A Phase III Non-randomized, Non-controlled, Open Label Clinical Trial to Study the Safety and Efficacy of Imipenem/Cilastatin/Relebactam (IMI/REL [MK-7655A]) in Japanese Subjects With Complicated Intra-Abdominal Infection (cIAI) or Complicated Urinary Tract Infection (cUTI)
Phase: PHASE3
Conditions: Complicated Intra-abdominal Infection, Complicated Urinary Tract Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03293485 
Document Date: 
18-May-2017
A Phase III Non-randomized, Non-controlled, Open Label Clinical 
Trial to Study the Safety and Efficacy of Imipenem/Cilastatin/
Relebactam (IMI/REL [MK-7655A]) in Japanese Subjects with 
Complicated Intra-Abdominal Infection (cIAI) or Complicated 
Urinary Tract Infection (cUTI)

Product:  MK-7655A
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THIS PROTOCOL 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.
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, New Jersey, 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 Non-randomized, Non-controlled, Open Label Clinical Trial to Study the Safety 
and Efficacy of Imipenem/Cilastatin/Relebactam (IMI/REL [MK-7655A]) in Japanese 
Subjects with Complicated Intra-Abdominal Infection (cIAI) or Complicated Urinary Tract 
Infection (cUTI)
  
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY.................................................................................................. 10
2.0
TRIAL DESIGN........................................................................................................ 10
Trial Design ........................................................................................................... 10
2.1
Trial Diagram........................................................................................................ 11
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 11
Primary Objective(s) & Hypothesis(es) .............................................................. 12
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 12
3.2
Exploratory Objective .......................................................................................... 12
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 12
Background ........................................................................................................... 12
4.1
Pharmaceutical and Therapeutic Background .................................................... 13
4.1.1
Pre-clinical and Clinical Trials ........................................................................... 13
4.1.2
Ongoing Clinical Trials....................................................................................... 16
4.1.3
Rationale................................................................................................................ 17
4.2
Rationale for the Trial and Selected Subject Population .................................... 17
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 18
4.2.2
Rationale for Dose selected for IMI/REL.................................................... 18
4.2.2.1
Rationale for Dose Modification of IMI/REL ............................................. 18
4.2.2.2
Rationale for Duration of Therapy............................................................... 19
4.2.2.3
Rationale for Endpoints ...................................................................................... 19
4.2.3
Safety Endpoints .......................................................................................... 19
4.2.3.1
Efficacy Endpoints....................................................................................... 19
4.2.3.2
Definition of Efficacy Endpoints ....................................................... 20
4.2.3.2.1
Clinical response ............................................................................ 20
4.2.3.2.1.1
Microbiological Response.............................................................. 22
4.2.3.2.1.2
4.2.3.2.1.2.1
Microbiological Response for cIAI......................................... 22
4.2.3.2.1.2.2
Microbiological Response for cUTI........................................ 24
4.2.3.2.1.2.3
Composite Clinical and Microbiological Response (only for 
cUTI) ................................................................................................. 26
 
 
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Efficacy Criteria for sepsis............................................................. 27
4.2.3.2.1.3
4.2.3.2.1.3.1
Clinical Response.................................................................... 27
4.2.3.2.1.3.2
Microbiological Response based on blood culture ................. 28
4.2.3.2.1.3.3
Composite Clinical and Microbiological Response Outcome for 
Sepsis ................................................................................................. 30
Pharmacokinetic Endpoints ......................................................................... 30
4.2.3.3
Planned Exploratory Biomarker Research................................................... 30
4.2.3.4
Future Biomedical Research........................................................................ 30
4.2.3.5
Benefit/Risk ........................................................................................................... 31
4.3
5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 31
5.1.1
Subject Inclusion Criteria.................................................................................... 31
5.1.2
Subject Exclusion Criteria .................................................................................. 36
5.1.3
Trial Treatment(s) ................................................................................................ 39
5.2
Dose Selection/Modification .............................................................................. 39
5.2.1
Dose Selection (Preparation) ....................................................................... 39
5.2.1.1
Timing of Dose Administration .......................................................................... 40
5.2.2
Trial Blinding...................................................................................................... 40
5.2.3
Randomization or Treatment Allocation............................................................ 40
5.3
Stratification.......................................................................................................... 40
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 40
5.5
Rescue Medications & Supportive Care............................................................. 41
5.6
Diet/Activity/Other Considerations..................................................................... 41
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 41
5.8
Discontinuation of Treatment ............................................................................. 41
5.8.1
Withdrawal from the Trial .................................................................................. 43
5.8.2
Subject Replacement Strategy............................................................................. 43
5.9
Beginning and End of the Trial ........................................................................... 43
5.10
Clinical Criteria for Early Trial Termination ................................................... 43
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 44
7.0
TRIAL PROCEDURES ........................................................................................... 47
 
 
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Trial Procedures ................................................................................................... 47
7.1
Administrative Procedures.................................................................................. 47
7.1.1
Informed Consent......................................................................................... 47
7.1.1.1
General Informed Consent.................................................................... 47
7.1.1.1.1
Consent and Collection of Specimens for Future Biomedical 
7.1.1.1.2
Research................................................................................................ 48
Inclusion/Exclusion Criteria ........................................................................ 48
7.1.1.2
Subject Identification Card .......................................................................... 48
7.1.1.3
Medical History ........................................................................................... 48
7.1.1.4
Prior and Concomitant Medications Review ............................................... 48
7.1.1.5
Prior Medications.................................................................................. 48
7.1.1.5.1
Concomitant Medications..................................................................... 49
7.1.1.5.2
Assignment of Screening Number............................................................... 49
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 49
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other) ................................... 49
7.1.1.8
Study Therapy Administration..................................................................... 49
7.1.1.9
Clinical Procedures/Assessments........................................................................ 50
7.1.2
APACHE II Score........................................................................................ 50
7.1.2.1
Full and Directed Physical Examinations .................................................... 50
7.1.2.2
Vital Signs.................................................................................................... 50
7.1.2.3
Height and Weight ....................................................................................... 50
7.1.2.4
Adverse Event Monitoring and Local Infusion Tolerability Monitoring .... 51
7.1.2.5
Clinical Signs and Symptoms of Infection .................................................. 51
7.1.2.6
Infection Source Control Review................................................................. 52
7.1.2.7
Laboratory Procedures/Assessments .................................................................. 52
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 52
7.1.3.1
Culture.......................................................................................................... 53
7.1.3.2
Prior Infection-Site Specimens ............................................................. 54
7.1.3.2.1
On-Study Infection-Site Specimens...................................................... 54
7.1.3.2.2
Blood Cultures ...................................................................................... 54
7.1.3.2.3
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 55
7.1.3.3
Planned Genetic Analysis Sample Collection.............................................. 55
7.1.3.4
Future Biomedical Research Samples ......................................................... 55
7.1.3.5
 
 
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Efficacy Evaluation...................................................................................... 55
7.1.3.6
Clinical Response ................................................................................. 55
7.1.3.6.1
By-Pathogen Microbiological Response .............................................. 55
7.1.3.6.2
Other Procedures................................................................................................. 56
7.1.4
Withdrawal/Discontinuation........................................................................ 56
7.1.4.1
Withdrawal From Future Biomedical Research ................................... 56
7.1.4.1.1
Subject Blinding/Unblinding ....................................................................... 56
7.1.4.2
Calibration of Critical Equipment................................................................ 57
7.1.4.3
Visit Requirements.............................................................................................. 57
7.1.5
Screening...................................................................................................... 57
7.1.5.1
Treatment Period.......................................................................................... 57
7.1.5.2
Post-Therapy (Follow up)............................................................................ 57
7.1.5.3
Assessing and Recording Adverse Events .......................................................... 57
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 58
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 59
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 59
7.2.3
Serious Adverse Events ............................................................................... 59
7.2.3.1
Events of Clinical Interest............................................................................ 60
7.2.3.2
Evaluating Adverse Events ................................................................................. 61
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 64
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 64
Statistical Analysis Plan Summary ..................................................................... 64
8.1
Responsibility for Analyses/In-House Blinding ................................................. 65
8.2
Hypotheses/Estimation ......................................................................................... 65
8.3
Analysis Endpoints ............................................................................................... 65
8.4
Safety Endpoints ................................................................................................. 65
8.4.1
Efficacy Endpoints.............................................................................................. 65
8.4.2
Analysis Populations............................................................................................. 66
8.5
Safety Analysis Population ................................................................................. 66
8.5.1
Efficacy Analysis Population.............................................................................. 66
8.5.2
Statistical Methods................................................................................................ 66
8.6
 
 
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Statistical Methods for Safety Analyses ............................................................. 67
8.6.1
Statistical Methods for Efficacy Analyses .......................................................... 67
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 68
8.6.3
Interim Analyses ................................................................................................... 68
8.7
Multiplicity ............................................................................................................ 68
8.8
Sample Size and Power Calculations .................................................................. 68
8.9
Subgroup Analyses ............................................................................................... 69
8.10
Compliance (Medication Adherence).................................................................. 70
8.11
Extent of Exposure................................................................................................ 70
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 70
Investigational Product ........................................................................................ 70
9.1
Packaging and Labeling Information ................................................................. 70
9.2
Clinical Supplies Disclosure................................................................................. 70
9.3
Storage and Handling Requirements.................................................................. 71
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 71
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 71
Confidentiality....................................................................................................... 71
10.1
Confidentiality of Data ....................................................................................... 71
10.1.1
Confidentiality of Subject Records ..................................................................... 71
10.1.2
Confidentiality of Investigator Information........................................................ 72
10.1.3
Confidentiality of IRB/IEC Information............................................................. 72
10.1.4
Compliance with Financial Disclosure Requirements....................................... 72
10.2
Compliance with Law, Audit and Debarment ................................................... 73
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 74
10.4
Quality Management System............................................................................... 75
10.5
Data Management................................................................................................. 75
10.6
Publications ........................................................................................................... 75
10.7
11.0
LIST OF REFERENCES......................................................................................... 76
12.0
APPENDICES........................................................................................................... 79
Merck Code of Conduct for Clinical Trials........................................................ 79
12.1
 
 
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Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 81
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.3
by Sample Types ................................................................................................... 85
APACHE II Severity of Disease Classification System – APACHE II 
12.4
Score Form ............................................................................................................ 86
List of Abbreviations ............................................................................................ 88
12.5
13.0
SIGNATURES........................................................................................................... 89
Sponsor's Representative ..................................................................................... 89
13.1
Investigator............................................................................................................ 89
13.2
 
 
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LIST OF TABLES
    
Table 1
Summary of Efficacy Endpoints............................................................................. 20
Table 2
Definitions of the Clinical Response Rating at the EOT Visit ............................... 21
Table 3
Definitions of the Clinical Response Rating at the TOC Visit............................... 21
Table 4
Definitions of the By-Pathogen Microbiological Response Rating for cIAI at 
the EOT Visit.............................................................................................................. 23
Table 5
Definitions of the By-Pathogen Microbiological Response for cIAI at the TOC 
Visit............................................................................................................................. 24
Table 6
Definitions of the By-Pathogen Microbiological Response Rating for cUTI 
at the EOT Visit .......................................................................................................... 25
Table 7
Definitions of the By-Pathogen Microbiological Response for cUTI at the 
TOC Visit.................................................................................................................... 26
Table 8
Definitions of the Clinical Response Rating for sepsis at the EOT Visit............... 27
Table 9
Definitions of the Clinical Response Rating for sepsis at the TOC Visit............... 27
Table 10
Definitions of the By-Pathogen Microbiological Response Rating at the 
EOT Visit.................................................................................................................... 29
Table 11
Definitions of the By-Pathogen Microbiological Response at the TOC Visit.... 29
Table 12
Trial Treatment ................................................................................................... 39
Table 13
Administration Dosage of IMI/REL According to Renal Function.................... 39
Table 14
Infection-Site Specific Clinical Signs and Symptoms........................................ 51
Table 15
Laboratory Tests ................................................................................................. 52
Table 16
Evaluating Adverse Events................................................................................. 62
Table 17
Definition of favorable clinical and microbiological responses by visit ............ 65
Table 18
Analysis Strategy for Key Efficacy Variables.................................................... 68
Table 19
Estimate percentages (95% CIs) of subjects achieving favorable response 
under various assumptions.......................................................................................... 69
Table 20
Product Descriptions........................................................................................... 70
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design ........................................................................................................ 11
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
IMI/REL (MK-7655A) in Japanese Subjects with Complicated Intra-
Abdominal Infection (cIAI) or Complicated Urinary Tract Infection 
(cUTI)
Sponsor Product Identifiers
MK-7655A
Imipenem/Cilastatin/Relebactam (IMI/REL)
Trial Phase
Phase III
Clinical Indication
Treatment of complicated intra-abdominal infection (cIAI) or 
complicated urinary tract infection (cUTI)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
IMI/REL (MK-7655A)
Number of trial subjects
Approximately 80 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 14.5 
months [54 weeks of enrollment + up to 14 days (2 weeks) of IV study 
therapy + 14 days (2 weeks) of follow up =58 weeks] from the time 
the first subject signs the informed consent until the last subject’s last 
study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 3 to 4 
weeks from the time the subject signs the Informed Consent Form 
(ICF) through the final contact.  After ≤ 24 hours of screening visit, 
each subject will be receiving IMI/REL for 5 to up to 14 days.  After 
the end of IV therapy, each subject will be followed for at least 14 
days. The total duration for each subject in the study will be up to 29
days.
A list of abbreviations used in this document can be found in Section 12.5.
2.0 TRIAL DESIGN
Trial Design
2.1
Relebactam (REL; also known as MK-7655) is being developed as a fixed dose combination 
(FDC) with imipenem/cilastatin (IMI), a beta-lactam antibiotic of the carbapenem class. 
Throughout this protocol the combination of imipenem/cilastatin/relebactam (also known as 
MK-7655A) will be referred to as IMI/REL and imipenem/cilastatin will be referred to as 
IMI.
This is a nonrandomized, non-controlled, multi-site, open-label trial of IMI/REL in Japanese 
subjects with complicated intra-abdominal infection (cIAI) or complicated urinary tract 
infection (cUTI).
Approximately 80 Japanese subjects with cIAI or cUTI as a primary infection site will be 
enrolled into this study. The number of subjects with either of infection types enrolled in this 
study should not exceed 50. Subjects with bloodstream infections (bacteremia) secondary to 
cIAI, or cUTI are eligible for enrollment. Of those, subjects who meet the criteria for sepsis 
will be evaluated for the efficacy on sepsis in addition to their infection at primary site. After 
a maximum 24-hour screening period, eligible subjects will receive a minimum of 5 days to 
up to a maximum of 14 days of IV study therapy. While on study therapy, study visits will be 
 
