for Urinalysis q
X
X
Serum/urine for β-Human Chorionic 
Gonadotropin (β-hCG), in women of 
reproductive potential only r
X
X
X
Blood for Genetic Analysisd
X
Lower Respiratory Tract Specimen for Gram 
stain, Culture and Susceptibility s,t
X s
Xt
Xt
Xt
X
X
Xt
Blood Specimen for Culture and 
Susceptibility u
X
As clinically indicated, or if pre-study blood culture was positive, 
repeat daily until negative on 2 consecutive cultures
Population Pharmacokinetics Analysis
Whole blood to obtain plasma for REL, 
impenem, and cilastatin assay v
X
X
X
X
X
 
 
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Trial Period:
Screening
IV Study Treatment
Post-treatment
Visit Title:
Visit 1
Visit 2
Randomization/
Initiation of 
Therapy
Visit 3
On 
Therapy #1
(OTX1)
Visit 4
On 
Therapy #2
(OTX2)
Visit 5
On 
Therapy #3
(OTX3)
Visit 6 a
End of 
Treatment 
(EOT)
Visit 7 a
Early 
Follow-Up 
(EFU)
Visit 8 a
Day 28b
Early Consent 
Option
Standard 
Consent Option
Scheduled Day 
Day -14 to 
-1
Day -2 
to -1
Day -2 to -1
Day 1
Day 3
Day 6
Day 10
Anytime 
from Day 7 
to Day 14c
7 to 14 
days post 
EOT
Day 28 Post-
Randomization
Scheduling Window: 
≤ 2 weeks 
prior to 
randomiz-
ation
≤ 48 hours 
prior to 
randomiz-
ation
≤ 48 hours 
prior to 
randomization
N/A
N/A
N/A
N/A
≤ 24 hours 
after last 
dose of IV 
study 
therapy
+ 2 days
+ 3 days
Efficacy Evaluation
Survival Assessment
X
X
Clinical Response Assessment w
X
X
X
X
X
X
Microbiological Assessment (By-Pathogen) x
X
X
Health Resource Utilization Measures
X
PaO2 = partial pressure of oxygen in arterial blood; FiO2 = Fraction of inspired oxygen
a
Register completion of EOT, EFU, and Day 28 visits in IVRS.
b
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 subject 
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. 
c
IV study therapy should be administered daily for a minimum of 7 full days. This translates to 28 doses of IMI/REL (Treatment Group 1) or PIP/TAZ (Treatment Group 2) for every 6 hour (q6h) 
dosing. Of note, subjects with evidence of concurrent bacteremia or with P. aeruginosa involvement should receive 14 days of IV study therapy. 
d
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response.  If there is either a documented law or regulation prohibiting collection, or 
if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is collected, leftover extracted DNA will be stored for 
future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the 
purpose of FBR.
e
If early screening criteria are met and the subject goes on to develop signs and symptoms of pneumonia, the subject will qualify to be assessed for disease eligibility and all other study entry criteria, 
which must be assessed and confirmed within 48 hours prior to randomization.  
f
The recommended treatment duration of IV linezolid at the 600 mg q12h dose for a confirmed MRSA infection is a minimum of 7 days, with a minimum of 14 days for MRSA bacteremia.  Empiric 
linezolid treatment will be stopped if the final culture results from the baseline lower respiratory tract sample do not demonstrate the presence of MRSA
g
Please refer to Appendix 12.5 and  Appendix 12.6 for the parameters and instructions for calculation of APACHE II score and CPIS, respectively.
h
Vital signs should be assessed and recorded daily during IV study therapy.  All findings should be documented on the appropriate electronic case report (eCRF) forms. Collection at randomization
should be performed prior to initiation of IV study therapy
i
Collection at randomization should be performed prior to initiation of IV study therapy.
j
Monitor for adverse events and local infusion tolerability daily during IV study therapy and adverse events for 14 days after completion of IV study therapy (including through EFU visit and Day 28 
post-randomization visit).  Events that emerge during IV study therapy and are considered as related to IV study therapy by the investigator must be followed until resolved or stabilized.  Serious 
adverse events (SAE) that are considered by the investigator to be possibly, probably, or definitely related (all considered related to study drug) to the investigational product that is brought to the 
attention of the investigator at any time outside of the EFU also must be reported immediately to the Sponsor.  Please refer to Section 7.2 for further details, including reporting of select adverse 
events that occur after the consent form is signed but before treatment randomization.
 
 
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k
Infection-specific clinical signs and symptoms, radiographic (daily reporting not required for radiographic findings) and laboratory assessments (see Table 10, Section 7.1.2.7)  will be collected daily
during IV study therapy and the additional visits specified .  All findings should be documented on the appropriate eCRF forms.  Collection at randomization (Visit 2) should be performed prior to
initiation of IV study therapy.
l
A baseline chest x-ray (prior to initiation of IV study therapy) should only be performed if a prior chest x-ray has not been performed in association with the current infection within 48 hours of 
randomization.  Relevant radiographic findings should be documented on the appropriate eCRF forms.
m
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.  All measured values should be documented on the appropriate eCRF forms.
n
Relevant information regarding infection source control should be documented on the appropriate eCRF. 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.
o
Laboratory safety tests collected from blood (hematology and chemistry) should be performed at the randomization visit (Day 1) prior to administration of the first dose of IV study therapy, on Day 
3 of IV study therapy (OTX1), Day 6 of IV study therapy (OTX2), and Day 10 of IV study therapy (OTX3, if applicable),.  Laboratory safety tests of blood (hematology and chemistry) should also 
be performed at the EOT, EFU, and Day 28 post-randomization visits. Laboratory safety tests of urine (urinalysis) should be performed at randomization and EOT.  Specific safety laboratory tests of 
blood are included in Section 7.1.3.1, Table 11.
p
For the purpose of monitoring renal function during IV treatment, a creatinine assessment should also be performed at the local laboratory on Days 1, 3, 6, and 10 prior to administration of IV study 
therapy.  For subjects with renal insufficiency or whose creatinine clearance changes during treatment with study therapy (refer to Table 8 and Table 9 in Section 5.2.1.1), 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.  Only those local laboratory abnormalities in serum creatinine that 
resulted in an adverse event or a clinically significant change in creatinine clearance which may or may not result in a dose adjustment should be collected on the appropriate eCRF.  Please note only 
the unblinded pharmacist of designee will know if the change in creatinine clearance resulted in a dose adjustment.  Blinded study staff will remain blinded.
q
The urinalysis should be performed on mid-stream clean catch urine or catheter urine specimen, if possible.  Specific safety laboratory tests performed as part of the urinalysis are included in Section 
7.1.3.1, Table 11.
r
Prior documentation of a negative serum β-HCG within 48 hours of enrollment is acceptable for women of reproductive potential.  If documentation is not available, a rapid urine β-HCG (dipstick)
may be used for screening; however, a serum β-HCG must be collected and sent to the Central Laboratory for confirmation of the dipstick result.  If the serum β-HCG test comes back positive from 
the Central Laboratory, the subject must be discontinued.  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. The sample collected at the Day 28 post-randomization visit should be a serum β-HCG.
s
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 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.
t
Culture from the lower respiratory tract site, including susceptibility testing of any identified pathogens on culture, should be performed at these visits 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 subject’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 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 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.
u
Two sets of blood cultures, from two separate venipuncture (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 daily 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.  
v
Whole blood (4 mL) to obtain plasma samples for determination of REL, imipenem, and cilastatin plasma concentrations will be collected at screening and on Day 1 (randomization), Day 3 
(OTX1), and Day 6 (OTX2) of IV study therapy at 2 time points: (1) at approximately 30 minutes post-start of first IV drug infusion, and (2) at approximately 4 hours post-start of first IV drug 
infusion. If it is not feasible to collect PK samples post-start of first IV drug infusion on Day 3 and Day 6, samples may be collected with a later infusion within a 24 hour period.  Both time points 
 