 
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performed on Day 1 (initiation of IV study drug), Day 3 (on therapy visit), and at end of
therapy (EOT). Following the completion of IV study therapy, all subjects will be evaluated 
5 to 9 days following completion of therapy (at test of cure, TOC visit). In addition, a Follow 
up (FU) visit will be performed in all subjects at 14 days after completion of IV study 
therapy. All subjects will remain in the study for a total of up to 29 days. 
Safety and tolerability will be carefully monitored throughout the study by the Sponsor in
accordance with standard procedures. 
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.
Trial Diagram
2.2
The trial design is depicted Figure 1.
a.
Subjects will receive a minimum of 5 days to up to a maximum of 14 days of IV study therapy. 
b.
The EOT visit must occur ≤24 hours after the last dose of IV therapy. 
c.
5 to 9 days following EOT.
d.
Follow up visit will occur 14 days following completion of IV study therapy.
Figure 1
Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In male/female Japanese subjects who are at least 18 years of age and have been diagnosed 
with complicated intra-abdominal infection (cIAI) or complicated urinary tract infection 
(cUTI):
 
 
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Primary Objective(s) & Hypothesis(es)
3.1
(1)
Objective:  For the subjects with cIAI or cUTI, to evaluate the safety and tolerability 
profile of IMI/REL.
(2)
Objective:  To estimate the proportion of subjects with favorable response to IMI/REL 
by infection type.
The response for each infection type will be estimated based on the following: 
(a) Clinical response at End of Therapy (EOT) visit for subjects with cIAI.
(b) Microbiological response at EOT visit for subjects with cUTI.
Secondary Objective(s) & Hypothesis(es)
3.2
(1) Objective:  For subjects with cIAI, to estimate the proportion of subjects with favorable 
clinical response to IMI/REL at test of cure (TOC) visit.
(2) Objective:  For subjects with cUTI, to estimate the proportion of subjects with favorable 
microbiological response to IMI/REL at TOC visit.
Exploratory Objective
3.3
(1) Objective: For subjects with cIAI, to estimate the proportion of subjects with favorable 
microbiological response to IMI/REL at EOT and TOC visit.
(2) Objective: For subjects with cUTI, to estimate the proportion of subjects with a
favorable clinical response to IMI/REL at EOT and TOC visit.
(3) Objective: For subjects with cUTI, to summarize the proportion of subjects with 
favorable composite clinical and microbiological response to IMI/REL at EOT and TOC
visit.
(4) Objective: For subjects with cIAI or cUTI who meet the criteria for sepsis, to describe
the composite clinical and microbiological response to IMI/REL at EOT and TOC visit.
(5) Objective: To provide the plasma concentrations of REL, imipenem, and cilastatin.
(6) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered, and mechanisms of disease. Variation across the human 
genome may be analyzed for association with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling 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
serum 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).
Pre-clinical and Clinical Trials
4.1.2
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 and 3 months in monkeys. Evidence of renal toxicity was 
 
 
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observed at levels 0.6 times the target human exposure; however, no clinically relevant 
findings associated with renal function have been identified in the Phase I studies or in the 
completed Phase II study in humans.
To date, REL has been evaluated in approximately 218 individuals who have received at
least one dose of REL across six completed Phase I studies (PN001, PN002, PN005, PN007,
PN009 and PN012). Healthy young and elderly male and female adults as well as subjects
with varying degrees of renal insufficiency have been studied, including subjects 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 and across the various subject populations. In PN009 (a standard thorough QTc
study evaluating the effect of REL on the QTc interval), a supratherapeutic dose of REL did
not prolong the QTc interval to a clinically meaningful extent and no risk of cardiac
repolarization prolongation was identified.
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 
coadministered 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.
Generally mild elevations in hepatic transaminases were also observed in Japanese subjects
receiving multiple doses of REL in PN012. Similar to observations in PN001, the increases
in ALT/AST resolved after completion of dosing. Elevations have not been observed in
subjects administered single or multiple doses in PN002, PN005, PN007 or single doses in
PN009.
The PK of REL, imipenem, and cilastatin (CIL) 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, with doses at 125 mg and above exceeding the identified REL PK
target of AUC0-∞≥37.5 μM-hr. PN012 showed that the pharmacokinetic profiles of REL,
imipenem and cilastatin in healthy Japanese subjects were similar to historical data obtained
from non-Japanese subjects in PN001. The PK of REL, imipenem, and CIL were also
evaluated in renally impaired subjects (PN005). PK data from PN005 were consistent with
expectations given that REL, imipenem, and CIL 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-∞) were significantly and similarly altered for each of these
three analytes when comparing subjects with renal impairment to their healthy matched
subjects. Based on this data, the dose adjustment for subjects with renal impairment was 
considered and included in this protocol (refer to the section 4.2.2.1 and 5.2.1.1 for the 
details). These data are consistent with the expected change in magnitude of glomerular
filtration rate (GFR). In addition, in subjects with ESRD, REL, imipenem, and CIL were
efficiently removed by hemodialysis. The PK of REL was also studied in healthy volunteers
in an intrapulmonary lung penetration study (PN007). In PN007, the intrapulmonary PK
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 penetration of both
 
 
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REL and imipenem into the extracellular (epithelial lung fluid [ELF]) and intracellular
(alveolar cells [AC]) spaces. In PN009, the pharmacokinetics of REL were assessed to
confirm that supratherapeutic levels were achieved for the evaluation of the effect of REL on
the QTc interval A single 1150 mg dose of REL in PN009 achieved AUC0-∞and a Ceoi that 
were ~4-fold higher than those observed following a single dose of 250 mg and similar to
exposures observed after an identical dose in PN001.
Additional details regarding the preclinical and Phase I clinical studies completed to date are
summarized in the Investigator's Brochure for MK-7655A.
PN004 was a randomized, double-blind, multicenter, comparative study evaluating the
safety, tolerability, and efficacy of IMI + REL versus IMI alone in adults with cIAI. A total 
of 351 subjects with cIAI were randomized in a 1:1:1 ratio to one of 3 treatment groups (1) 
IMI + REL (250 mg), (2) IMI + REL (125 mg), or (3) IMI + placebo to REL. The primary 
efficacy endpoint was the proportion of subjects with favorable clinical response at 
discontinuation of IV study therapy (DCIV). The primary analysis population was the 
microbiologically evaluable (ME) population. The primary efficacy analysis indicates that 
treatment with either 250 mg or 125 mg of IMI + REL is at least as effective as IMI alone. 
Specifically, at DCIV in the ME population, the proportion of subjects with a favorable 
clinical response was 96.3 % (78/81) in subjects who received IMI + REL (250 mg), 98.8 % 
(85/86) in subjects who received IMI + REL (125 mg), and 95.2 % (79/83) in subjects who 
received IMI + placebo to REL.
The incidence rate of adverse experiences observed in subjects who received either dose of
IMI + REL (either the 125 mg or the 250 mg dose of REL) was generally comparable to that
observed in subjects who received IMI + placebo to REL. No evidence of significant renal
toxicity or hepatotoxicity was observed. Given the findings from PN001, close monitoring
for transaminase elevations was included in PN004. As part of this monitoring, there were 2
pre-specified events of clinical interest (ECI) that triggered staged evaluation and monitoring
of subjects with these elevations. The events of clinical interest included: 1) confirmed AST
or ALT ≥ 5 X ULN and 2) ALT or AST ≥ 3 X ULN and total bilirubin ≥ 2 X ULN and, at
the same time, alkaline phosphatase < 2 X ULN. A total of 2 (1.7%) subjects who received
IMI + REL (250 mg), 0 subjects who received IMI + REL (125 mg) and 2 (1.8%) subjects
who received IMI + placebo to REL experienced ECI #1. The two subjects with ECI #1 in
the IMI + REL (250 mg) group were due to elevations in the subject’s ALT, while the two
subjects in the IMI + placebo to REL met criteria for ECI #1 based on elevations in AST.
There were no statistically significant differences between either of the two IMI + REL
groups versus the IMI + placebo to REL in the percentage of subjects meeting the definition
of ECI #1.
There was 1 subject who received IMI + REL (250 mg) who met the criteria for ECI #2. On 
the second day of IV therapy, the subject developed elevated ALT/AST during treatment 
with IV study therapy, which normalized with continued therapy. The subject subsequently 
completed study therapy and was considered a cure. In the investigator’s opinion, the 
elevations were not related to study therapy and could be due to concurrent septic shock or 
history of cholelithiasis. There were no statistically significant differences between either of 
the two REL groups vs the IMI + placebo to REL group in the percentage of subjects 
meeting the ECI #2 definition.
 
 
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PN003 was a randomized, double-blind, multicenter, comparative study evaluating the safety, 
tolerability, and efficacy of IMI + REL versus IMI alone (IMI + placebo to REL) in adults 
≥18 years of age with cUTI. A total of 302 subjects with cUTI (including pyelonephritis) 
were randomized in a 1:1:1 ratio to one of 3 treatment groups (1) IMI + REL (250 mg), (2) 
IMI + REL (125 mg), or (3) IMI alone. The primary efficacy endpoint was the proportion of 
subjects with favorable microbiological response at discontinuation of IV study therapy 
(DCIV). The primary analysis population was the microbiologically evaluable (ME) 
population. The primary efficacy analysis indicates that treatment with IMI plus either 250 
mg or 125 mg of REL is at least as effective as IMI alone for the treatment of cUTI. 
Specifically, at DCIV in the ME population, the proportion of subjects with a favorable 
microbiological response was 95.5 % (64 /67) in subjects who received IMI + REL (250 mg), 
98.6 % (70/71) in subjects who received IMI + REL (125 mg), and 98.7 % (74/75) in 
subjects who received IMI + placebo.
The incidence rate of AEs observed in subjects who received either dose of IMI + REL
(either the 125 mg or the 250 mg dose of REL) was generally comparable to that observed in
subjects who received IMI alone. No evidence of significant renal toxicity or hepatotoxicity
was observed. Close monitoring for transaminase elevations was included in PN003 in the
same fashion as in PN004. One (1.0%) subject who received IMI + REL 250 mg, 1 (1.0%)
subject who received IMI + REL 125 mg and 0 subjects who received IMI + placebo
experienced ECI #1 (confirmed AST or ALT ≥ 5 X ULN). There were no statistically
significant differences in the percentage of subjects meeting the definition of ECI #1 between
either of the two IMI + REL groups versus the IMI + placebo group. No subjects met the
criteria for ECI #2 (ALT or AST ≥ 3 X ULN and total bilirubin ≥ 2 X ULN and, at the same
time, alkaline phosphatase < 2 X ULN).
Additional details regarding the Phase II clinical studies are summarized in the Investigator's
Brochure for MK-7655A.
Ongoing Clinical Trials
4.1.3
Two Phase III studies to evaluate safety and efficacy of MK-7655A are ongoing (Protocol 
013 [PN013] and Protocol 014 [PN014]). Japan is currently participating in both studies.  
PN013 is a Phase III 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-resistant bacterial infection, including hospital-acquired or
ventilator-associated bacterial pneumonia (HABP/VABP), cIAI, or cUTI. Subjects are
randomized in a 2:1 ratio to receive 1 of 2 of the following treatments for a minimum of 5 or
7 days (depending on primary site of infection) to a maximum of 21 days, administered q6h: 
1) IMI/REL (500 mg/250 mg) + placebo to CMS; 2) IMI (500 mg) + CMS. PN013 also 
includes a third, open label treatment arm in subjects with imipenem- and colistin-resistant 
infection who will receive IMI/REL as a fixed-dose combination. PN014 is a Phase III
randomized, double-blind, active comparator-controlled study to evaluate the safety, 
tolerability, and efficacy of IMI/REL versus piperacillin/tazobactam in hospitalized subjects 
with HABP/VABP. Approximately 536 subjects will be randomized in a 1:1 ratio to one of 
the following treatment groups: 1) IMI/REL (500 mg/250 mg) administered IV as a fixed-
dose combination, or 2) piperacillin/tazobactam (4000 mg/500 mg) administered IV as a 
fixed dose combination.
 
 
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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 Investigators Brochure (IB) and Informed Consent documents.
As previously mentioned, 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 including imipenem-resistant infection.
The current epidemic of multi-drug resistant (MDR) bacterial infections is a critical
challenge in healthcare today. The organisms known as "ESKAPE" pathogens (Enterococus
faecium, Staphylococcus aureus, K. pneumoniae, A. baumanni, P. aeruginosa, and
Enterobacter species) predominate in the resistance epidemic and have become a significant
problem in hospital-acquired infections [1]. The ESKAPE organisms currently cause a
substantial proportion of U.S. hospital infections and are responsible for increasing numbers
of outbreaks in healthcare facilities around the world [2-11]. Over the last decade, the
emergence of several highly resistant Gram-negative pathogens, including Carbapenem-
Resistant (CR) P. aeruginosa and CR Enterobacteriaceae (predominantly KPC), had posed a 
particularly troubling, and escalating, global health issue [3, 12]. Multi-drug resistance 
(MDR) severely limits the utility of currently available antibiotics. Due to the absence of 
effective and tolerable antibiotics, infections caused by CR Gram-negative organisms have a 
high mortality rate. Even with treatment using last-resort therapies such as colistin, mortality 
rates in critically ill patients with MDR pathogens, including CR pathogens, range from 16% 
up to as high as 60% [13-20]. Thus, there is an urgent need for new, well-tolerated drugs with
activity against these emerging antibiotic-resistant bacteria.
Some of the most common sites of infection in patients with MDR, including CR, Gram-
negative infections are the lungs, the abdomen and the urinary tract [13-20]. These are also of 
the most common sites of healthcare-associated infections. 
Based on the above situation, subjects with certain CR, Gram-negative infections (CR P. 
aeruginosa and KPC) at several prevalent infection sites, including HABP/VABP, cIAI, and 
cUTI are enrolled in PN013.  In addition to PN013 study, PN014 study which evaluate the 
efficacy and safety of IMI/REL in subjects with HABP/VABP, regardless of pathogen 
susceptibility. Approximately 40 Japanese subjects will be enrolled into this study. Half of 
subjects who enrolled into the PN014 study will be treated with IMI/REL. However, there is 
a need for additional data which supports the safety and efficacy for Japanese subjects treated 
with IMI/REL, especially for infections other than HABP/VABP which are evaluated in 
PN014. Although the safety and efficacy of IMI + REL has been evaluated in 2 Phase II 
studies (PN003 in subjects with cUTI, and PN004 in subjects with cIAI) in order to establish 
clinical proof-of concept and to identify the optimal dose for REL for subsequent studies, 
comparable data in Japanese subjects are not yet available. The current proposed study will 
enroll subjects with cIAI and cUTI, and all of them will be treated with open-label IMI/REL.
Subjects with bloodstream infections (bacteremia) secondary to cIAI, or cUTI are also 
eligible for enrollment. If there are subjects enrolled who meet the criteria of sepsis 
 
 
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predefined in this protocol (refer to section 5.1.2, inclusion criteria #2) are enrolled, those 
subjects will be evaluated for efficacy of sepsis treatment in addition to the efficacy of 
treatment of their primary infections.
A hundred (100) subjects are considered as a targeted number in evaluation of safety for 
Japanese subjects. Approximately 20 subjects will be enrolled and treated in the ongoing 
PN014 study, and an additional 80 subjects will need to be enrolled in this study (PN017).  
Considering the limitation of total number of subjects enrolled in this study, and the two 
different types of infection are to be enrolled in one study, the number of subjects for each 
infection is not defined in the protocol. However, the number of subjects with either of 
infection types enrolled in this study should not exceed 50. 
Rationale for Dose Selection/Regimen/Modification
4.2.2
Rationale for Dose selected for IMI/REL
4.2.2.1
Based on data from in vivo animal models of imipenem-resistant Gram-negative infections,
the target PK parameter for REL has been defined as a plasma AUC 0-24hr 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, some 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. 
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.
Both a 125 mg and 250 mg dose of REL have been evaluated in the Phase II clinical studies
(PN003 and PN004). 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. This 
dose has been evaluated in the ongoing Phase III studies (PN013 and PN014) in which Japan 
is participating.
Rationale for Dose Modification of IMI/REL
4.2.2.2
As previously discussed, REL, imipenem, and CIL 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 (IMI/REL). 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. PK-based simulation results indicate that in subjects with normal renal function, 
the dose of 250 mg REL and 500 mg IMI is appropriate. For subjects with mild renal 
insufficiency, the dose should be reduced to 200 mg REL and 400 mg IMI, for moderate 
renal insufficiency 150 mg REL and 300 mg IMI, and for severe renal insufficiency 100 mg 
 
 
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REL and 200 mg IMI. The specific dosing guidelines are included in Section 5.2.1.1 (Table 
13).
Rationale for Duration of Therapy
4.2.2.3
IV study therapy will be administered for a minimum of 5 days up to a maximum of 14 days.
Subjects with severe infections required hospitalization and IV therapy will be enrolled.
Guidelines published by the Japanese Association for Infectious Diseases/the Japanese 
Society of Chemotherapy (JAID/JSC) [22] recommend at least 3 days of initial treatment for 
severe cUTI infections and 5 to 7 days of treatment for cIAI for most infections.
The 
guideline also recommends that maximum 14 days for cUTI. The Infectious Diseases Society 
of America (IDSA) guideline [23, 24] provided similar recommendation; limiting treatment 
of catheter-associated UTI to less than 2 weeks, limiting treatment of cIAI to less than 1 
week for most infections. 
Considering the above and the expectation that subjects with infection caused by MDR, 
including CR which is the target population of PN013 study may also participate in this study
since pathogen susceptibility is not confirmed before subjects enrolled into this study, the 
minimum duration of IV therapy was determined as same as PN013 study, i.e., 5 days, and 
maximum duration was determined as 14 days based on the current clinical practice 
recommended by guidelines. 
In addition the current data for REL support up to 1 month of administration; REL was 
studied for toxicity in monkeys and rats up to 3 months with acceptable results. Refer to the 
Investigator’s Brochure (IB) for more detailed information on preclinical toxicity studies for 
MK-7655A.
Rationale for Endpoints
4.2.3
Safety Endpoints
4.2.3.1
As the primary objective, of this study, the safety and tolerability of IMI/REL will be 
assessed by clinical evaluation of adverse experiences 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 experiences 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.
Efficacy Endpoints
4.2.3.2
The efficacy in clinical studies is typically measured differently for different infection types. 
As the primary efficacy endpoints, clinical response at End of Therapy (EOT) for subjects 
with cIAI and the overall (per subject) microbiological response at EOT for subjects with 
cUTI will be evaluated. Each of these endpoints are selected considering to the efficacy 
endpoints used in Phase II studies for IMI/REL, i.e., PN003 and PN004 to confirm the 
efficacy of IMI/REL in the targeted infection types. The primary intention of this study is to 
evaluate the true impact of IMI/REL for Japanese subjects. Hence, the primary endpoint will 
focus on the timepoint of EOT in order to evaluate the effect of IMI/REL.
 
 
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Throughout the study, clinical and microbiological responses will be evaluated at EOT, and 
at 5 to 9 days after completion of treatment (the Test of Cure, TOC). Evaluation of 
microbiological and clinical response at these timepoints will provide valuable data to fully 
characterize the response profile of IMI/REL when administered to Japanese subjects. Those 
endpoints relevant to the response to IMI/REL and which are not included as primary
endpoints will be evaluated secondary or exploratory. For subjects with cUTI, composite 
clinical and microbiological response will be also evaluated at each timepoint.
In addition, for subjects who meet the criteria of sepsis (refer to section 5.1.2, inclusion 
criteria #2), the efficacy will be assessed using specified criteria based on composite of 
clinical and microbiological evaluation, referring to the guideline published in Japan as well 
as FDA guideline [25, 26]. Because of expectation that the number of subjects with sepsis 
may be very small, the outcome of sepsis will be described for each subject. These subjects 
are also included in the general assessment of cIAI or cUTI.
Refer to Table 1 for efficacy endpoints by infection type, and by timing. Details regarding
the endpoints are presented in subsequent sections.
Table 1
Summary of Efficacy Endpoints
Infection Type
Endpoints
Timing
cIAI
Clinical response (per subject)
EOT (Primary), TOC
Microbiological response (per subject)
EOT, TOC
cUTI
Clinical response (per subject)
EOT, TOC
Microbiological response (per subject)
EOT (Primary), TOC
Composite clinical and microbiological 
response
EOT, TOC
Sepsis
Composite clinical and microbiological 
response
EOT, TOC
Definition of Efficacy Endpoints
4.2.3.2.1
In this study clinical response and microbiological response will be evaluated at the EOT and 
TOC visits. Refer to the following details of definitions for each efficacy response.
Clinical response
4.2.3.2.1.1
Clinical response will be assessed for all subjects based on evaluation by the investigator at 
the EOT and TOC visits.  Based on comparison to baseline clinical signs and symptoms of 
the subject’s infection(s), the investigator will determine the clinical response rating (and 
record the response on the appropriate eCRF) at each visit as described in Table 2 (for EOT 
visit) and Table 3 (for TOC visit).   
In support of evaluation of efficacy endpoints that include clinical response, 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 as well as Section 8.4.2.
 
 
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Table 2
Definitions of the Clinical Response Rating at the EOT Visit
Clinical Responsea
Response Definition
Cure
All pretherapy signs and symptomsb of the index infection(s) have resolved 
(or returned to "preinfection status") AND no additional IV antibiotic therapy 
is required, AND, for cIAI subjects, no unplanned surgical procedures or 
percutaneous drainage procedures have been performed.
Improved
All or most pretherapy signs and symptomsb of the index infection(s) have 
improved or resolved (or returned to "preinfection status") AND no 
additional IV antibiotic therapy is required, AND, for cIAI subjects, no 
unplanned surgical procedures or percutaneous drainage procedures have 
been performed.
Failure
No apparent response to IV study therapy in prestudy signs and symptomsb
of the index infection(s): persistence or progression of most or all pretherapy 
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 discontinued for any reason before sufficient data had been 
obtained to permit evaluation for any reason; OR
c)
Extenuating circumstances 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 Table 14 in section 7.1.2.6  for a description of disease-specific clinical signs and symptoms.
Table 3
Definitions of the Clinical Response Rating at the TOC Visit
Clinical Responsea
Response Definition
Cure
All pretherapy signs and symptomsb of the index infection(s) have resolved 
(or returned to "preinfection status") AND no additional IV antibiotic 
therapy is required, AND, for cIAI subjects, no unplanned surgical 
procedures or percutaneous drainage procedures have been performed.
Failure
No apparent or insufficient response to IV study therapy in prestudy signs 
and symptoms of the index infection(s): persistence, progression, or 
improvement (without full resolution) of all pretherapy signs and 
symptomsb
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 discontinued for any reason before sufficient data had been 
obtained to permit evaluation of clinical response; OR
c)
Extenuating circumstances preclude classification as "cure" or "failure" 
OR
d)
Death occurred during the study period and the index infection was 
clearly noncontributory.
a
A favorable clinical response at TOC visit requires an assessment of “cure”.
b
Refer to Table 14 in section 7.1.2.6 for a description of disease-specific clinical signs and 
symptoms.
 
 
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Microbiological Response
4.2.3.2.1.2
Microbiological response will be evaluated separately for each baseline pathogen (i.e., by-
pathogen).  The by-pathogen response rating will be determined by investigator. Separate 
criteria for microbiological evaluation will be utilized for cIAI and cUTI. According the 
following criteria, the by-pathogen microbiological response will be determined at the EOT
and TOC visits based on local laboratory results from cultures collected at each of these 
visits relative to the pathogen(s) isolated at baseline/admission.
In support of evaluation of efficacy endpoints that include microbiological response, the by-
pathogen microbiological response rating 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 culture) as “favorable” or “unfavorable.”  
For subjects from whom only one pathogen is isolated, the overall microbiological response 
assessment will be based on the microbiological response rating for that pathogen.  For 
subjects from whom more than one baseline pathogen is isolated, the overall microbiological 
response outcome will be based on microbiological culture results for 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 as well as in Section 8.4.2.
4.2.3.2.1.2.1 Microbiological Response for cIAI
The following tables are for the definitions of Microbiological Response for cIAI, as 
described in Table 4 (for the EOT visit) and Table 5 (for the TOC visit). Only subjects with 
an intra-operative culture positive for the presence of at least 1 gram-negative enteric(s) 
and/or anaerobic pathogen(s) commonly isolated in IAI will be considered microbiologically 
evaluable.
 
 
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Table 4
Definitions of the By-Pathogen Microbiological Response Rating for cIAI at the 
EOT Visit
Microbiological 
Responsea,b
Response Definition
Eradication
The follow-up culture at the site of infection taken at the EOT visit 
(or, if not available, from the last available culture after at least 48 
hours of IV study therapy) shows eradication of the pathogen 
found at study entry.
Presumptive 
eradication
Absence of material to culture from the site of infection in a 
subject who had responded clinically to treatment.
Persistencec
The follow-up culture at the site of infection taken at the EOT visit 
(or, if not available, from the last available culture after at least 48 
hours of IV study therapy) grows the pathogen found at study 
entry.
Super infection
The follow-up culture at the site of infection taken at the EOT visit 
(or, if not available, from the last available culture after at least 48 
hours of IV study therapy) 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) Entry culture at the site of infection either not obtained or no 
growth ; OR
b) Follow-up cultures are not available from the site of infection 
due to subject death or withdrawal from study; OR
c) Microbiological data are incomplete; OR
d) Assessment not possible due to protocol violation; OR
e) Any other circumstance which makes it impossible to define 
the microbiological response
a
A microbiological response rating will be determined 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 will be considered “super infection” for any new/emergent pathogen isolated after initiation of IV study 
therapy.
b
A favorable overall microbiological response at EOT requires “eradication” or “Presumptive eradication” of all 
baseline pathogens.
c
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 5
Definitions of the By-Pathogen Microbiological Response for cIAI at the TOC 
Visit
Microbiological 
Responsea,b
Response Definition
Sustained 
eradicationc
The follow-up culture at the site of infection taken at TOC visit, 
shows eradication of the pathogen found at study entry.
Presumptive 
eradication
Absence of material to culture from the site of infection in a 
subject who had responded clinically to treatment.
Persistence
The follow-up culture at the site of infection taken at TOC visit 
grows the pathogen found at study entry. These subjects are carried 
forward with this status from the EOT visit otherwise it meets the 
criteria for ‘New infection’ or ‘Recurrence’ to those 2 follow up 
visit.
New Infection
Eradication of the original pathogen from the site of infection 
followed by replacement (at the same site and after completion of 
IV study therapy) by a new species or by a new serotype or biotype 
of the same organism in the presence of signs or symptoms of 
infection. If a pathogen was isolated from a site distant to the 
primary infection after IV study therapy has been completed, then 
this is also designated as a new infection. 
Recurrence
The follow-up culture from the site of infection taken anytime after 
documented eradication at the EOT visit grows the original 
pathogen. 
Indeterminate
a) Follow-up culture is not available at the TOC visit due to 
subject death or withdrawal from study; OR
b) Microbiological data are incomplete; OR
c) Assessment not possible due to protocol violation;  OR
d) Any other circumstance which makes it impossible to define
the microbiological response
a
A microbiological response rating will be determined 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 will be considered a “new infection” for any new/emergent pathogen isolated after initiation of IV study 
therapy.
b.
A favorable overall microbiological response at TOC visit requires “sustained eradication” or “Presumptive 
eradication” of all baseline pathogens.
c A microbiological response of “sustained eradication” at TOC is used when the microbiological response assessment at 
EOT visit is also “eradication”. 
4.2.3.2.1.2.2 Microbiological Response for cUTI
The following tables are for the definitions of Microbiological Response for cUTI, as 
described in Table 6 (for the EOT visit) and Table 7 (for the TOC visit).
 
 
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Table 6
Definitions of the By-Pathogen Microbiological Response Rating for cUTI at the 
EOT Visit 
Microbiological 
Responsea,b
Response Definition
Eradication
A urine culture taken at the EOT visitd shows eradication of the 
uropathogen (e.g., ≥105 CFU/mL is reduced to <104 CFU/mL) 
found at study entry.
Persistencec
A urine culture taken at the EOT visitd grows a uropathogen (at 
≥104 CFU/mL) found at study entry.
Super infection
An infection-site culture grows a uropathogen (at ≥105 CFU/mL) 
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 (non-urine), sterile site along with worsening signs and 
symptoms of infection.
Indeterminate
a) Follow-up urine culture is not available at the EOT visit due to 
subject death or withdrawal from study; OR
b) Microbiological data are incomplete; OR 
c) Assessment not possible due to protocol violation;  OR
d) Any other circumstance which makes it impossible to define the 
microbiological response
a
A microbiological response rating will be determined 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 will be considered “super infection” for any new/emergent pathogen isolated after initiation of IV study therapy.
b
A favorable overall microbiological response at EOT requires “eradication” of all baseline pathogens.
c
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.
d
If a culture is not available at EOT, an assessment at this visit can be made from the last available urine culture which 
was collected after at least 48 hours of IV study therapy.
 