 
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should be collected after the same dose (i.e., 30 minutes and 4 hours post Dose #3). Whole blood sample collection procedures are provided in a separate Laboratory Manual.  Sample handling, 
processing, and shipment procedures will be provided separately in a Laboratory Manual.  Actual whole blood collection date and times should be recorded on the appropriate eCRF forms.
w
The presence and/or absence of infection-specific clinical signs and symptoms will be evaluated by the investigator at each specified visit compared with baseline signs and symptoms to determine 
the clinical response assessment (see Section 4.2.3.1.1.2, Table 2,Table 3, and Table 4).  Relevant clinical signs and symptoms are included in Inclusion Criterion #3.
x
A by-pathogen microbiological response rating will be determined by the investigator at EOT and EFU visits  based on the local laboratory results of lower respiratory tract cultures collected for 
subjects at each of these visit.  Please refer to Section 4.2.3.1.1.3 for additional details.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  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 subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. In addition to 
the evaluation of a subject’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 subject 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).
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, and record all prior 
medication taken by the subject within 14 days and any antimicrobial medications taken 
within 30 days before starting the trial.
Following a diagnosis HABP/VABP and prior to the receipt of first dose of IV study therapy,  
subjects may receive no more than 24 hours (for example, >1 dose of a once daily 
antibiotic, >2 doses of a twice daily antibiotic) of active non-study antibiotic therapy in the 
 
 
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72 hours preceding the first dose of IV study therapy for treatment of the current index 
infection.
Subjects who have failed prior antibiotic therapy for the current episode of HABP/VABP 
(i.e., 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 subjects, the baseline LRT culture must be obtained while the 
subject is on the failing antibiotic therapy and before the subject receives the first dose of IV 
study therapy.  Following collection of the baseline LRT culture, only IV study therapy is 
permitted in these subjects.  
Subjects receiving prior therapy with a non-absorbed antibiotic used for gut decontamination 
(example, low dose erythromycin or polymyxin) or to eradicate C. difficile (oral vancomycin 
or fidaxomicin) are eligible for enrollment, irrespective of duration of prior antibacterial 
therapy.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
As the study will enroll subjects 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 (600 mg q12h) for methicillin-resistant S. 
aureus (MRSA) infection is required. The recommended treatment duration for a confirmed 
MRSA infection is a minimum of 7 days, with a minimum of 14 days for MRSA bacteremia.  
Empiric linezolid treatment will be stopped if the final culture results from the baseline lower 
respiratory tract sample do not demonstrate the presence of MRSA.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
Rescreening of an individual subject for enrollment is not expected to occur commonly. 
However, any subject who is screened multiple times will retain the original screening 
number assigned at the initial screening visit.
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
 
 
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Randomization will be stratified according to the following factors, as described in 
Section 5.4: (1) Pneumonia type at baseline: non-ventilated HABP vs. ventilated 
HABP/VABP; and (2) APACHE II score at baseline: < 15 vs. ≥ 15. .
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified specified IV study therapy treatment regimen 
totaling greater than or equal to 4 doses of IV study therapy during the first 7 days of therapy 
OR greater than or equal to 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 subject management.
Administration of trial medication will be performed by the blinded qualified trial site 
personnel.
7.1.1.9
Study Therapy Administration
All IV study therapy will be reconstituted and administered according to the details provided 
in a separate Pharmacy Manual.  Dosing regimens for IMI/REL (Treatment Group 1) and 
PIP/TAZ (Treatment Group 2) are described in Section 5.2. The specific dosage as well as 
frequency and timing of administration for IMI/REL and PIP/TAZ is provided in Sections 
5.2.1.1.1 and 5.2.1.1.2, respectively.
An Unblinded Study 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 Pharmacist (or qualified designee) to ensure that other 
study personnel and all subjects remain blinded to clinical material assignments.  
All IV study therapy infusions should be administered by the blinded investigator and/or 
blinded trial staff over 30 minutes +/- 10 minutes.  The IV 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 is available, an appropriate volume of saline flush must be used between 
IV infusions. 
Further details on the preparation, storage, and administration of all intravenous study 
antibiotics by the Unblinded Study Pharmacist (or qualified designee) are provided in a 
separate Pharmacy Binder.
IV study therapy should be administered for a minimum of 7 full days to up to a maximum of 
14 days.  Subjects with evidence of concurrent bacteremia or with P. aeruginosa involvement 
should receive 14 days of treatment.
 
 
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7.1.1.10 Linezolid Therapy Administration
Since the study will enroll subjects 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 IV open-label linezolid (600 mg q12h) for methicillin-resistant 
S. aureus (MRSA) infection is required.
The recommended treatment duration for a 
confirmed MRSA infection is a minimum of 7 days, with a minimum of 14 days for MRSA 
bacteremia.  Empiric linezolid treatment will be stopped if the final culture results from the 
baseline lower respiratory tract sample do not demonstrate the presence of MRSA.
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.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
APACHE II Score
Severity of illness in this study will be determined by APACHE II score at screening [20]. 
See Appendix 12.5 for details regarding the calculation of this score. Results of APACHE II
score calculations must be entered on the appropriate eCRF(s).
7.1.2.2
Clinical Pulmonary Infection Score (CPIS)
The CPIS will be calculated based on clinical signs and symptoms of pneumonia at screening
[21]. See Appendix 12.6 for details regarding the calculation of this score.  Results of CPIS 
must be entered on the appropriate eCRF(s).
7.1.2.3
Full and Directed 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 exam, a physical exam targeted to the subject’s illness and 
complaints will be performed at subsequent visits as specified in Section 6.0 (Trial Flow 
Chart).  
7.1.2.4
Vital Signs
Vital signs should be collected daily while on IV study therapy and at other time points/visits 
as specified in Section 6.0 (Trial Flow Chart).  Collection at randomization (Visit 2) should
be performed prior to initiation of IV therapy.
 
 
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For this study, vital signs include heart rate (HR), blood pressure (BP), respiratory rate (RR), 
and oral temperature. Subjects should be resting in a seated or semi-recumbent position for at 
least 10 minutes prior to having vital sign measurements obtained. For subjects 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 findings from the physical examinations must be 
recorded on the appropriate eCRF. 
7.1.2.5
Height and Weight
The subject’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
7.1.2.6
Adverse Event Monitoring and Local Infusion Tolerability Monitoring
Clinical adverse events will be collected daily from the time of initiation of the first dose of 
IV study therapy through 14 days following completion of all IV study therapy (including 
through EFU visit and Day 28 post-randomization visit).  All adverse events should be 
documented on the appropriate eCRF.  In general, events that emerge during IV study 
therapy and are considered as related to IV study therapy by the investigator must be 
followed until resolved or stabilized.  Serious adverse events (SAE) that are considered by 
the investigator to be possibly, probably, or definitely related (i.e., all considered as related to 
study drug) to the investigational product that is brought to the attention of the investigator at 
any time outside of the EFU also must be reported immediately to the Sponsor.  
In addition, 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 subject 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.
Laboratory adverse events will be based on safety laboratory tests, including hematology and 
chemistry tests from blood and urinalysis from urine. Please refer to Section 6.0 and Section 
7.1.3 for more details on type of tests and timing of collection.
Please refer to Section 7.2 for details regarding assessment and documentation of adverse 
events.
7.1.2.7
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 subject’s infection will be reviewed and documented on the 
appropriate eCRFs at time points specified in Section 6.0 (Trial Flow Chart).
 