 
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Table 7
Definitions of the By-Pathogen Microbiological Response for cUTI at the TOC 
Visit
Microbiological 
Responsea,b
Response Definition
Sustained 
eradicationc
A urine culture taken at the TOC visit still shows eradication of the 
uropathogen (e.g., ≥105 CFU/mL is reduced to <104 CFU/mL) 
found at study entry.
Persistence
A urine culture taken at the TOC visit grows a uropathogen (at 
≥104 CFU/mL) found at study entry.
New Infection
A uropathogen, other than a microorganism found at baseline is 
present in the urine (at a level ≥105 CFU/mL) any time after IV 
study therapy is finished; OR
A pathogen is isolated from a distant (non-urine), sterile after IV 
study therapy has been completed.
Recurrence
A urine grows a uropathogen (at a level ≥105 CFU/mL) taken any 
time after documented eradication. 
Indeterminate
a) Follow-up urine culture is not available at the EFU visit due to 
subject death or withdrawal from study; OR
b) Microbiological data are incomplete; OR
c) Assessment not possible due to protocol violation;  OR
d) Any other circumstance which makes it impossible to define the 
microbiological response
a
A microbiological response rating will be determined 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 will be considered a “new infection” for any new/emergent pathogen isolated after initiation of IV study therapy.
b.
A favorable overall microbiological response at TOC visit requires “sustained eradication” of all baseline pathogens.
c A microbiological response of “sustained eradication” at TOC is used when the microbiological response assessment at 
EOT visit is also “eradication”. 
4.2.3.2.1.2.3 Composite Clinical and Microbiological Response (only for cUTI)
Composite clinical and microbiological response at each timepoint will be determined by 
Sponsor based on the clinical response evaluated by investigator and overall microbiological 
response (per subject) determined by Sponsor. Only the subject who have favorable 
outcomes for both of the clinical response and overall microbiological response will be 
determined as ‘favorable’ for composite clinical and microbiological response at each 
timepoint. 
Details regarding determination of the category of clinical response and overall 
microbiological response outcome (“favorable” or “unfavorable”) in support of relevant 
study endpoints are provided in the tables describing clinical response or microbiological 
response as well as in Section 8.4.2.
 
 
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Efficacy Criteria for sepsis
4.2.3.2.1.3
4.2.3.2.1.3.1 Clinical Response
Clinical response for sepsis will be assessed for subjects meets the criteria of sepsis (refer to 
section 5.1.2, inclusion criteria #2) based on evaluation by the investigator at the EOT and
TOC visits.  Based on comparison to baseline clinical signs and symptoms of sepsis, the 
investigator will determine the clinical response rating (and record the response on the 
appropriate eCRF) at each visit as described in Table 8 (for EOT visit) and Table 9
(For 
TOC visit).
In support of evaluation of efficacy endpoints of composite clinical and microbiological 
response for sepsis, the clinical response rating determined by the investigator at each visit 
will be categorized as “favorable” or “unfavorable”. 
Table 8
Definitions of the Clinical Response Rating for sepsis at the EOT Visit
Clinical Responsea
Response Definition
Cure
All pretherapy signs and symptoms of the sepsis have resolved (or returned to 
"preinfection status") AND no additional IV antibiotic therapy is required, 
Improved
All or most pretherapy signs and symptomsb of sepsis have improved or resolved 
(or returned to "preinfection status") AND no additional IV antibiotic therapy is 
required
Failure
No apparent response to IV study therapy in prestudy signs and symptoms of 
sepsis: persistence or progression of most or all pretherapy signs and symptoms
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 preclude classification as "cure", "improved",
"failure" , or "relapse" ; 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”.
Table 9
Definitions of the Clinical Response Rating for sepsis at the TOC Visit
Clinical Responsea
Response Definition
Cure
All pretherapy signs and symptoms of the sepsis have resolved (or returned to 
"preinfection status") AND no additional IV antibiotic therapy is required, 
Failure
No apparent or insufficient response to IV study therapy in prestudy signs and 
symptoms of sepsis: persistence, progression, or improvement (without full 
resolution) of all pretherapy signs and symptoms
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 preclude classification as "cure" or "failure" OR
d)
Death occurred during the study period and the index infection was clearly 
noncontributory
a A favorable clinical response at TOC requires an assessment of “cure”.
 
 
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4.2.3.2.1.3.2 Microbiological Response based on blood culture
Microbiological response will be evaluated separately for each baseline pathogen (i.e., by-
pathogen).  The by-pathogen response rating will be determined by investigator. According 
the following criteria, the by-pathogen microbiological response will be determined at the 
EOT and TOC visits based on local laboratory results from blood cultures collected during 
the study relative to the pathogen(s) isolated at baseline blood culture.
In support of evaluation of efficacy endpoints of composite clinical and microbiological 
response for sepsis, the by-pathogen microbiological response rating 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 culture) as “favorable” 
or “unfavorable.”  For subjects from whom only one pathogen is isolated, the overall 
microbiological response assessment will be based on the microbiological response rating for 
that pathogen.  For subjects from whom more than one baseline pathogen is isolated, the 
overall microbiological response outcome will be based on microbiological culture results for 
all baseline pathogens.
The following tables are for the definitions of Microbiological Response for sepsis, as 
described in Table 10 (for the EOT visit) and Table 11 (for the TOC visit).
 
 
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Table 10
Definitions of the By-Pathogen Microbiological Response Rating at the EOT 
Visit
Microbiological 
Responsea,b
Response Definition
Eradication
A blood culture taken at or prior to the EOT visit shows eradication of the 
pathogen found at study entry.
Persistencec
A blood culture taken at EOT visit grows a pathogen found at study entry.
Super infection
A blood culture grows a pathogen other than a baseline pathogen during the 
course of IV study therapy 
Indeterminate
a)
Follow-up blood culture is not available at or prior to the EOT visit due to 
subject death or withdrawal from study; OR
b)
Microbiological data are incomplete; OR 
c)
Assessment not possible due to protocol violation;  OR
d)
Any other circumstance which makes it impossible to define the 
microbiological response
a
A microbiological response rating will be determined 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 will be considered “super infection” for any new/emergent pathogen isolated after initiation of IV study therapy.
b
A favorable overall microbiological response at EOT requires “eradication” of all baseline pathogens.
c
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.
Table 11
Definitions of the By-Pathogen Microbiological Response at the TOC Visit
Microbiological 
Responsea,b
Response Definition
Sustained eradicationc
A blood culture taken at or prior to TOC visit still shows eradication of the 
pathogen found at study entry. If blood culture taken at or prior to EOT visit 
shows negative and  blood culture at TOC visit is not available because subject’s 
infection is clinically resolved, the result will be carry forward with status at EOT 
visit to TOC visit
Persistence
A blood culture taken at TOC visit grows a pathogen found at study entry.
New Infection
A pathogen, other than a microorganism found at baseline is present in the blood 
any time after IV study therapy is finished. 
Recurrence
A blood culture grows a pathogen taken any time after documented eradication. 
Indeterminate
a)
Follow-up blood culture is not available at the TOC visit due to subject death 
or withdrawal from study; OR
b)
Microbiological data are incomplete; OR
c)
Assessment not possible due to protocol violation;  OR
d)
Any other circumstance which makes it impossible to define the 
microbiological response
a
A microbiological response rating will be determined 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 will be considered a “new infection” for any new/emergent pathogen isolated after initiation of IV study therapy.
b.
A favorable overall microbiological response at TOC visit requires “sustained eradication” of all baseline pathogens.
c A microbiological response of “sustained eradication” at TOC is used when the microbiological response assessment at 
EOT visit is also “eradication”. 
 
 
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4.2.3.2.1.3.3 Composite Clinical and Microbiological Response Outcome for Sepsis
Composite clinical and microbiological response for sepsis at each timepoint will be 
determined by Sponsor based on the clinical response evaluated by investigator and overall 
microbiological response (per subject) determined by Sponsor. Only the subject who have 
favorable outcomes for both of the clinical response and overall microbiological response 
will be determined as ‘favorable’ for composite clinical and microbiological response at each 
timepoint. 
Pharmacokinetic Endpoints
4.2.3.3
At the timepoints specified in the Trial Flow Chart (Section 6.0), whole blood samples will
be collected for determination of plasma concentration of REL, imipenem, and CIL. These
samples will support further evaluation of the PK profiles of these drugs by confirming that
subjects achieve expected exposures, and will also aid in further assessment of the clinical
relationship between REL plasma concentrations and efficacy against resistant isolates.
Planned Exploratory Biomarker Research
4.2.3.4
Planned Genetic Analysis
Understanding genetic determinants of drug response and the molecular basis of disease 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 and/or disease. If genetic variation is found to predict efficacy or adverse events, 
the data might inform optimal use of therapies in the patient population. Knowledge of the 
molecular basis of disease contributes to the development of novel biomarkers and the 
identification of new drug targets. This research contributes to understanding molecular basis 
of disease and the genetic determinants of efficacy and safety associated with the treatments 
in this study.
Future Biomedical Research
4.2.3.5
The Sponsor will conduct Future Biomedical Research on DNA specimens consented 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/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. 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.
 
 
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Benefit/Risk
4.3
Subjects enrolled in this trial are hospitalized subjects with infections requiring treatment
with IV therapy. Subjects will receive treatment, in part, with an agent, IMI, recommended 
and commonly used for the treatment of such infections, and, in addition, subject can 
potentially benefit from treatment with the investigational agent REL.
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 subject 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 with potential to support treatment of subjects for whom
no or limited alternative therapies are available.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying 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/Female Japanese subjects who are at least 18 years of age and have been diagnosed 
with complicated intra-abdominal infection (cIAI) or complicated urinary tract infection 
(cUTI) 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.
2. require hospitalization and treatment with IV antibiotic therapy for complicated intra-
abdominal infection (cIAI) or complicated urinary tract infection (cUTI)
NOTE: Subjects have to meet the following diagnostic criteria, including relevant 
clinical and microbiological evidence for each infection type.
Complicated Intra-Abdominal Infection (cIAI)
A. Definition
Intra-abdominal infection (IAI) is broadly defined as peritoneal inflammation in 
response to microorganisms, resulting in purulence in the peritoneal cavity. IAI are 
classified as uncomplicated or complicated based on the extent of infection. 
Complicated IAI (cIAI) extends beyond the hollow viscus of origin into the peritoneal 
space and is associated with either abscess formation or peritonitis.
 
 
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B. Diagnostic Guidelines
Subject has clinical evidence on the basis of operative findings and is able to provide 
the specimen to confirm the microbiological findings at baseline. Procedures include 
open laparotomy, laparoscopy, and percutaneous drainage of intra-abdominal abscess. 
Postoperative (or intraoperative) enrollment of subjects is encouraged. If, however, 
preoperative data are available that strongly suggest an appropriate diagnosis for 
entry (e.g., intraperitoneal abscess or perforation on computed tomography [CT] 
scan), then these subjects may be enrolled preoperatively. For preoperative 
enrollment, subjects must have a surgical intervention performed within 24 hours of 
the initiation of IV study drug.
1. Clinical
A diagnosis of cIAI should include at least one of the following as evidence of intra-
peritoneal infection (or strongly suggested with an appropriate diagnosis confirmed 
by CT scan):
•
Intra-abdominal abscess, including splenic or liver abscess
•
Appendicitis complication by perforation or abscess formation
•
Diverticulitis complicated by perforation or abscess formation
•
Cholecystitis with evidence of perforation or empyema
•
Perforation of the large or small intestine with abscess or fecal contamination
•
Gastric or duodenal ulcer perforation, only if operated on >24 hours after 
perforation
•
Peritonitis due to perforated viscus, surgical intervention, or other focus of 
infection. Spontaneous bacterial peritonitis associated with cirrhosis and 
chronic ascites are not eligible.
AND
At least one of the following clinical signs and symptoms of infection should be 
present:
•
Fever, defined as oral temperature greater than or equal to 38.0°C [or axillary 
temperature greater than or equal to 37.5°C];
•
Hypothermia, defined as core body temperature less than or equal to 35°C;
•
Abdominal pain or flank pain, or pain caused by cIAI that is referred to another 
anatomic area such as back or hip
•
Nausea or vomiting
•
Elevated white blood cells (WBC; >10,500/mm3)
2. Microbiological
Purulent material from intra-abdominal space is able to be obtained during a surgical 
operation or percutaneous drainage at baseline. Specimens from the surgical 
intervention must be sent for aerobic and anaerobic culture.
 
 
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Complicated Urinary Tract Infection (cUTI)
A. Definition
A complicated urinary tract infection is an infection of one or more structures in the 
urinary system in the presence of a functional or anatomical abnormality of the 
urinary tract or in the presence of catheterization. Pyelonephritis, regardless of 
underlying abnormalities of the urinary tract, is a type of cUTI that affects one or both 
kidneys. UTIs are a clinical syndrome characterized by pyuria and a documented 
microbial pathogen on culture of urine or blood, accompanied by local and systemic 
signs and symptoms of infection.
B. Diagnostic Guidelines
For a diagnosis of cUTI, including pyelonephritis, supportive clinical and 
microbiological findings should be present.
1. Clinical
Subject has at least two of the following local or systemic signs and symptoms:
•
Local signs and symptoms: Dysuria, urinary frequency, suprapubic or pelvic 
pain, urinary urgency, or flank pain or costovertebral angle (CVA) tenderness 
on physical examination
•
Systemic signs and symptoms: Fever (defined as oral temperature greater than 
or equal to 38.0°C [or axillary temperature greater than or equal to 37.5°C], 
chills or rigors (accompanied by fever), nausea or vomiting
AND
Pyuria determined by a midstream clean-catch (MSCC) or catheterized (indwelling or 
straight catheter) urine specimen with ≥10 white blood cells (WBCs) per high-power 
field (hpf) on standard examination of urine sediment or ≥10 WBCs/mm3 in unspun 
urine.
NOTE: If pyuria cannot be determined by urinalysis in a clinically relevant 
timeframe, a urine dipstick may be employed as a rapid diagnostic aid. If urine 
dipstick is used, a positive test for leukocyte esterase is the preferred indicator for the 
presence of pyuria.
2. Anatomical
Subject has at least one of the following conditions associated with a risk for 
developing cUTI:
•
Indwelling urinary catheter or other urinary bladder instrumentation
•
Urinary retention (at least 100 mL of residual urine after voiding)
•
Neurogenic bladder
•
Obstructive uropathy (nephrolithiasis, fibrosis or prostatic hypertrophy)
•
Azotemia
OR,
 
 
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Subject has pyelonephritis and normal urinary tract anatomy.
3. Microbiological
Subject has a positive urine culture at baseline as defined below:
•
≥105 CFU/mL of uropathogen either from a mid-stream clean catch (MSCC) or 
indwelling catheter urine specimen, OR
•
≥104 CFU/mL of uropathogen either from a MSCC or indwelling catheter urine 
specimen if blood culture is also positive
NOTE: For subjects with an indwelling catheter, samples should be collected 
following the placement of a new catheter. If the placement of a new catheter is 
contraindicated or is not feasible, specimens should be collected using aseptic 
techniques with the urine obtained through a properly disinfected collection port. 
Urine samples should never be obtained from a collection bag.
NOTE: If more than one pathogen is identified, each should be present at the colony 
counts noted above to be considered pathogens. In general, if more than 2 bacterial 
pathogens are identified in an admission urine culture at the predefined colony 
counts, the sample should be considered contaminated (unless one of the pathogens is 
also identified in a blood culture).
NOTE: A subject can be enrolled before the urine culture results are available if it is 
likely to be positive (based on clinical findings and urinalysis). 
Sepsis secondary to cIAI or cUTI
The investigator should confirm if the subjects meet the following diagnosis for 
sepsis upon the study entry in addition to the one of diagnostic criteria for their 
primary infection. Subjects don’t need to meet the criteria for sepsis to be enrolled 
into this study. However for subjects with sepsis, investigators should also follow the 
procedures for sepsis as determined in this protocol.
A. Definition
Sepsis is defined as a systemic inflammatory response syndrome induced by 
infection, with microbiologically documented.
B. Diagnostic Guidelines
Subjects should have clinical signs defined below and meet the following
microbiologic criteria;
1. Clinical:
Temperature ≥38.0°C or < 36°C [defined as oral temperature, and ≥37.5°C or  < 
35.5°C as axillary temperature], with one of the following:
•
WBC count >12,000 or <4,000, or with a differential count showing 10% band 
forms
•
Tachycardia: Pulse rate > 100 bpm
 
 
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•
Tachypnea: Respiratory rate > 20 breaths/minute
•
Hypotension: Systolic blood pressure < 90 mm Hg
2. Microbiologic criteria:
Subject has positive blood culture at baseline (within 24 hours of initiation IV study 
therapy)
3. have an infection known or thought to be, in the opinion of the investigator, caused
by microorganisms susceptible to the IV study therapy.
4. whose baseline specimen from the primary infection-site for culture could be 
obtained during the following period;
•
For cIAI: intra-abdominal specimen obtained at operative procedure at 
screening period.
NOTE: For cIAI subject who enrolled pre-operatively enrollment, the specimen
from the infection site obtained during the interventional procedure should be 
provided as baseline.
•
For cUTI: Urine specimen within 48 hours prior to initiation of IV study drug. 
5. agree to allow any bacterial isolates obtained from protocol-required specimens
related to the current infection to be provided the Central Microbiology Reference
Laboratory for study-related microbiological testing, long-term storage, and other
future testing.
6. 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 or
legally acceptable representative may also provide consent for Future Biomedical
Research. However, the subject may participate in the main trial without participating 
in Future Biomedical Research.
7. meet one of the following categories:
a) The subject is a male who is not of reproductive potential, defined as a male who
has azoospermia (whether due to having had a vasectomy or due to an underlying
medical condition).
b) The subject is a female who is not of reproductive potential, defined as a female
who either: (1) is postmenopausal (defined as at least 12 months with no menses in
women ≥45 years of age); (2) has had a hysterectomy and/or bilateral oophorectomy,
bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to
screening; OR (3) has a congenital or acquired condition that prevents childbearing.
 
 
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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)
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
Combination method (requires use of two of the following):
•
diaphragm with spermicide
•
contraceptive sponge (nulliparous women only)
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or
progestin-only pill)
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. has received any amount of effective antibiotic therapy (defined as therapy known to 
be active against the identified pathogen) after obtaining the culture for admission to 
this study (admission culture) and prior to the administration of the first dose of IV 
study therapy.
Note: For subjects with cIAI, use of intra-operative antibiotics per each institution’s
standard procedure is allowed.
2. has received treatment with systemic effective antibiotics for > 24 hours within the 72
hours immediately prior to initiation of study therapy.
NOTE: For a subject has received >48 hours of systemic antimicrobial therapy, 
he/she is eligible for this study if there are clear evidence that the subject has failed 
this regimen or developed the current index infection while on the previous antibiotic 
regimen. Such evidence would include new or continued fever or persistence or 
worsening of symptoms related to the index infection and persistent laboratory or 
radiographic changes (if previously present). In addition, investigators should confirm
the evidence of positive cultures which suggests persistent bacterial infection. Culture 
results do not need to be known before entry; however, the evidence should be 
obtained as support the presence of bacteria in sample from index infection such as 
Gram stain. These measures should be confirmed prior to study entry.
 
 
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3. has a concurrent infection that would interfere with evaluation of response to
IMI/REL, including any of the following:
•
endocarditis
•
osteomyelitis
•
meningitis
•
prosthetic joint infection
4. has a cIAI or cUTI due to a confirmed fungal pathogen.
NOTE: Use of antifungal therapy for treatment of mucocutaneous infections (e.g.,
vaginal candidiasis or onychomycosis) is allowed (see Section 5.5).
5. has cUTI which meets any of the following:
•
complete obstruction of any portion of the urinary tract (requiring a permanent
indwelling urinary catheter or instrumentation)
•
known ileal loop
•
intractable vesico-uretral reflux
•
presence of indwelling urinary catheter which cannot be removed at study 
entry
NOTE: All indwelling urinary catheters must be removed prior to the start of IV
therapy. Unless medically necessary, it is recommended that an indwelling urinary 
catheter not be reinserted while on IV study therapy.
6. has cIAI which meets any of the following:
•
Subject has an infection which should be managed by Staged Abdominal 
Repair (STAR) or open abdomen technique.
•
Infections limited to the hollow viscus, such as simple cholecystitis and 
simple appendicitis, ischemic bowel disease without perforation, acute 
suppurative cholangitis and acute necrotizing pancreatitis 
7. has a history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious
reaction to any of the following:
•
Any carbapenem, cephalosporin, penicillin, or other β-lactam agent
•
other β-lactamase inhibitors (e.g., tazobactam, sulbactam, clavulanic acid,
avibactam)
8. 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.
9. has a history of a seizure disorder (requiring ongoing treatment with anti-convulsive
therapy or prior treatment with anti-convulsive therapy within the last 3 years).
 
 
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10. is anticipated to be treated with any of the following medications during the course of
study therapy:
•
valproic acid (or has used valproic acid in the 2 weeks prior to screening)
•
concomitant IV or oral antimicrobial treatments which is considered effective 
to the index pathogen, in addition to the study treatments.
NOTE: Use of IV vancomycin, IV daptomycin, or IV linezolid to treat confirmed or 
suspected methicillin-resistant S. aureus (MRSA) infection or use of IV linezolid to 
treat confirmed or suspected vancomycin-resistant Enterococcus spp. (VRE) infection 
is allowed. (Refer to Section 5.5).
11. is currently receiving immunosuppressive therapy, including use of high-dose
corticosteroids (i.e., ≥40 mg prednisone or prednisone equivalent per day).
NOTE: Prior short term use (≤7 days) of steroid therapy in the 30 days prior to study
entry is allowed.
12. has an estimated or actual creatinine clearance of less than 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 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
13. is currently undergoing hemodialysis or peritoneal dialysis.
14. has any of the following laboratory abnormalities at the time of screening:
•
Alanine aminotransferase (ALT) values ≥ 4 times the upper limit of normal
(ULN)
•
Aspartate aminotransferase (AST) values ≥ 4 times ULN
•
ALT or AST  ≥3 × ULN and total bilirubin ≥2 × ULN and, at the same time, 
Alkaline phosphatase (ALP) < 2 × ULN
•
Total bilirubin value ≥ 3 times ULN
NOTE: Subjects with acute hepatic failure or acute decompensation of chronic
hepatic failure should also be excluded.
15. 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.
 
 
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16. is currently participating in, or has participated in, any other clinical study involving
the administration of investigational or experimental medication (not licensed by
regulatory agencies) at the time of the presentation or during the previous 30 days
prior to screening or is anticipated to participate in such a clinical study during the
course of this trial.
17. has previously participated in this study at any time
18. 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 treatment(s) to be used in this trial is outlined below in Table 12.
Table 12
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use 
Imipenem/cilastatin/
relebactam (IMI/REL)
Imipenem: 500 mg
Relebactam:250 mg
Every 6
hours
IV
5 to 14 days
experimental
The first dose of prescribed study therapy should be administered at the Day 1 visit. Subjects
will receive a minimum of 5 days to up to a maximum of 14 days of intravenous (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.
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.
Dose Selection/Modification
5.2.1
Dose Selection (Preparation)
5.2.1.1
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 (q6h). For subjects with renal 
insufficiency or whose creatinine clearance changes during treatment with study therapy, the 
dose must be adjusted 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 13.
Table 13
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.
 
 
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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 13, the dose of IMI/REL 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 should be administered over 30 minutes +/- 5 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.
Trial Blinding 
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
Subjects participating in this trial will be allocated by non-random assignment using an 
integrated web response system (IWRS).
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, 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.
 
 
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The following concomitant medications/therapies are not permitted in this study:
1. Valproic acid (during treatment with study drug and the 2 weeks prior to screening)
2. Non-study systemic (IV or oral) antibacterial treatments
NOTE: Use of IV vancomycin, IV daptomycin, or IV linezolid to treat confirmed or 
suspected methicillin-resistant S. aureus (MRSA) infection or use of IV linezolid to 
treat confirmed or suspected vancomycin-resistant Enterococcus spp. (VRE) infection 
is allowed. 
3. Systemic (IV or oral) antifungal therapy
NOTE: Concomitant use of antifungal therapy for treatment of mucocutaneous
infections (e.g., vaginal candidiasis, onychomycosis) is allowed.
4. Immunosuppressive therapy, including use of high-dose corticosteroids (i.e., ≥40 mg 
prednisone or prednisone equivalent per day)
NOTE: Short-term use (≤7 days) of systemic (Oral or IV) steroid therapy and Topical 
steroids for the treatment of skin conditions are also allowed.
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.
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation are important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 - Trial Flow Chart and Section 7.1.5.3 – Discontinued Subjects 
Continuing to be Monitored in the Trial.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Any of the following post-baseline elevations in liver transaminase levels:
 
 
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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 temperature ≥38.0°C), 
rash, and/or eosinophilia (>5%)
NOTE: In subjects in whom fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness was a part of the subject's presenting illness, the subject may continue on 
therapy if there is no elevation in transaminases from baseline measurements. In such 
subjects who experience a return of their original symptoms with accompanying 
elevations in transaminases it may be difficult to determine the cause, and investigators 
may discuss subjects in this situation with the Sponsor Clinical Director prior to 
discontinuation, if desired.
In subjects with preexisting transaminase elevations,

Further increase in transaminases to ≥8X ULN 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 Day 1] and new onset of clinical signs and symptoms of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever (defined as oral
temperature ≥38.0°C), 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; ALT or AST ≥3 X ULN [with at least 
50% increase from transaminase values collected at Day 1] and new onset of 
clinical signs and symptoms listed) at baseline.
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.
o
A post-baseline decline in estimated or actual creatinine clearance to a value of less 
than 15 mL/min.
o
The subject requires initiation of hemodialysis or peritoneal dialysis.
o
The subject has a confirmed positive serum or urine (sensitivity of < 25 million IU/L 
is required if using urine test) pregnancy test.
o
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.
 
 
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For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Withdrawal from the Trial
5.8.2
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
5.9
A subject who discontinues from 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 study-related phone-call or visit, withdraws 
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 Therapy
Post-Therapy
Visit Number/Title:
Visit 1 
Screening
Visit 2
Initiation of 
Therapy
Visit 3
On Therapy
(OTX)
Visit 4
End of Therapy
(EOT)
Visit 5
Test of Cure
(TOC)
Visit 6
Follow up
(FU)
Scheduled Day:
≤24 hours pre-
initiation of study
Day 1
Day 3
Day 5 to 
Day 141
5 to 9 days 
following EOT
14 (+2) days
following EOT
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research2
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Medical History, including full assessment of details of 
infection site diagnoses3
X
Concomitant Medication Review
X
X
X
X
X
X
Allocation of treatment assignment4
X
Administration of IV Study Therapy
←                 Daily                  →
Clinical Procedures/Assessments
APACHE II Score (only for subjects with cIAI)5
X
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
Vital Signs (heart rate, blood pressure, respiratory rate, 
oral/tympanic temperature) 6
←   Daily during IV therapy   →
X
X
Height
X
Weight7
X
X
Adverse Events Monitoring8
X
←   Daily during IV therapy   →
X
X
Local infusion tolerability monitoring
←   Daily during IV therapy   →
Review of clinical signs and symptoms of infection  
(including primary infection and sepsis if applicable)9
←   Daily during IV therapy   →
X
Infection source control review10
X
X
X
Laboratory Procedures/Assessments
Blood for hematology11
X
X
X
X
X
Blood for chemistry11
X
X
X
X
X
Urine for urinalysis11,12
X
X
X
Serum β-Human Chorionic Gonadotropin (β-hCG)
– if applicable13
X
X
Blood for genetic analysis2
X
Infection Site Specimen for Culture
   cIAI14
X
X
X
X
   cUTI15
X16
X
X
X
 