 
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In particular, clinical signs and symptoms specific to the index infection for this study are 
based predominantly on criteria outlined in Inclusion Criteria #3 (Section 5.1.2) and are 
summarized in Table 10 below.  Presence or absence of these symptoms will be recorded 
daily while on IV study therapy and at visits as specified in Section 6.0 (Trial Flow Chart).  
Intensity of signs and symptoms will also be graded by the investigator as mild, moderate, or 
severe (See Section 7.2). Collection at randomization (Visit 2) should be performed prior to
initiation of IV study therapy.
Table 10
Infection-Site Clinical Signs and Symptoms
Infection Site
Clinical Signs and Symptoms
HABP/VABP

Cough

Dyspnea

Tachypnea (e.g., 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 (core body temperature ≤35 degrees 
Celsius
7.1.2.8
Chest X-Ray
A baseline chest x-ray should be performed in all subjects prior to initiation of IV study 
therapy on the Day 1 (Randomization) visit and at other visits as specified in Section 6.0 
(Trial Flow Chart). 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 48 hours of randomization. 
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).
 
 
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7.1.2.9
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 subjects 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 subjects or ventilated subjects 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.
7.1.2.10 Infection Source Control Review
Information related to infection source control must be collected for all subjects at the visits 
specified in Section 6.0 (Trial Flow Chart).
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.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Appendix 12.4.
 
 
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 11.
Table 11
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Rapid 
urine
β-human 
chorionic gonadotropin (β-
hCG)
Hemoglobin
Alkaline phosphatase
Glucose
Serum β-hCG
Platelet count
Alanine aminotransferase (ALT)
Protein
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Bicarbonate
Microscopic exam, if 
abnormal results are 
noted
Blood Urea Nitrogen
Calcium
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin (direct bilirubin 
also assessed if total bilirubin is 
elevated above the upper limit of 
normal range)
Total protein
With the exception of the rapid urine β-hCG (dipstick), all blood and urine samples for safety 
laboratory testing (hematology, chemistry and urinalysis) will be sent to a central safety 
laboratory for testing.  Additional details regarding biological specimen processing, handling, 
and shipment will be provided by the Sponsor in a separate laboratory manual.  
The timing for the collection of blood and urine samples for safety monitoring is provided in 
Section 6.0 (Trial Flow Chart).  
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 subject’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.  
 
 
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Specifically, for the purpose of monitoring an individual subject’s renal function in “real 
time”, a creatinine assessment should be performed at the local laboratory on Days 1, 3, 6, 
and 10 during IV study therapy in addition to the chemistry safety panel performed at the 
central laboratory.  For subjects with renal insufficiency or whose creatinine clearance 
changes during treatment with study therapy (refer to Table 8 and Table 9 in Section 
5.2.1.1), 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.
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.
7.1.3.2
Culture and Susceptibility Testing
7.1.3.2.1 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 
subjects.  A previously obtained culture is acceptable if it was obtained within 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 subjects with gram-positive cocci only
detected. For specimens obtained by direct sampling of the lower respiratory tract (i.e., 
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 
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 (e.g., fewer than 10 squamous epithelial 
cells and greater than 25 neutrophils is an example of an adequate expectorated/suctioned 
sputum specimen).  In addition, a high-power microscopic view of the Gram stain can be 
used to characterize the general type of bacteria causing the pneumonia.  Specimens should 
be processed for 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.   
 
 
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Additional details regarding bacterial specimen collection, processing, handling, and 
shipment will be provided by the Sponsor in a separate microbiology laboratory manual.
7.1.3.2.2 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 6.0 (Trial Flow Chart).  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 (e.g., 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 subject’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.  
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.
7.1.3.2.3 Blood Cultures
Two sets of blood cultures, from two separate venipuncture (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 daily until 2 consecutive cultures demonstrate no growth. Follow-up up blood 
cultures in subjects with no evidence of bacteremia (i.e., 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.  
 
 
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7.1.3.2.4
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 subject’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.  
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations
Whole blood to obtain plasma samples will be collected for pharmacokinetic evaluation of 
REL, imipenem, and cilastatin concentrations. These samples may also be used for 
pharmacokinetic/pharmacodynamic analyses associated with efficacy and safety data. 
As outlined in Section 6.0 (Trial Flow Chart), whole blood (4 mL) should be collected at 
screening and on Day 1 (randomization), Day 3 (OTX1), and Day 6 (OTX2) of IV study 
therapy at 2 time points: (1) at approximately 30 minutes post-start of first IV drug infusion, 
and (2) at approximately 4 hours post-start of first IV drug infusion.  If it is not feasible to 
collect PK samples post-start of first IV drug infusion on Day 3 and Day 6, samples may be 
collected with a later infusion within a 24 hour period.  Both time points should be collected 
after the same dose (i.e., 30 minutes and 4 hours post-start of Dose #3).
Actual date and time for the whole blood samples must be recorded in the eCRFs.  
7.1.3.3.1 Blood Collection for Plasma for REL, Imipenem, and Cilastatin
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
a separate operations/laboratory manual. 
7.1.3.4
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in a separate laboratory manual.
7.1.3.5
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future research
 
 
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7.1.3.6
Efficacy Evaluation
7.1.3.6.1 Survival Assessment 
For each subject, survival status (i.e., whether the subject is alive or dead) will be assessed at 
Day 28 post-randomization.  Results of the assessment, including date and cause of death if 
relevant, will be recorded on the appropriate eCRF.
7.1.3.6.2 Clinical Response
Clinical signs and symptoms of infection (e.g., cough, dyspnea, fever, etc.) will be assessed 
at visits specified in Section 6.0 (Trial Flow Chart) in support of determination of a clinical 
response rating for each subject. A detailed list of disease-specific signs and symptoms in 
support of evaluation of the clinical response rating are included in Section 7.1.2.7, Table 10.  
Based on comparison to baseline clinical signs and symptoms of the subject’s infection, the 
investigator will determine and record the clinical response rating at each visit as described in 
Section 4.2.3.1.1.2 (see Table 2, Table 3 and Table 4.)
7.1.3.6.3
Microbiological Response
Microbiological response will be evaluated separately for each lower respiratory tract 
pathogen isolated in the baseline culture (i.e., 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 
subjects at each of these visits relative to the pathogen(s) isolated at baseline/admission as 
described in Table 5 (for EOT visit) and Table 6 (for EFU visit) in Section 4.2.3.1.1.3.  
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 (i.e., sample contains fewer than 10 squamous epithelial cells and greater than 
25 neutrophils on low power microscopy review of the Gram stain).
7.1.3.6.4 Disease-Related Complications
As a component of the second exploratory efficacy objective, disease-related complications 
(e.g., empyema, onset of acute respiratory distress syndrome, bacteremia) will be assessed 
through Day 28 post-randomization.  
A full list of the complications is being developed in close collaboration with the Foundation 
of the National Institute of Health (FNIH) Biomarkers Consortium for HABP/VABP 
Efficacy Endpoints.  The full list will be defined in a memo which will be authored prior to 
the database lock for the study.  As a result, for this ongoing assessment, the disease-related 
complication terms will be identified based on serious adverse events (SAE) presented in the 
appropriate eCRF or based on microbiology data reported in the appropriate eCRF.  Hence, 
no further data collection tools or study-related procedures will be anticipated or required for 
this assessment.
 
 
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7.1.3.6.5 Health Resource Utilization Measures
In an effort to address an exploratory objective, several health resource utilization variables 
will be collected in the study, including duration in the hospital (length of stay), duration on 
mechanical ventilation, and duration in the ICU.  
These measures will be collected at the Day 28 post-randomization visit on the appropriate 
eCRF; however, if the subject is discontinued from the study prior to this time point, these 
events would still be collected up through the time of study discontinuation.
Length of Stay in Hospital
7.1.3.6.5.1
The number of days spent in the hospital post-randomization will be recorded on the 
appropriate eCRF for each subject.
Duration of Mechanical Ventilation
7.1.3.6.5.2
The number of days spent on mechanical ventilation post-randomization will be recorded on 
the appropriate eCRF for those subjects who were randomized to the
ventilated 
HABP/VABP stratum.
ICU Length of Stay
7.1.3.6.5.3
The number of days spent in the intensive care unit post-randomization will be recorded on 
the appropriate eCRF for those subjects who were randomized to the
ventilated 
HABP/VABP stratum.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from IV study therapy prior to completion of the IV 
study therapy regimen should continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Please refer to Section 5.8 for trial-specific subject 
discontinuation criteria.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
 
 
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responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding. As requested by the investigator or sub-investigator, the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the Sponsor. The emergency unblinding call center will make a record
promptly; however, the investigator or sub-investigator must enter the intensity of the 
adverse experiences observed, their relation to study drug, the reason thereof, etc., in the 
medical chart etc., before unblinding is performed.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible. Only the principal investigator, or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor directly associated with the 
conduct of the trial should not be unblinded.
At the end of the trial, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
7.1.4.3
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
 
 
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7.1.5.1
Screening
Early Consent Option
Potential subjects enrolled under the early consent option will be evaluated against all 
inclusion and exclusion criteria through a 2-step process within a 2-week timeframe. The first 
step, at the time of early consent, entails evaluation against a subset of inclusion criteria 
(Inclusion Criteria #1, #7, and #9), as described in Section 6.0 (Trial Flow Chart). If these 
3 early screening criteria are fulfilled and the subject goes on to develop signs and symptoms 
of pneumonia, the second step of evaluations will occur. The subject will be evaluated 
against all remaining inclusion criteria and all exclusion criteria as described in Section 5.1; 
if all remaining entry requirements are fulfilled, the subject will be randomized within 
48 hours. Subjects who meet the early screening criteria but do not go on to meet the 
remaining study entry criteria will be considered screen failures.
Standard Consent Option
Within 48 hours prior to randomization, potential subjects will be evaluated to determine that 
they fulfill the entry requirements as set forth in Section 5.1. 
Rescreening of an individual subject for enrollment is not expected to occur commonly. In 
Screening procedures may be repeated in some circumstances but only after consultation 
with the Sponsor.
7.1.5.2
Treatment Period
IV study therapy (with either IMI/REL or PIP/TAZ) will be administered in a blinded 
fashion.  IV study therapy should be administered for a minimum of 7 full days to up to a 
maximum of 14 days. Subjects with evidence of concurrent bacteremia of with P. aeruginosa 
infections should receive 14 days of IV study therapy. 
Since the study will enroll subjects 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 IV open-label linezolid (600 mg q12h) for methicillin-resistant 
S. aureus (MRSA) infection is required.
The recommended treatment duration for a 
confirmed MRSA infection is a minimum of 7 days, with a minimum of 14 days for MRSA 
bacteremia.  Empiric linezolid treatment will be stopped if the final culture results from the 
baseline lower respiratory tract sample do not demonstrate the presence of MRSA.
For subjects 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 the Flow Chart in Section 6.0.  The EOT visit for 
subjects 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 on the Flow Chart.  
Subjects 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 the Flow Chart in Section 6.0.   The EOT visit will be completed within 24 hours after 
the last dose of IV study therapy (i.e., on Day 10, 11 … Day 14) followed by the subsequent
 
 
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post-treatment visits as indicated on the Flow Chart in Section 6.0.  Subjects 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.
7.1.5.3
Post-Therapy
An EFU visit (7 to 14 days after the cessation of IV study therapy [i.e., 7 to 14 days after 
EOT]) and a Day 28 post-randomization visit must be completed for each subject.  
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 subject 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.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
 
 
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All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
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).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, 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 16g (PIP) and 2g (TAZ)..
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 serious adverse event, even if no other 
seriousness criteria are met.
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 Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours 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).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.
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, 
 
 
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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.
Such events must be reported within 24 hours 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).
Immediate Reporting of Adverse EventsAdverse Events and Incidents to the 
7.2.3
Sponsor
7.2.3.1
Serious Adverse EventsAdverse Events and Incidents
serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 12 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours 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).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome.
 
 
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7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours 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).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated 
with clinical symptoms or abnormal laboratory results. 
2. post baseline laboratory test values that meet the following criteria: 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 trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
3. a confirmed (i.e., 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.
NOTE:  In subjects 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.
 
 
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Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 12. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 12 for instructions in evaluating adverse events.
 
 
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Table 12
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event 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 drug and the adverse event 
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 adverse event:
Exposure
Is there evidence that the subject 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 trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
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 trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      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 trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT 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 SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
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 case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
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
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
7.3.2
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
external Data Monitoring Committee (eDMC) regarding the trial.
Data Monitoring Committee
7.3.3
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.2 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
A DMC recommendation will be communicated to the Sponsor as agreed to in the 
Collaboration agreement.
 