 
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Trial Period:
Screening
IV Study Therapy
Post-Therapy
Visit Number/Title:
Visit 1 
Screening
Visit 2
Initiation of 
Therapy
Visit 3
On Therapy
(OTX)
Visit 4
End of Therapy
(EOT)
Visit 5
Test of Cure
(TOC)
Visit 6
Follow up
(FU)
Scheduled Day:
≤24 hours pre-
initiation of study
Day 1
Day 3
Day 5 to 
Day 141
5 to 9 days 
following EOT
14 (+2) days
following EOT
Blood Specimen for Culture17, 18
X
As clinically indicated or, if pre-study blood culture was 
positive, repeat blood culture until confirmed negative.
Population Pharmacokinetics Analysis
Whole blood to collect plasma for REL, IMI, and CIL 
assay19
X
X
X
Efficacy Evaluation
Clinical Response Assessment (including sepsis if 
applicable)20
X
X
X
Microbiological Response Rating21
X
X
X
1.
IV study therapy should be administered for a minimum of 5 full days. The total duration of IV study therapy should not exceed 14 days. 
2.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at the site if there 
is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. 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.
3.
The details of subject’s infection-site diagnoses (cIAI or cUTI) will be documented separately on the appropriate eCRF(s). Details should include the diagnosis and 
additional diagnostic details associated with the infection site (e.g., characterization of the complicated nature of the cIAI or cUTI).
4.
The most recently collected creatinine clearance should be used to support dosage determination. (refer to Table 13 in Section 5.2.1.1).  Any local or central laboratory 
abnormalities in serum creatinine that result in an adverse event or a dose adjustment should be recorded.
5.
APACHE II score is calculated at screening only for subjects with cIAI. Please refer to Appendix 12.4 for the parameters and instructions for calculation of APACHE II 
score.
6.
Vital signs should be performed and documented on the appropriate electronic case report forms (eCRFs) at the Day 1 prior to administration of the first dose of study 
therapy and daily during IV study therapy.  Vital signs should also be performed and documented at the additional visits specified. 
7.
For all subject, weight must be measured at baseline. Enter weight if a clinically significant weight change occurred and resulted in a change in CrCl category.
8.
Monitor for adverse events and local infusion tolerability and collect infection-specific clinical signs and symptoms daily during IV study therapy and adverse experiences 
for 14 days after completion of IV study therapy.  Laboratory abnormalities that emerge during IV therapy and are considered adverse experiences by the investigator must 
be followed until resolved or stabilized.  Serious adverse experiences that are considered by the investigator to be related to the investigational product that is brought to the 
attention of the investigator at any time outside of 14 days post-therapy also must be reported immediately to the Sponsor.  
9.
Clinical signs and symptoms, radiographic (daily reporting not required for radiographic findings) and laboratory characteristics associated with the primary bacterial 
infection and with sepsis (see Table 14 in section 7.1.2.6) will be reviewed and documented on the appropriate electronic case report forms (eCRFs) daily during IV study 
therapy and at the additional visits specified.
10.
Includes information regarding infection source control should be documented on the appropriate eCRF. Source control includes the following for each infection site: cUTI  -
baseline information associated with catheterization (e.g., recent surgery or instrumentation, presence of catheter/stent) as well as any details related to removal and/or 
replacement of urinary catheters at any time during the study.  cIAI: details associated with the qualifying abdominal surgical intervention or any subsequent interventions, 
including an anonymized narrative of the operative note and/or interventional radiology report.
11.
Blood for laboratory safety tests (hematology and chemistry) should be collected for submission to the central safety laboratory at Day 1 prior to administration of the first 
dose of study therapy, on Day 3 (OTX), and every 3 days thereafter until EOT (including the EOT visit).  Blood should also be collected at TOC and FU. Urine for urinalysis 
 
 
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Trial Period:
Screening
IV Study Therapy
Post-Therapy
Visit Number/Title:
Visit 1 
Screening
Visit 2
Initiation of 
Therapy
Visit 3
On Therapy
(OTX)
Visit 4
End of Therapy
(EOT)
Visit 5
Test of Cure
(TOC)
Visit 6
Follow up
(FU)
Scheduled Day:
≤24 hours pre-
initiation of study
Day 1
Day 3
Day 5 to 
Day 141
5 to 9 days 
following EOT
14 (+2) days
following EOT
should be collected for submission to the central safety laboratory at the Day 1 prior to administration of the first dose of study therapy and at EOT and FU.  
12.
The urinalysis should be performed on mid-stream clean catch urine or catheter urine specimen, if possible.
13.
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 may be used for screening. 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 million IU/L. If a rapid urine test is performed at screening, a serum β HCG must be collected and sent to the Central Lab for confirmation of 
the dipstick result.  If the serum β HCG test comes back positive from the Central Laboratory, the subject must be discontinued.  The sample collected at FU visit should be a 
serum β-HCG.
14.
Obtain sample for culture from infection site prior to initiation of IV study therapy for all subjects with cIAI during the screening period. (For cIAI subject who enrolled pre-
operatively enrollment, the specimen from the infection site obtained during the interventional procedure should be provided as baseline.). However, for subjects in which 
infection site specimen collection is not medically acceptable (e.g., cIAI subject in whom an additional sample would require surgical intervention), additional collection for 
subsequent visit is not required. Bacterial isolates will be stored for future testing.  In addition, the most recently available laboratory data for the suspected causative 
pathogen(s), including specimen type, and culture ID must be collected on the appropriate eCRF.
15.
Urine culture is required at all specified timepoints for all subjects with cUTI. Acceptable methods of collection include mid-stream-clean-catch, indwelling catheter or 
straight catheter specimen. For subjects with an indwelling catheter, samples should be collected following the placement of a new catheter. If the placement of a new 
catheter is contraindicated or is not feasible, specimens should be collected using aseptic techniques with the urine obtained through a properly disinfected collection port. 
Urine samples should never be obtained from a collection bag. Bacterial isolates will be stored for future testing. In addition, the most recently available laboratory data for 
the suspected causative pathogen(s), including specimen type, culture ID, and colony count must be collected on the appropriate eCRF.
16.
Urine samples must be collected within 48 hours prior to initiation of IV study therapy.
17.
Two sets of blood cultures, from two separate venipuncture (or 1 venipuncture and 1 catheter) sites are required before study therapy is initiated in all subjects.  Subjects with 
positive blood cultures at screening should have follow-up blood cultures collected until 2 sequential cultures demonstrates no growth.  If further testing is required, samples 
for blood culture collected after screening should be collected immediately prior to subsequent doses.  Bacterial isolates will be stored for future testing.
18.
For subjects who meet the criteria of sepsis, the blood collection for culture is required at EOT and TOC, unless blood cultures taken at prior to the corresponding visits show 
negative.
19.
Whole blood (4 mL) for attainment of plasma samples for determination of REL, IMI, and CIL plasma concentrations will be collected at screening and on Day 1 and Day 3 
at 2 timepoints: (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, samples may be collected with a later infusion within a 24 hour period. Both time points should be collected 
after the same dose (for example, 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 are required for these 
samples.
20.
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.  Clinical and other signs and symptoms of each infection type are included in Table 14 in section 7.1.2.6. In 
addition, investigator should also evaluate the clinical response of sepsis for subjects who meets the criteria for sepsis (refer to 5.1.2)
21.
A by-pathogen and overall microbiological response will be determined by the Sponsor based on culture data reported on the appropriate eCRFs..
 
 
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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
Informed Consent
7.1.1.1
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. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
General Informed Consent
7.1.1.1.1
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/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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Consent and Collection of Specimens for Future Biomedical Research
7.1.1.1.2
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.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
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. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
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.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee. In addition to
the evaluation of a patient’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 prior history of bacterial infection must also be recorded. Any history of conditions that 
may predispose a subject to infection (e.g., malignancies, management of organ transplant, 
treatment for rheumatologic disease) will also be documented on the appropriate eCRF.
A full evaluation of infection-site diagnoses (cIAI or cUTI) will also be performed. The 
details of these diagnoses will be documented separately on the appropriate eCRF(s). Details 
should include the diagnosis and any additional diagnostic details associated with the 
infection site (e.g., characterization of the complicated nature of the cIAI and/or cUTI).
Prior and Concomitant Medications Review
7.1.1.5
Prior Medications
7.1.1.5.1
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 14 days and any antimicrobial medications taken within 30 days before starting the 
trial.
 
 
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Concomitant Medications
7.1.1.5.2
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Assignment of Screening Number
7.1.1.6
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 treatment allocation.  Each subject will be 
assigned only one screening number.  Screening numbers must not be re-used for different 
subjects.
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation.   Once a treatment/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 treatment/randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
7.1.1.8
Interruptions from the protocol specified IV study therapy treatment plan of 1) greater than or
equal to 2 doses of IV study therapy during the first 5 days of therapy; OR 2) greater than or
equal to 4 doses of IV study therapy during days 6 to 14 of therapy require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Study Therapy Administration
7.1.1.9
Trial treatment is described in Section 5.2. The specific dosage as well as frequency and 
timing of administration for IMI/REL are provided in Section 5.2.1 and 5.2.2.
All IV study therapy infusions should be administered over 30 minutes +/- 5 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 the intravenous study
antibiotics are provided in a separate Pharmacy Binder.
IV study therapy should be administered for a minimum of 5 full days to up to a maximum of
14 days. Administration of trial medication will be witnessed by the investigator and/or trial 
staff.
 
 
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Clinical Procedures/Assessments
7.1.2
APACHE II Score
7.1.2.1
Only for cIAI subjects, severity of illness will be determined by APACHE II score at 
screening [27].
See Appendix 12.4 for details regarding the calculation of this score. Results of APACHE II
score calculations must be entered on the appropriate eCRF(s).
Full and Directed Physical Examinations
7.1.2.2
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).
Vital Signs
7.1.2.3
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 Day 1 should be performed prior 
to initiation of IV therapy.
For this study, vital signs include heart rate (HR), blood pressure (BP), respiratory rate (RR),
and oral temperature. Subjects should be resting in a seated or semi-recumbent position for at
least 10 minutes prior to having vital sign measurements obtained. Oral temperatures should 
be taken, but if oral is not possible, tympanic, rectal, or axillary methods are acceptable.
The method of body temperature should be consistent during the trial.
Any abnormal or clinically significant findings from the physical examinations must be
recorded on the appropriate eCRF.
Height and Weight
7.1.2.4
The subject’s height and weight should be measured prior to initiation of IV study therapy at
Day 1. Weight should be measured and recorded during the study if a clinically significant 
weight change occurred and resulted in a change in CrCl category.
 
 
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Adverse Event Monitoring and Local Infusion Tolerability Monitoring
7.1.2.5
Clinical adverse events will be collected daily from the time of initiation of the first dose of
IV study therapy to completion of FU 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 as related to study drug that is 
brought to the attention of the investigator at any time outside of the study period 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.
Clinical Signs and Symptoms of Infection
7.1.2.6
A detailed diagnosis as well as relevant clinical information associated with diagnosis
including clinical signs and symptoms, radiographic and laboratory characteristics related to
the primary bacterial infections sites will be reviewed and documented on the appropriate 
eCRFs at timepoints specified in Section 6.0 (Trial Flow Chart).
Presence or absence of specific clinical signs and symptoms relevant for each infection site
of interest (Table 14) will be recorded daily during IV study therapy and at visits 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).
Table 14
Infection-Site Specific Clinical Signs and Symptoms
Infection Site
Clinical Signs and Symptoms a
cIAI
Body temperature (fever or hypothermia), abdominal pain, flank pain, 
pain caused by cIAI that is referred to another anatomic area such as back 
or hip, tenderness to palpation, rebound tenderness, guarding, mass, 
ascites, ileus, bowel sounds, need for enteral feeding, nausea and vomiting
cUTI
Body temperature (fever), chills or rigors, flank pain, costovertebral angle 
(CVA) tenderness on physical examination, dysuria, urinary frequency, 
suprapubic pain, pelvic pain, and urinary urgency, nausea and vomiting
a Evaluation of clinical response for infection type may also include resolution of lab abnormalities present at 
baseline (see inclusion criteria #2 in section 5.1.2 for relevant abnormalities for each infection site).
 
 
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For Sepsis, if there are systemic sign and symptoms (for example, chills or tremble) in 
addition to lab abnormalities present at baseline (defined as inclusion criteria #2 in section 
5.1.2), those should be evaluated as a part of clinical response for sepsis. Those must be 
recorded on the appropriate eCRF.
Infection Source Control Review
7.1.2.7
Information related to infection source control must be collected for all subjects in the
appropriate eCRFs. Information collected will be specific to the site(s) of bacterial infection.
For subjects with cUTI, baseline information associated with catheterization (e.g., recent
surgery or instrumentation, presence of catheter/stent) as well as any details related to
removal and/or replacement of urinary catheters at any time during the study must be
collected. For subjects with cIAI, details associated with the qualifying abdominal surgical
intervention or any subsequent interventions, including an anonymized narrative of the 
operative note and/or interventional radiology report must be collected.
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 Section 12.3.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 15.
Table 15
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
 
 
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Hematology
Chemistry
Urinalysis
Other
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin 
is 
elevated 
above the upper limit of 
normal
Total protein
C-reactive protein (CRP)
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. Of note is
that, following the Day 3 blood sample, blood for safety laboratory testing must be collected
every 3 days until EOT (including EOT). Refer to Section 6.0 (Trial Flow Chart) for all
specific time points for these laboratory assessments.
Safety laboratory results from the central laboratory will likely not be available in a timely
fashion for patient management purposes. 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. Results of these local laboratory tests must be documented
in the subject’s medical record (or other source document). Laboratory abnormalities
resulting in an adverse experience 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 experience or event of clinical interest
should be repeated until the abnormal value has normalized, stabilized, or returned to
baseline.
In addition, creatinine values obtained locally which determine the dose of study drug at 
baseline and/or result in a change in dose of study drug during the treatment period, the data 
should be entered within the appropriate eCRF.
Culture
7.1.3.2
Culture (aerobic for all infection-site specimens and anaerobic for cIAI specimens) of 
infection site specimens collected at the study-specified time points (see Section 6.0, Trial
Flow Chart) will be performed at the local clinical microbiology laboratory for each site. All 
Suspected causative bacterial pathogens obtained from infection-site specimens collected 
from enrolled subjects will be retained by the local clinical microbiology laboratory and sent 
to the central microbiology reference laboratory. 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.  Additional details regarding bacterial specimen collection, 
processing, handling, and shipment will be provided by the Sponsor in a separate 
microbiology laboratory manual.
 