 
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8.0 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/final database lock, changes are made to 
primary and/or key 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/final database lock, will be documented in a supplemental 
SAP (sSAP) and referenced in the Clinical Study Report (CSR) for the study. In addition, a 
separate EU-SAP will be prepared for this protocol specifically to document a revised 
ordering of the primary and secondary objectives from what is outlined in Section 3.0.  This 
revised ordering of the primary and secondary objectives is designed to be consistent with the 
2014 CHMP Addendum to the Guideline on the Evaluation of Medicinal Products Indicated 
for Treatment of Bacterial Infections as well as guidance received during the CHMP 
Scientific Advice Oral Hearing for MK-7655A held in February 2015.  The analyses 
documented in the protocol SAP and the EU SAP will be executed simultaneously following 
the final database lock.  The analyses described in the protocol SAP will be used to support 
U.S. FDA review (and other regions of the world); the analyses described in the EU-SAP 
will be used to support EU review.  As such, issues of multiplicity and Type I error inflation 
do not arise [22].  The initial publication of the trial results will follow the ordering of the 
primary and secondary objectives that is outlined in Section 3.0.  Post hoc exploratory 
analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.0-8.12.
Study Design Overview
A randomized, double-blind (with in-house blinding), active-
controlled, parallel-group, multi-site, trial of imipenem/cilastatin/ 
relebactam (also known as MK-7655A; hereafter referred to as 
IMI/REL) compared with piperacillin/tazobactam (PIP/TAZ) in 
subjects with hospital-acquired bacterial pneumonia (HABP) or 
ventilator-associated bacterial pneumonia (VABP).
Treatment Assignment
This study will randomize subjects in a 1:1 ratio to the two 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).  
A double-blind/masking technique will be used.  IMI/REL and 
PIP/TAZ will be dispensed in a blinded fashion by an unblinded 
pharmacist.  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 pharmacist to ensure that other study 
personnel and all subjects 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 subject, the investigator and Sponsor personnel or 
delegate(s) who are involved in the treatment or clinical evaluation of 
the subjects are unaware of the group assignments.
 
 
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Analysis Populations
Primary Efficacy
Analysis: modified intention-to-treat (MITT) 
population (defined as all randomized subjects who receive at least 
one 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
Key Secondary Endpoints
Percentage of subjects achieving a favorable clinical response at EFU
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
For the primary hypothesis (mortality), IMI/REL will be compared to 
PIP/TAZ using the stratified Miettinen and Nurminen method.  
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 10%.  If non-inferiority is established, then superiority of 
IMI/REL compared to PIP/TAZ will be evaluated.
For the key secondary hypothesis (clinical response), IMI/REL will be 
compared to PIP/TAZ using the stratified Miettinen and Nurminen 
method.  IMI/REL will be considered non-inferior (NI) to PIP/TAZ if 
the lower bound of the 2-sided 95% confidence interval (CI) for the 
difference in percentages between the treatment groups (IMI/REL 
minus PIP/TAZ) is greater than -12.5%.  If non-inferiority is 
established, then superiority of IMI/REL compared to PIP/TAZ will 
be evaluated.
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 subjects with events; these analyses will be performed 
using the Miettinen and Nurminen method
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=402) have completed 28 days of follow up.  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 to strongly control 
Type 1 error across primary and key secondary endpoints. 
Sample Size and Power 
The planned sample size of 268 subjects per group will provide 90% 
power to reject the null hypothesis that the true difference in all-cause 
mortality exceeds the NI margin of 10% assuming true rates for both 
the control and experimental regimens of 15% (1-tailed alpha of 
2.5%).  The planned sample size of 268 subjects per group will 
provide 84% power to reject the null hypothesis that the true 
difference in favorable clinical response at the EFU visit exceeds the 
NI margin of 12.5% assuming true rates for both the control and 
experimental regimens of 60% (1-tailed alpha of 2.5%).  
 
 
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Responsibility for Analyses/In-House Blinding
8.2
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.  Certain specific analyses such as 
pharmacokinetics and the evaluation of pharmacokinetic-pharmacodynamic association will 
be the responsibility of the appropriate departments 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.
Separate functional unblinding for bioanalysis will be conducted in support of 
pharmacokinetic evaluations. A small team as specified in a separate Modeling and 
Simulation (M&S) Analysis Plan, and who are separate from the study team, will be 
unblinded for the purpose of preparing the pharmacokinetic analyses. No interim data or 
results will be shared with the study team before the primary analyses have been completed, 
and the unblinded group will not be members of the study team. No decisions will be made 
based on this functional unblinding that could influence the conduct of the trial.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for
study treatment assignment.  Randomization will be implemented using an interactive voice 
response system (IVRS).
Planned interim analyses are described in Section 8.7.  Study enrollment is likely to be 
ongoing at the time of any interim analyses.  Blinding to treatment assignment will be 
maintained at all investigational sites. The results of interim analyses will not be shared with 
the investigators prior to the completion of the study.  Subject-level unblinding will be 
restricted to an external unblinded statistician and scientific programmer performing the 
interim analysis, who will have no other responsibilities associated with the study.
There are no plans to conduct a formal interim analysis of unblinded efficacy data in the 
study.  Periodic reviews of the safety data will be performed by the eDMC.  Treatment-level 
results will be provided by the external unblinded statistician to the external Data Monitoring 
Committee (eDMC). Limited additional SPONSOR personnel (e.g., members of the EOC) 
may be unblinded to the treatment level results, if required, in order to act on the 
recommendations of the eDMC.  The extent to which individuals are unblinded with respect 
to results will be documented by the unblinded statistician.
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.  
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
 
 
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Efficacy Endpoints
8.4.1
A full description of the efficacy measures is provided in Section 4.2.3.1.  The primary 
efficacy endpoint is the incidence of all-cause mortality within 28 days after initiation of 
study therapy.  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 10%.  The 10% NI margin is 
selected to be consistent with guidance provided in the 2014 FDA Guidance for Industry 
Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: 
Developing Drugs for Treatment [23].  If non-inferiority is established, then a subsequent test 
will be performed to determine whether or not IMI/REL is superior to PIP/TAZ (i.e., the 
upper bound of the 2-sided 97.5% CI for the difference in incidence between the treatment 
groups is less than 0%).  The rationale for the 97.5% CI will be explained in Section 8.8 
(Multiplicity).
The key secondary endpoint is the percentage of subjects achieving a 
favorable clinical response at EFU (favorable is defined as an assessment of “cure” or 
“sustained cure”) in the IMI/REL group will be compared to that in the PIP/TAZ group.  
IMI/REL will be considered non-inferior (NI) to PIP/TAZ if the lower bound of the 2-sided 
95% confidence interval (CI) for the difference in percentages between the treatment groups 
(IMI/REL minus PIP/TAZ) is greater than -12.5%.  An NI margin of 12.5% is selected for 
this endpoint based on the 2014 CHMP Addendum to the Guideline on the Evaluation of 
Medicinal Products Indicated for Treatment of Bacterial Infections.  If non-inferiority is 
established, then a subsequent test will be performed to determine whether or not IMI/REL is 
superior to PIP/TAZ (i.e., the lower bound of the 2-sided 97.5% CI for the difference in 
percentages between the treatment groups is greater than 0%).  The rationale for the 97.5% 
CI will be explained in Section 8.8 (Multiplicity).
IV study therapy will be administered for a minimum of 7 days up to a maximum of 14 days 
(see Section 4.2.2).  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.
Safety Endpoints
8.4.2
A description of safety measures is provided in Section 4.2.3.2.  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.  It 
will not be counted as a Tier 1 event if the preceding conditions were present at 
randomization (Day 1).
2. A confirmed (i.e., 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).
 
 
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The broad clinical and laboratory adverse event (AE) categories, consisting of the percentage 
of subjects 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
8.5
Efficacy Analysis Populations
8.5.1
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 subjects 
who receive at least one dose of IV study therapy and do not have the presence of Gram 
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 
subjects who receive at least one 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 clinically-evaluable (CE) and microbiologically-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:
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.
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.
The ME population is a subset of the 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.
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.  
 
 
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Subjects 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 8.6 (Statistical Methods)
Safety Analysis Populations
8.5.2
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 subjects who received at least 
one dose of IV study therapy.  Subjects 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 subjects this will be the treatment group to which they are randomized.  
Subjects 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 one laboratory or vital sign measurement obtained subsequent to at least one 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 
8.4.2, subjects will be excluded from specific analyses if the conditions defining the event 
were present at randomization (Day 1).
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 (Statistical Methods).
Statistical Methods
8.6
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8 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=0.050 (2-sided) level (equivalent to the 
α=0.025 (1-sided) level often associated with non-inferiority trials).  
Statistical Methods for Efficacy Analyses
8.6.1
The analysis of between-treatment differences in the incidence (or percentage of subjects) 
with binary events will be performed using the Miettinen and Nurminen method (1985) [24],
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) and Cochran-Mantel-Haenszel (CMH) weights will be used.  
Missing Values
Any subject 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:

Subjects discontinuing IV study therapy due to lack of efficacy (i.e., 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.
 
 
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
Subjects 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 key secondary endpoints, primary analysis population, and statistical 
methods that will be employed for the efficacy analyses are presented in Table 13.  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.
For microbiological response, “Indeterminate - No specimen taken because subject is deemed 
clinically cured or improved” will be considered “presumed eradication”. Since a favorable 
microbiological response requires an assessment of “eradication” or “presumed eradication”, 
the response “Indeterminate - No specimen taken because subject is deemed clinically cured 
or improved” will be considered a favorable response, while other types of “indeterminate” 
response will be considered a failure to achieve a favorable microbiological response. 
Table 13
Summary of Analysis Strategy for Primary and Key Secondary Efficacy 
Endpoints
Endpoint/Variable
(Description, Time point)
Statistical Method
Analysis 
Population
Missing Data 
Approach1
Primary:
Incidence of all-cause mortality 
through Day 28 post-
randomization.  NI comparison of 
IMI/REL to PIP/TAZ using 10% 
margin
Stratified M&N1
MITT2
M=F3
Secondary:
Percentage of subjects achieving a 
favorable clinical response at 
EFU.  NI comparison of IMI/REL 
to PIP/TAZ using 12.5% margin
Stratified M&N1
MITT2
M=F3
1
M&N is Miettinen and Nurminen method [24] stratified by pneumonia type at baseline (non-ventilated HABP vs. 
ventilated HABP/VAB and APACHE II score (< 15 vs. ≥ 15) using CMH weights.  
2
MITT population includes all randomized subjects who receive at least one dose of IV study therapy and do not have 
the presence of Gram positive cocci only on baseline Gram stain.  
3
M=F is missing=failure
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach as shown in Table 14.  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% 
 
 
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confidence intervals (Tier 1 and Tier 2) will be provided for between-treatment differences in 
the percentage of subjects 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.
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 subjects in at least one 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.  In addition, summary statistics for the 
difference between treatment groups will also be provided.  
 
 
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Table 14
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
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 
subjects in at least one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 
subjects 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.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of descriptive statistics.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects 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 using descriptive statistics for continuous or categorical 
variables, as appropriate.
Population PK Analyses
Based on PK data and PD data obtained within this study, population PK and the relationship 
between PK and PD will be assessed. The results of these exploratory analyses will be 
included in a separate report performed by the Sponsor. 
Interim Analyses
8.7
There are no plans to conduct a formal interim analysis of unblinded efficacy data in the 
study.  Periodic reviews of the safety and efficacy data will be performed by the eDMC so as 
to assess the benefit vs. risk, as outlined in Section 7.3.3.  
 
 
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While there is no intention to stop the trial early based on a positive efficacy outcome, it is 
recognized that the eDMC might consider a recommendation to stop the trial should 
overwhelming efficacy in favor of either treatment be observed.  To provide some guidance 
for the eDMC in this situation, a 2-sided p-value ≤0.001 is proposed for the test of superiority 
for the Day 28 all-cause mortality endpoint (stratified Miettinen and Nurminen method).  
This conservative criterion for the superiority test will have no impact on the overall 
multiplicity strategy described in Section 8.8.
Additional details will be provided in the detailed eDMC charter.  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=402) of the planned sample size (N=536) 
have completed 28 days of follow up.  If the observed 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 15.  If the observed mortality rate is less than 15%, the 
overall sample size will be maintained at the planned N=536 and power for this 
endpoint/hypothesis will exceed 90%.  The maximum sample size will not exceed N=768 
(384 per group) regardless of the observed 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 15
Sample Size Adjustments based on Interim Blinded Review of Day 28 All-
Cause Mortality
Observed 
Mortality 
Rate (%) †
Power based on 
Original Sample 
Size (N=536)
Revised 
Sample Size ‡
Percent Increase from 
Original Sample Size
16%
88.4%
566
5.4%
17%
86.9%
594
10.8%
18%
85.4%
622
15.9%
19%
83.9%
648
20.7%
20%
82.5%
674
25.6%
21%
81.1%
698
30.2%
22%
79.8%
722
34.7%
23%
78.5%
746
39.0%
24%
77.4%
768
43.1%
†
This is the aggregate Day 28 all-cause mortality rate expressed as a percent and rounded 
to the nearest integer value.
‡
Calculated to provide 90% power based on the observed mortality rate
 
 
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Multiplicity
8.8
A sequential testing approach will be employed to strongly control Type 1 error across the
primary efficacy endpoint (incidence of Day 28 all-cause mortality) and the key secondary 
efficacy endpoint (percentage of subjects achieving a favorable clinical response at EFU).  
Testing will be performed in the following sequence: 
Step 1:
Non-inferiority for the Day 28 all-cause mortality endpoint will be evaluated using 
α=0.050, 2-sided (equivalent to α=0.025, 1-sided often associated with non-
inferiority tests).  If non-inferiority is met, then Step 2 will be performed.
Step 2:
Non-inferiority for the favorable clinical response at EFU endpoint will be 
evaluated using α=0.050, 2-sided (equivalent to α=0.025, 1-sided often associated 
with non-inferiority tests). If non-inferiority is met, then Step 3 will be performed.
Step 3:
Superiority will be evaluated simultaneously for both endpoints with the alpha 
divided equally between the two (α=0.025, 2-sided for each).
This multiplicity strategy strongly controls the overall Type I error rate at 0.050 across the 
primary and key secondary efficacy hypotheses.
Sample Size and Power Calculations
8.9
This study will randomize subjects in a 1:1 ratio to the two treatment arms of the study 
(Group 1: IMI/REL and Group 2: PIP/TAZ), in order to obtain approximately 536 subjects 
who meet the criteria for inclusion in the modified intention-to-treat (MITT) population.  A 
sample size of 268 subjects per group will provide 90% power to reject the null hypothesis 
that the true difference in all-cause mortality exceeds the NI margin of 10% assuming true 
rates for both the control and experimental regimens of 15% (1-tailed alpha of 2.5%).  A 
sample size of 337 subjects per group would be required to maintain 90% power assuming a 
20 percent mortality rate for both groups.  The power would fall to 82% with the original 
sample size of 268 subjects per group assuming a 20 percent mortality rate for both groups.
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 10%).  This maximum observed difference will increase as the 
observed mortality in the control group decreases.  An observed difference of 3.0 percentage 
points will just meet the criterion for non-inferiority given an observed mortality of 19.8% 
(53/268) in the control group and 22.8% (61/268) in the experimental group.  An observed 
difference of 4.1 percentage points will just meet the criterion for non-inferiority given an 
observed mortality of 10.1% (27/268) in the control group and 14.2% (38/268) in the 
experimental group.
A key secondary endpoint for this trial is to evaluate the efficacy of IMI/REL versus 
PIP/TAZ with respect to clinical response at the early follow-up visit 7 to 14 days after the 
end of therapy (EFU).  In two publications of HABP/VABP trials, clinical response at a 
similar time point was reported as 60% and 55% for the PIP/TAZ group and 66% and 52% 
for the IMI group.  Assuming true rates for the control and experimental regimens of 60%, a 
sample size of 268 subjects per group will provide 84% power to reject the null hypothesis 
 