 
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Prior Infection-Site Specimens
7.1.3.2.1
A specimen will be obtained at baseline for culture from infection site prior to initiation of IV 
study therapy for all subjects. For cUTI subjects, a previously obtained culture is acceptable 
if urine specimen was obtained within 48 hours of initiation of IV study drug. For cIAI 
subjects, intra-abdominal specimen should be obtained at operative procedure at screening 
period. Culture should be performed at the local microbiology laboratory according to
recognized methods and per each laboratory's standard procedures. Relevant culture data 
from these samples should also be recorded on the appropriate eCRFs. Suspected causative
bacterial pathogens should also be stored at the local laboratory for possible future testing.
Relevant culture data from these samples should also be recorded on the appropriate eCRFs.
On-Study Infection-Site Specimens
7.1.3.2.2
Infection-site specimens for culture should be obtained according to Section 6.0 (Trial Flow 
Chart). 
For subjects with cIAI, collection of specimens from the infection site is preferred; however, 
for subjects in which infection site specimen collection is not medically acceptable follow up 
specimen is not required. Additional unscheduled cultures from the infection site should also
be collected at the time of any surgical or drainage procedure (if required). 
For subjects with cUTI, infection-site specimens for culture are required for all visits 
specified in Section 6.0 (Trial Flow Chart). 
Culture should be performed at the local microbiology laboratory according to recognized 
methods and per each laboratory's standard procedures. Relevant culture data from these 
samples should also be recorded on the appropriate eCRFs. Suspected causative bacterial 
pathogens should also be stored at the local laboratory for possible future testing. Relevant 
culture data from these samples should also be recorded on the appropriate eCRFs.
Blood Cultures
7.1.3.2.3
Two sets of blood cultures, from two separate venipuncture (or 1 venipuncture and 1 
catheter) sites are required before study therapy is initiated in all subjects. Subjects with 
positive blood cultures at screening should have follow-up blood cultures until 2 sequential 
cultures demonstrate no growth is confirmed. For subjects who meet the criteria of sepsis, the 
blood collection for culture is required at EOT and TOC, unless blood cultures taken at prior 
to the corresponding visits show negative. 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 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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Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.3
Whole blood to obtain plasma samples will be collected for pharmacokinetic evaluation of
REL, imipenem, and cilastatin concentrations. 
As outlined in Section 6.0 (Trial Flow Chart), whole blood (4 mL) should be collected at
screening and on Day 1 and Day 3 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, samples may be collected with a later infusion within a 24 hour period. 
Both time points should be collected after the same dose (e.g., 30 minutes and 4 hours post 
Dose #3). Actual date and time for the whole blood samples must be recorded in the eCRFs.
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
Planned Genetic Analysis Sample Collection
7.1.3.4
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.
Future Biomedical Research Samples
7.1.3.5
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for genetic analysis
Efficacy Evaluation
7.1.3.6
Clinical Response
7.1.3.6.1
Clinical signs and symptoms of infection (e.g., fever) as well as local signs of infection 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. Based on comparison to baseline clinical signs and 
symptoms of the subject’s infection(s), the investigator will determine and record the clinical 
response rating at each visit as described in Section 4.2.3.2.1.1 (Table 2, and Table 3).  In 
subjects with sepsis, a separate clinical response rating will be determined according to the 
definition of clinical response for sepsis as described in Section 4.2.3.2.1.3.1 (Table 8, and 
Table 9). The clinical response for sepsis will be determined in addition to the clinical 
response for cIAI or cUTI, since those subjects also included in the evaluation population for 
their primary infection. A detailed list of disease-specific signs and symptoms in support of 
evaluation of the clinical response rating are included in Section 5.1.2, inclusion criteria #2)
and Section 7.1.2.6, Table 14.
By-Pathogen Microbiological Response
7.1.3.6.2
The by-pathogen microbiological response rating will be determined by investigator at the 
visits specified in Section 6.0 (Trial Flow Chart) based on local laboratory results (per eCRF 
data provided by the investigator) of infection-site and/or blood cultures collected at each 
visit relative to the pathogen(s) isolated at baseline/admission. 
 
 
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Separate criteria for microbiological evaluation will be utilized for cIAI and cUTI, as 
described in Table 4 (for EOT visit) and Table 5 (for TOC visit) in Section 4.2.3.2.1.2.1 for 
cIAI and Table 6 (for EOT visit) and Table 7 (for TOC visit) in Section 4.2.3.2.1.2.2 for 
cUTI. In subjects with sepsis, an additional microbiological response rating for sepsis will be 
determined according
to Table 10, and Table 11 in Section 4.2.3.2.1.3.2. 
The 
microbiological response for sepsis will be determined in addition to the microbiological
response for cIAI or cUTI, since those subjects also included in the evaluation population for 
their primary infection.
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue treatment prior to completion of the treatment regimen should be 
encouraged to continue to be followed for all remaining study visits.
When a subject withdraws from participation in the trial, all applicable activities scheduled 
for the final trial visit should be performed at the time of withdrawal.  Any adverse events 
which are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2 - Assessing and Recording Adverse Events. Please also 
refer to Section 5.8 for details of Subject Withdrawal/Discontinuation Criteria..
Withdrawal From Future Biomedical Research
7.1.4.1.1
Subjects may withdraw their consent for Future Biomedical Research.  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).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal 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 withdrawal cannot be processed.
Subject Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
 
 
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Calibration of Critical Equipment
7.1.4.3
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
1.
Refrigerator
IV study therapy must be stored in a secure, limited-access location under the storage
conditions specified on the label, which may include refrigeration.
2.
Freezer
For specimens or study samples that may require storage at -20°C or -70°C.
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.
Screening
7.1.5.1
Within 24 hours prior to randomization, potential subjects will be evaluated to determine that 
they fulfill the entry requirements as set forth in Section 5.1.  Screening procedures may be 
repeated in some circumstances after consultation with the Sponsor.
Treatment Period
7.1.5.2
IV study therapy should be administered for a minimum of 5 full days. This translates to 
either 20 dose of IMI/REL based on the q6h dosing regimen.  The total duration of IV study 
therapy should not exceed 14 days.
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. All study assessments are 
recommended to be performed at approximately consistent time of day for the study patient 
(e.g. every morning) for each calendar day.
The EOT visit will be completed within 24 hours after the last dose of IV study therapy.
Post-Therapy (Follow up)
7.1.5.3
TOC (5 to 9 days after completion of IV study therapy) and FU visit [14 days (+2) after 
completion of IV study therapy] must be completed for each subject.
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 
 
 
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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.
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 Electronic Data Capture (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 administration of a total daily dose 
of IMI/REL in excess of 4 g (IMI) or 2 g (REL).
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 
 
 
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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, 
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 Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A 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 16 for additional details regarding each of the above criteria.
 
 
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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.
Events of Clinical Interest
7.2.3.2
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. 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.*
 
 
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*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.
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 16. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 16 for instructions in evaluating adverse events.
 
 
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Table 16
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.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
the analyses made after the protocol has been finalized, but prior to the database lock, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study. Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan
is provided in Sections 8.2-8.12.
Study Design Overview
A non-randomized, non-controlled, open-label trial of IMI/REL in 
subjects with cIAI or cUTI.
Treatment Assignment
All enrolled subjects will receive IV study therapy of IMI/REL in an 
open-label manner.
Analysis Populations
Safety
All Subjects as Treated (ASaT) population
Efficacy
Modified intention to treat (MITT) population and microbiologically-
evaluable (ME) population; ME population will serve as the primary 
analysis population
Primary Endpoint(s)
Safety
Safety parameters including adverse events (AEs), pre-defined limits of 
change (PDLCs), change from baseline in vital signs and laboratory tests
Efficacy
1. Proportion of subjects with cIAI achieving favorable clinical 
response to IMI/REL at the EOT visit
2. Proportion 
of 
subjects 
with 
cUTI 
achieving 
favorable 
microbiological response to IMI/REL at the EOT visit
Secondary Endpoints
1.
Proportion of subjects with cIAI achieving favorable clinical
response to IMI/REL at the TOC visit
2.
Proportion 
of 
subjects 
with 
cUTI 
achieving 
favorable 
microbiological response to IMI/REL at the TOC visit
Statistical Methods for 
Key Safety Analyses
AEs and PDLCs will be summarized by numbers and percentages of 
subjects. For broad clinical and laboratory AE category, 95% confidence 
intervals (CIs) based on the method of Agresti and Coull will be 
calculated for the proportion of subjects. Change from baseline in vital 
signs and laboratory tests will be calculated by visit.
Statistical Methods for 
Key Efficacy Analyses
A 95% CI based on the method of Agresti and Coull will be provided for 
the proportion of subjects with cIAI achieving favorable clinical 
response to IMI/REL at the EOT visit. The same analysis will be 
performed for the proportion of subjects with cUTI achieving favorable 
microbiological response to IMI/REL at the EOT visit. The same
measures at the TOC visit will also be analyzed in the same manner.
 
 
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Interim Analyses
No interim analysis is planned.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power
A total of 80 subjects will be enrolled.
For an AE or a specific safety event of interest, if the underlying 
incidence is 2%, then there is 80% chance that it is observed in at least 
one subject among the 80 subjects enrolled.
In each of the cIAI and cUTI cohorts, if 40 subjects are enrolled, 28 
subjects are included in the ME population and evaluable at the EOT 
visit, and 26 subjects achieve favorable response, then the estimated 
percentage and corresponding 95% CI of subjects achieving favorable 
response will be 92.9% (76.3%, 99.1%).
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. This trial is being conducted as a non-
randomized, open-label study, i.e., subjects, investigators, and SPONSOR personnel will be 
aware of subject treatment assignments after each subject is enrolled and treatment is 
assigned.
Hypotheses/Estimation
8.3
The objectives of the study are stated in Section 3.
Analysis Endpoints
8.4
Safety Endpoints
8.4.1
A description of safety measures is provided in Section 4.2.3.1. Safety endpoints will include
AEs, PDLCs, and change from baseline in vital signs and laboratory tests. The baseline value 
is defined as the last available measurement prior to the start of the IV study therapy, which 
typically corresponds to the value obtained at Visit 2.
Efficacy Endpoints
8.4.2
A full description of the efficacy measures is provided in Section 4.2.3.2. The definition of 
favorable clinical and by-pathogen microbiological responses at each visit is summarized in 
Table 17.
A favorable overall microbiological response for a subject at a particular visit 
requires favorable responses in all baseline pathogens at that visit.
Table 17
Definition of favorable clinical and microbiological responses by visit
Visit
Rating(s) considered a favorable response
Clinical
Microbiological† (by-pathogen)
EOT
“cure” or “improved”
“eradication” or “presumptive eradication” ‡
TOC
“cure”
“sustained eradication” or “presumptive eradication” ‡
† A favorable overall microbiological response for a subject at a particular visit requires favorable 
responses in all baseline pathogens at that visit.
‡ cIAI only
 
 
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Analysis Populations
8.5
Safety Analysis Population
8.5.1
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all enrolled subjects who receive at least one dose of IV study therapy.
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.
Efficacy Analysis Population
8.5.2
Two populations, the MITT and the ME populations, will be used for the analysis of efficacy 
data in this study. The ME population will serve as the primary population for efficacy 
analyses in this study.
The MITT population is defined as all enrolled subjects who receive at least one dose of IV 
study therapy. In this study, this is identical with the ASaT population. The ME population is
a subset of the MITT population that excludes subjects due to major deviations from the 
protocol that may substantially affect the results of the efficacy analyses. Potential deviations 
that may result in the exclusion of a subject from the ME population include the following:
1.
The subject fails to meet the protocol definition of cIAI or cUTI
2.
The subject had significant violations of inclusion/exclusion criteria that could impact
the efficacy assessment (e.g., receipt of previous or concurrent systemic antibacterial 
therapy beyond those allowed per protocol)
3.
The subject received less than 96 hours of IV study therapy (16 infusions)
4.
(cIAI only) The subject’s pre-study/post-operative culture from the site of infection fails 
to grow at least 1 gram-negative enteric(s) and/or anaerobic pathogen(s) commonly 
isolated in IAI. (Note: Subjects who fail to grow a single gram-negative enteric and/or 
anaerobic pathogen from the site of infection are excluded from the ME population. That 
is, subjects with only gram-positive pathogens identified will be excluded, as well as 
those who do not grow any pathogens.)
(cUTI only) The subject’s pre-study urine culture fails to grow at least 1 gram-negative 
and/or anaerobic, pathogen at sufficient quantity specified in the inclusion criteria (See 
Section 5.1.2 for details)
The composition of the ME population at each time point of interest will be made prior to the 
database lock and will be documented in a separate memo.
Details on the approach to handling missing data are provided in Section 8.6.
Statistical Methods
8.6
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
 
 
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Statistical Methods for Safety Analyses
8.6.1
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, vital signs and laboratory tests.
The broad clinical and laboratory AE categories such as 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, as well as specific 
AEs (system organ classes and preferred terms) and PDLCs will be summarized by numbers 
and percentages of subjects, along with 95% CIs based on the method of Agresti and Coull 
for the proportion of subjects (broad clinical and laboratory AE categories only).
Summary statistics for baseline, on-treatment, and change from baseline values will be
provided for continuous measures such as vital signs and laboratory tests.
Statistical Methods for Efficacy Analyses
8.6.2
Missing values
In the analyses using the ME population, any subject with missing or indeterminate 
assessments for a specific endpoint (clinical or microbiological response) at any particular 
visit will be excluded from the assessment of that response at that time point. Exceptions 
follow:
1.
(cIAI only) Subjects with a missing culture in the setting of a favorable clinical response: 
In such subjects, even in the setting of a missing culture at a particular time point, a
favorable microbiological response will be presumed from the clinical response (i.e.,
“presumptive eradication”).
2.
Subjects discontinuing IV study therapy due to lack of efficacy (i.e., withdrawals with 
subsequent non-study antibiotic therapy, subjects requiring therapy beyond 14 days), 
including death due to index infection:

These subjects will be considered to be “failures” with respect to clinical response at 
the time of discontinuation and all subsequent time points post discontinuation,
irrespective of whether the clinical response is listed as “indeterminate”.

These subjects will be considered to have presumed persistence with respect to 
microbiological response at the time of discontinuation and all subsequent time 
points post discontinuation, irrespective of whether the microbiological response is 
listed as "indeterminate."
In the analyses using the MITT population, missing or indeterminate clinical or 
microbiological responses will be considered failure.
Proportions of subjects with favorable clinical/microbiological responses
A 95% CI based on the method of Agresti and Coull will be provided for the proportion of 
subjects with cIAI in the ME population achieving favorable clinical response at the EOT 
visit. The same analysis will be performed for the proportion of subjects with cUTI in the 
ME population achieving favorable microbiological response at the EOT visit. The same
measures at the TOC visit will also be analyzed in the same manner. Supportive analysis 
using the MITT population will also be performed.
 