 
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that the true difference in clinical response at the EFU visit exceeds the NI margin of 12.5% 
(1-tailed alpha of 2.5%). [12] [13]
Subgroup Analyses and Effect of Baseline Factors
8.10
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the Day 28 all-
cause mortality and favorable clinical response at EFU endpoints (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 patients in each subgroup in each 
treatment group:

Age category (<65, ≥65 years)

Gender (female, male)

Race (white, non-white)

Stratification variable: non-ventilated HABP, ventilated HABP/VABP

Pneumonia type at baseline (non-ventilated HABP, ventilated HABP, VABP)

Stratification variable: APACHE II score at baseline (< 15, ≥15)

Region (US, Ex-US)

CPIS score: (<6 , ≥6)

Concurrent bacteremia (Y, N)
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 16.  
Table 16
Product Descriptions
Product Name & Potency
Dosage Form
MK-7655A, MK-7655 250 mg / 
Imipenem 500 mg / Cilastatin 500 mg
Powder for Constitution
Piperacillin / Tazobactam 4g / 0.5g
Powder for Reconstitution
 
 
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All other supplies not indicated in Table 16 above will be provided centrally by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number.  
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Open label, single-dose vials will be supplied to the unblinded individual(s) at the clinical 
site.  No kitting is required.
Clinical Supplies Disclosure
9.3
This trial is blinded but provided open label; therefore, an unblinded pharmacist or qualified 
trial site personnel will be used to blind supplies. IV study therapy identity (name, strength or 
potency) is included in the label text and lists are provided.
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind subjects and to unmask identity.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial 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 
 
 
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discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign IV study therapy to subjects and to 
manage the distribution of clinical supplies. Each person accessing the IVRS system must be 
assigned an individual unique PIN.  They must use only their assigned PIN to access the 
system, and they must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
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 institutional review board, ethics review committee (IRB/ERC) 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 trial 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 Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject 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 subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1.
name, address, telephone number and e-mail address;
2.
hospital or clinic address and telephone number;
3.
curriculum vitae or other summary of qualifications and credentials; and
 
 
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4.
other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  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.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal 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.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
 
 
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
 
 
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
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 trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.eu
or other local registries. Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trials directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial 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 trial or its results to those 
registries.
 
 
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Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
 
 
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For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
1. U.S. Prescribing Information: ZOSYN (piperacillin/tazobactam) for Injection: single-
dose and pharmacy bulk vials, ZOSYN (piperacillin/tazobactam) Injection: single dose 
GALAXY containers: 2013.1
2. U.S. Product Circular: ZYVOX (linezolid) injection, tablets and for oral suspension: 
2011.
3. Niederman MS, Craven DE. American Thoracic Society Documents: Guidelines for the 
management of adults with hospital-acquired, ventilator-associated, and healthcare-
associated pneumonia. Am J Respir Crit Care Med 2005;171: 388-416. 
4. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice 
guidelines by the infectious diseases society of america for the treatment of methicillin-
resistant Staphylococcus aureus infections in adults and children: executive summary. 
Clin Infect Dis. 2011 Feb 1;52(3):285-92.
5. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant 
Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin 
Infect Dis 2012; 54:621-629.
6. Kollef MH, Chastre J, Clavel M, Restrepo MI, Michiels B, Kaniga K, et al. A 
randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator
associated pneumonia. Crit Care 2012;16:1-17.
7. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison 
of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. 
Diagn Microbiol Infect Dis 2010;68:140-51.
8. Rubinstein, E, Tahaniyat, L, et al. Telavancin versus Vancomycin for Hospital-Acquired 
Pneumonia due to Gram-positive Pathogens. Clin Infect Dis 2011; 52(1):31-40.
9. Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and economic consequences of 
ventilator-associated pneumonia: A systematic review. Crit Care Med 2005;33(10):2184-
93.
10. Hyle EP, Lipworth AD, Zaoutis TE, Nachamkin I, Bilker WB, Lautenbach E. Impact of 
inadequate initial antimicrobial therapy on mortality in infections due to extended 
spectrum-lactamase-producing enterobacteriaceae: Variability by site of infection. Arch 
Intern Med 2005;165:1375-80.
11. Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized 
phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens 
versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antibiot 
Chemother 2013;57(4):1756-62.
12. Joshi M, Metzler M, McCarthy M, Olvey S, Kassira W, Cooper A. Comparison of 
piperacillin/tazobactam and imipenem/cilastatin, both in combination with tobramycin, 
administered every 6 h for treatment of nosocomial pneumonia. Respir Med 
2006;100:1554-65.
 
 
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13. Schmitt DV, Leitner E, Welte T, Lode H. Piperacillin/tazobactam vs. imipenem/cilastatin 
in the treatment of nosocomial pneumonia - a double blind prosepective multicentre 
study. Infection 2006; 34(3):127-34.
14. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison 
of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. 
Diagn Microbiol Infect Dis 2010;68:140-51.
15. Chastre J, Wunderink R, Prokocimer P, Lee M, Kaniga K, Friedland I. Efficacy and 
safety of intravenous infusion of doripenem versus imipenem in ventilator-associated 
pneumonia: a multicenter, randomized study. Crit Care Med 2008;36(4):1089-96.
16. Pugh R, Grant C, Cooke RP, Dempsey G. Short-course versus prolonged-course 
antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane 
Database Syst Rev. 2011 Oct 5;(10):CD007577.
17. Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, et al. Comparison of 8 
vs. 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a 
randomized trial. JAMA. 2003 Nov 19; 290(19):2588-98. 
18. West M, Boulanger BR, Fogarty C, Tennenberg A, Wiesinger B, Oross M, et al. 
Levofloxacin compared with imipenem/cilastatin followed by ciprofloxacin in adult 
patients with nosocomial pneumonia: a multicenter, prospective, randomized, open-label 
study. Clin Ther 2003;25(2):485-506.
19. Torres A, Bauer TT, León-Gil C, Castillo F, Alvarez-Lerma F, Martínez-Pellús A, et al. 
Treatment of severe nosocomial pneumonia: a prospective randomised comparison of 
intravenous ciprofloxacin with imipenem/cilastatin. Thorax 2000;55(12):1033-9.
20. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II:  a severity of disease 
classification system. Crit Care Med 1985; 13(10):818-29.
21. M. Zilberberg and A. Shorr. Ventilator-Associated Pneumonia: The Clinical Pulmonary 
Infection Score as a Surrogate for Diagnostics and Outcome.  Clin Infect Dis, 
2010;51(S1): S131–S135.
22. Robert J. Hemmings & John A. Lewis . The Implications of Current Methodological 
Issues for International Guidance. Statistics in Biopharmaceutical Research, 2013;5:3, 
211-222.
23. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). 
Guidance for Industry: Hospital-acquired bacterial pneumonia and ventilator- associated 
bacterial pneumonia: developing drugs for treatment [Internet]. Silver Spring, MD: 
Department of Health and Human Services; 2014 [Updated May 2014]. Available from: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/defaul
t.htm
24. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4:213
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck 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 including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
 