 
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Table 18 summarizes key efficacy analyses.
Table 18
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
supportive 
approach†
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary objectives
Proportion of subjects with cIAI achieving 
favorable clinical response at the EOT visit
P
Agresti and 
Coull
ME
Data as observed‡
S
Agresti and 
Coull
MITT
Missing = Failure
Proportion of subjects with cUTI achieving 
favorable microbiological response at the 
EOT visit
P
Agresti and
Coull
ME
Data as observed§
S
Agresti and 
Coull
MITT
Missing = Failure
Secondary objectives
Proportion of subjects with cIAI achieving 
favorable clinical response at the TOC visit
P
Agresti and 
Coull
ME
Data as observed‡
S
Agresti and 
Coull
MITT
Missing = Failure
Proportion of subjects with cUTI achieving 
favorable microbiological response at the 
TOC visit
P
Agresti and 
Coull
ME
Data as observed§
S
Agresti and 
Coull
MITT
Missing = Failure
† P = primary, S = supportive
‡ Subjects discontinuing IV study therapy due to lack of efficacy will be considered failures with respect to their 
clinical response. In subjects with missing culture in the setting of a favorable clinical response, a favorable 
microbiological response will be presumed from the clinical response.
§ Subjects discontinuing IV study therapy due to lack of efficacy will be considered persistence with respect to
their microbiological response.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for study/study therapy discontinuation will be displayed. 
Demographic variables (e.g., age, gender), primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by descriptive statistics or categorical tables.
Interim Analyses
8.7
No interim analysis is planned.
Multiplicity
8.8
No multiplicity adjustment is planned.
Sample Size and Power Calculations
8.9
A total of 80 subjects will be enrolled.
 
 
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For an AE or a specific safety event of interest, if the underlying incidence is 2%, then there
is 80% chance that it is observed in at least one subject among the 80 subjects enrolled.
Based on the completed phase II studies (Protocols 003 and 004), it is expected that at least 
70% of the enrolled subjects will be included in the ME population. In each of the cIAI and 
cUTI cohorts, if 40 subjects are enrolled, 28 subjects are included in the ME population and 
evaluable at the EOT visit, and the 26 subjects achieve favorable response, then the estimated 
percentage and corresponding 95% CI of subjects achieving favorable response will be 
92.9% (76.3%, 99.1%). The estimated percentages and corresponding 95% CIs of subjects 
achieving favorable response under various assumptions are shown in Table 19.
Table 19
Estimate percentages (95% CIs) of subjects achieving favorable response under 
various assumptions
Number of subjects
Estimated percentage (95% 
CI)† of subjects achieving 
favorable response
Enrolled
Included in ME 
population and 
evaluable at EOT visit
Achieve
favorable 
response
30
21
19
20
90.5 (69.9, 98.6)
95.2 (75.6, 100.0)
40
28
25
26
27
89.3 (72.0, 97.1)
92.9 (76.3, 99.1)
96.4 (80.8, 100.0)
50
35
32
33
34
91.4 (76.9, 97.8)
94.3 (80.4, 99.4)
97.1 (84.2, 100.0)
† Based on the method of Agresti and Coull
The maximum enrollment for each of the cIAI and cUTI cohorts will be limited to 50 
subjects to ensure that a single disease cohort will not dominate the study population.
Subgroup Analyses
8.10
The proportion of subjects with cIAI achieving favorable clinical response at the EOT visit, 
as well as the proportion of subjects with cUTI achieving favorable microbiological response 
at the EOT visit, will be provided within each category of the classification variables listed 
below. The subgroup analyses will be performed for the ME population, separately by 
infection type.

gender (female, male)

age category (<65 years, ≥65 years)

renal function (CLCr at baseline) [normal (≥90), mild insufficiency (60 to <90), 
moderate insufficiency (30 to <60), severe insufficiency (<30)]

(cIAI only) APACHE II score at study entry (≤15, >15)

(cIAI only) clinical diagnosis (liver abscess, appendicitis, cholecystitis, peritonitis, other)

(cIAI only) poly vs. monomicrobial infections (poly infections, monomicrobial 
infections)
 
 
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
(cUTI only) presence/absence of pyelonephritis with/without complication (complicated 
lower urinary tract infection, complicated pyelonephritis, uncomplicated pyelonephritis)
Compliance (Medication Adherence)
8.11
For each subject, treatment compliance will be calculated as follows.
Compliance (%) =
Number of completed IV doses
x100
Number of expected IV doses
Descriptive statistics of treatment compliance will be calculated for the ME and MITT
populations.
Extent of Exposure
8.12
The extent of exposure to study treatment will be evaluated for the ASaT population.
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 20.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 20
Product Descriptions
Product Name 
& Potency
Dosage Form
Source/Additional Information
MK-7655A, MK-7655 
250 mg /Imipenem 
500 mg / Cilastatin 500 mg
Powder for Constitution
Provided centrally by the Sponsor
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label, single-dose vials. No kitting is required.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
 
 
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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 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
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.
 
 
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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
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 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. 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.
 
 
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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.
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/IEC 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 
 
 
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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.
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 Protocol/CSR 
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.clinicaltrialsregister.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 trial 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.  
 
 
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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.
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 
 
 
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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.
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.
11.0 LIST OF REFERENCES
1.
Rice LB. Federal Funding for the Study of Antimicrobial Resistance in Nosocomial 
Pathogens: No ESKAPE. J Infect Dis 2008;197:1079-81.
2.
Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae 
carbapenemase-producing bacteria. Lancet Infect Dis 2009;9:228-36.
3.
Boucher HW, Talbot GH, Bradley JS, Edwards JE Jr, Gilbert D, Rice LB, et al. Bad 
bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of 
America. Clin Infect Dis 2009;48(1):1-12.
4.
Curiao T, Morosini MI, Ruiz-Garbajosa P, Robustillo A, Baquero F, Coque TM, et al. 
Emergence of blaKPC-3-Tn4401a associated with a pKPN3/4-like plasmid within 
ST384 and ST388 Klebsiella penumoniae clones in Spain. J Antimicrob Chemother 
2010;65:1608-14.
5.
Giani T, D'Andrea MM, Pecile P, Borgianni L, Nicoletti P, Tonelli F, et al. Emergence 
in Italy of
Klebsiella pneumoniae Sequence Type 258 Producing KPC-3 
Carbapenemase. J Clin Microbiol 2009;47(11):3793-4.
 
 
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6.
Gregory CJ, Llata E, Stine N, Gould C, Santiago LM, Vazquez GJ, et al. Outbreak of
Carbapenem-Resistant Klebsiella pneumoniae in Puerto Rico Associated with a Novel
Carbapenemase Variant. Infect Control Hosp Epidemiol 2010;31(5):476-84.
7.
Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. 
Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a 
molecular, biological, and epidemiological study. Lancet Infect Dis 2010;10:597-602.
8.
Osterblad M, Kirveskari J, Koskela S, Tissari P, Vuorenoja K, Hakanen AJ, et al. First 
isolations of KPC-2-Carrying ST258 Klebsiella Pneumoniae strains in Finland, June and 
August 2009. Euro Surveill 2009;14(40):19349.
9.
Roche C, Cotter M, O'Connell N, Crowley B. First identification of class A 
carbapenemase-producing Klebsiella pneumoniae in the Republic of Ireland. Euro 
Surveill 2009;14(13):19163.
10. Tóth Á, Damjanova I, Puskás E, Jánvári L, Farkas M, Dobák A, et al. Emergence of a
colistin-resistant KPC-2-producing Klebsiella pneumoniae ST258 clone in Hungary. Eur 
J Clin Microbiol Infect Dis 2010;29:765-9.
11. Wendt C, Schütt S, Dalpke AH, Konrad M, Mieth M, Trierweiler-Hauke B, et al. First 
outbreak of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae in 
Germany. Eur J Clin Microbiol Infect Dis 2010;29:563-70.
12. Chopra I, Schofield C, Everett M, O'Neill A, Miller K, Wilcox M, et al. Treatment of
health-care-associated infections caused by Gram-negative bacteria: a consensus 
statement. Lancet Infect Dis 2008;8:133-9.
13. Markou N, Apostolakos H, Koumoudiou C, Athanasiou M, Koutsoukou A, Alamanos I, 
et al. Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative 
bacilli in critically ill patients. Critical care 2003;7(5):R78-R83.
14. Reina R, Estenssoro E, Saenz G, Canales HS, Gonzalvo R, Vidal G, et al. Safety and 
efficacy of colistin in Acinetobacter and Pseudomonas infections: a prospective cohort 
study. Intensive Care Med 2005;31:1058-65.
15. Falagas ME, Fragoulis KN, Kasiakou SK, Sermaidis GJ, Michalopoulos A. 
Nephrotoxicity of intravenous colistin: A prospective evaluation. Int J Antimicrob Ag 
2005;26:504-7.
16. Pintado V, García San Miguel L, Grill F, Mejía B, Cobo J, Fortún J, et al. Intravenous 
colistin sulphomethate sodium for therapy of infections due to multidrug-resistant gram-
negative bacteria. Journal of Infection 2008;56:185-90.
17. Montero M, Horcajada JP, Sorli L, Alvarez-Lerma F, Grau S, Riu M, et al. Effectiveness 
and Safety of Colistin for the Treatment of Multidrug-Resistant Pseudomonas 
aeruginosa Infections. Infection 2009;37:461-5.
18. Cheng C-Y, Sheng W-H, Wang J-T, Chen Y-C, Chang S-C. Safety and efficacy of 
intravenous colistin (colistin methanesulphonate) for severe multidrug-resistant Gram-
negative bacterial infections. Int J Antimicrob Agents 2010;35:297-300.
 
 
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19. Kallel H, Bahloul M, Hergafi L, Akrout M, Ketata W, Chelly H, et al. Colistin as a 
salvage therapy for nosocomial infections caused by multidrug-resistant bacteria in the 
ICU. Int J Antimicrob Agents 2006;28:366-9.
20. Hachem RY, Chemaly RF, Ahmar CA, Jiang Y, Boktour MR, Rjaili GA, et al. Colistin 
Is Effective in Treatment of Infections Caused by Multidrug-Resistant Pseudomonas 
aeruginosa in Cancer Patients. Antimicrob Agents Chemother 2007;51(6):1905-11.
21. Paul M, Bishara J, Levcovich A, Chowers M, Goldberg E, Singer P, et al. Effectiveness 
and safety of colistin: Prospective comparative cohort study. J Antimicrob Chemother 
2010;65:1019-27.
22. Guideline-preparing Committee. The JAID/JSC Guide to Clinical Management of 
Infectious Disease. 2014
23. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al. 
Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and 
Children: Guidelines by the Surgical Infection Society and the Infectious Diseases 
Society of America. Surg Infect (Larchmt) 2010;11:79-109.
24. Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, et al. 
Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in 
adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases 
Society of America. Clin Infect Dis 2010;50:625-63.
25. U.S. Department of Health and Human Services - Food and Drug Administration Center 
for Drug Evaluation and Research (CDER). Guidance for Industry: Catheter-Related 
Bloodstream Infections — Developing Antimicrobial Drugs for Treatment. 1999
26. Japanese Soc. of Intensive Care Medicine - Sepsis Registry Committee. The Japanese 
Guidelines for the Management of Sepsis. J Jpn Soc Intensive Care Med 2013;20:124-
73.
27. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. Apache II: A severity of disease 
classification system. Crit Care Med 1985;13(10):818-29.
 
 
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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 consented and/or collected in this trial as outlined in Section 7.1.3.5 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology 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 the Sponsor or those working for 
or with the Sponsor.
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 the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
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, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This 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 unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. 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 specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their
biospecimens not be used for Future Biomedical Research.  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). 
 
 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/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 withdrawal of consent and/or destruction cannot 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 the end of the main study. 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 Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-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 Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives 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 on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
 
 
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name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor 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.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. 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
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.3
Sample Types
Trial Visit/Cycle/etc:
Screening
Treatment 
Post-Treatment
Visit 1
Visit 2
Visit 3
(OTX)
Visit 4
(EOT)
Visit 5
(TOC)
Visit 6
(FU)
Blood Parameter
Approximate Blood Volume (mL)
Hematology
2.0
2.0
2.0
2.0
2.0
Serum/Plasma Chemistry
9.0
9.0
9.0
9.0
9.0
Blood for Planned Genetic 
Analysis 
8.5
Plasma for PK
4.0
8.0
8.0
Expected Total (mL) a, b
4.0
27.5
19.0
11.0
11.0
11.0
a. Additional blood samples may be collected in support for evaluation of an underlying etiology that may have 
caused an abnormal laboratory result (e.g., elevated liver transaminase level). The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File Binder. 
b. 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 until 2 sequential cultures demonstrate no 
growth. Depending on the results and frequency, 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. For Subjects who meet the criteria for 
sepsis, blood samples for culture are also required at EOT and, TOC visits (40 mL x 2/patients).
 
 
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APACHE II Severity of Disease Classification System – APACHE II Score Form
12.4
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 or at rest or with minimal self-care activities
Pulmonary -chronic hypoxemia or hypercapnia or polycythemia or PHT >40 mm Hg
Kidney -chronic peritoneal or hemodialysis
Immune -immune compromised host
Chronic Health Points=________
APACHE-II Score is sum of A+B+C
APS points
A _______
Age points +B _______
Chronic Health Points
+C _________
Total APACHE-II Score=________
 
 
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List of Abbreviations
12.5
Abbreviation
Definition
AC
alveolar cells
AE
adverse event
ALT
alanine aminotransferase
APACHE
acute physiology and chronic health evaluation 
ASaT
All subjects as treated
AUC0-∞
area under the concentration time curve 
AST
Aspartate aminotransferase
β-hCG
β-Human Chorionic Gonadotropin
BLI
β-lactamase inhibitor 
C-G
Cockcroft-Gault
cIAI
complicated intra-abdominal infection
CIL
cilastatin
CLCr
Creatinine clearance
CLplasma
plasma clearance
CMS
colistimethate sodium
CR
carbapenem-resistant
cUTI
complicated urinary tract infection
DCIV
discontinuation of IV therapy
eCRF
electronic case report form
ELF
epithelial lung fluid
EOT
end of therapy
ESRD
end-stage renal disease
GFR
glomerular filtration rate
HABP
hospital-acquired bacterial pneumonia
IMI
imipenem/cilastatin
IV
intravenous (parental)
KPC
Klebsiella pneumoniae carbapenemase 
MDR
multi-drug resistant
ME
microbiologically-evaluable
MITT
modified intent-to-treat
MSCC
mid-stream clean catch
OTX
on-therapy visit
PD
pharmacodynamic
PGt
pharmacogenetic
PK
pharmacokinetic
REL
relebactam
t1/2
terminal half-life 
TOC
test of cure
ULN
upper limit of normal
VABP
ventilator-associated bacterial pneumonia
 
 
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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 – TRIAL PROCEDURES (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
 
 
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