 
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The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
 
 
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analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
 
 
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If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
 
 
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14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Trial Visit
Screening
IV Study Treatment 
Post-Treatment
V1
Screening
V2
Randomization
V3
OTX1
V 4
OTX2
V 5
OTX3
V 6
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
Serum/Plasma 
Chemistry
5.0
5.0
5.0
5.0
5.0
5.0
5.0
Serum β-Human 
Chorionic 
Gonadotropin (β-
hCG)a
3.5
3.5
Blood for Planned 
Genetic Analysis 
8.5
Serum/plasma for 
PK/PD evaluation
4.0
8.0
8.0
8.0
Expected Total 
(mL)bc
7.5
23.5
15.0
15.0
7.0
7.0
7.0
10.5
a.
For female subjects of child bearing potential only
b.
Additional blood samples may be collected in support of evaluation for an underlying etiology throughout the study.  The 
trial site guidance for assessment and follow up of these criteria can be found in the Investigator Trial File Binder.  
Depending on the results of initial testing, additional blood volumes could range from approximately 8.5 mL up to 
approximately 92.0 mL and could include HIV and/or Hepatitis testing.
c.
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. 
Depending on the results, additional blood volumes could range from approximately 40mL/patient (2 sets of blood cultures 
(10mL x 2 = 20mL)/aerobic culture; (10mL x 2 = 20mL)/anaerobic culture.) up to 560 mL.  Blood cultures will be 
performed at the local microbiology laboratory according to recognized methods and per each laboratory’s standard 
procedures.
 
 
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APACHE II Severity of Disease Classification System – APACHE II Score Form
12.5
A. Acute Physiology Score:
HIGH ABNORMAL RANGE
LOW ABNORMAL RANGE
PHYSIOLOGIC VARIABLE
+4
+3
+2
+1
0
+1
+2
+3
+4
1
Temperature rectal (oC)
□
≥41
□
39-40.9
□
38.5-38.9
□
36.0-38.4
□
34-35.9
□
32-33.9
□
30-31.9
□
≤29.9
2
Mean arterial pressure =
(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
Oxygenation
A-aDO2 or PaO2 (mm Hg)
a)FiO2≥0.5:record A-aDO2
□
≥500
□
350-499
□
200-349
□
<200
b)FiO2<0.5:record only PaO2
□
>70
□
61-70
□
55-60
□
<55
6
Arterial pH (*If no ABGs record Serum HCO3 
below)
□
≥7.7
□
7.6-7.69
□
7.5-7.59
□
7.33-7.49
□
7.25-7.32
□
7.15-7.24
□
<7.15
7
Serum Sodium
□
≥180
□
160-179
□
155-159
□
150-154
□
130-149
□
120-129
□
111-119
□
≤110
8
Serum Potassium
□
≥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
□
≥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 - decorticate
2 - decerebrate
1 - no response
Verbal - Response (V)
5-oriented and 
controversed
4-confused and 
disoriented
3-inappropriate words
2-incomprehensible 
sounds
1-no response
GLASGOW COMA SCORE† = E + M + V
†Subjects 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 subjects 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)
If any of the 5 CHE categories is answered with yes give +5 points for nonoperative or 
emergency postoperative subjects, or +2 points for elective postoperative subjects
Liver - Cirrhosis with Portal Hypertension (PHT) or encephalopathy
Cardiovascular –NYHA Class IV angina at rest or with minimal self-care activities
Pulmonary -chronic hypoxemia or hypercapnia or polycythemia or PHT >40 mm Hg
Kidney -chronic peritoneal dialysis 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=________
Source:  [20]
 
 
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Clinical Pulmonary Infection Score (CPIS)
12.6
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 ≤18 mmHg, and acute bilateral infiltrates
ARDS = acute respiratory distress syndrome; PaO2/FiO2 = ratio of partial pressure of arterial oxygen to the 
fraction of inspired oxygen; PAOP = pulmonary artery occlusion pressure
Source:  Modified from [21]
 
 
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List of Abbreviations
12.7
Abbreviation
Definition
ABG
arterial blood gas
AC
alveolar cells
AE
adverse event
ALT
alanine aminotransferase
APACHE
acute physiology and chronic health evaluation 
ARDS
acute respiratory distress syndrome
ASaT
All Subjects as Treated
AST
aspartate aminotransferase
ATS
American Thoracic Society
AUC0-∞
area under the concentration time curve 
BAL
bronchoalveolar lavage
β-hCG
β-Human Chorionic Gonadotropin
BLI
β-lactamase inhibitor 
CE
clinically evaluable
C-G
Cockcroft-Gault
CHMP
Committee for Medicinal Products for Human Use
cIAI
complicated intra-abdominal infection
CLplasma
plasma clearance
CMS
colistimethate sodium
CMH
Cochran-Mantel-Haenszel
CPIS
Clinical Pulmonary Infection Score
CSR
clinical study report
cUTI
complicated urinary tract infection
DCIV
discontinuation of IV therapy
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECI
event of clinical interest
eCRF
electronic case report form
eDMC
external Data Monitoring Committee
EFU
early follow-up
ELF
epithelial lung fluid
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EOT
end of therapy
ESRD
end-stage renal disease
EU
European Union
FDA
Food and Drug Administration
GFR
glomerular filtration rate
HABP
hospital-acquired bacterial pneumonia
ICF
Informed Consent Form
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICU
intensive care unit
IDSA
Infectious Diseases Society of America
IMI
imipenem/cilastatin
 
 
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Abbreviation
Definition
Imipenem-R
imipenem-resistant
INR
international normalized ratio
IRB/ERC
Institutional Review Board/Ethics Review Committee
IU
international units 
IV
intravenous (parental)
IVRS/IWRS
interactive voice response system/integrated web response system
KPC
Klebsiella pneumoniae carbapenemase 
LOS
length of stay
MAOI
monoamine oxidase inhibitors
MDR
multi-drug resistant
ME
microbiologically-evaluable
Mg
milligram 
MITT
modified intention-to-treat
mMITT
microbiological modified intention-to-treat
MRSA
methicillin-resistant Staphylococcus aureus
MSCC
mid-stream clean catch
MSSA
methicillin-susceptible Staphylococcus aureus
NI
non-inferior
OTX
on-therapy visit
PaO2/FiO2
partial pressure of oxygen to the fraction of inspired oxygen
PD
pharmacodynamic
PIP
piperacillin
PGt
pharmacogenetic
PK
pharmacokinetic
q6h
every 6 hours
q12h
every 12 hours
REL
relebactam
SAE
serious adverse event
SAP
statistical analysis plan
siDMC
standing internal Data Management Committee
sSAP
supplemental Statistical Analysis Plan
TAH
total abdominal hysterectomy
TAZ
tazobactam
t1/2
terminal half-life 
ULN
upper limit of normal
US
United States
VABP
ventilator-associated bacterial pneumonia
WBC
white blood cell
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
050LQG