Clinical trial NCT02728089
Conditions: Urinary Tract Infection (UTI) Complicated Urinary Tract Infection Pyelonephritis Uncomplicated Pyelonephritis
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-04-14; Completion date: 2017-09-05
Enrollment: 115 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3, multi-site, non-randomized, open-label study evaluating the safety and efficacy of MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) for the treatment of complicated urinary tract infection (cUTI) including pyelonephritis (uncomplicated or complicated pyelonephritis and complicated lower urinary tract infection) in Japanese participants. Efficacy will be primarily assessed by microbiological response defined as eradication of the baseline pathogen or pathogens.

Detailed description:

Arms: arm 1: MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) administered as an intravenous (IV) infusion every 8 hours for 7 days. The dose may be reduced to 750 mg (ceftolozane 500 mg/tazobactam 250 mg) for participants with a creatinine clearance (CrCl) of 30-50 mL/min.
Interventions: intervention 1: MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g)
Intervention descriptions: intervention 1: MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) administered as an intravenous (IV) infusion

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02728089  
Document Date: 
21-Dec-2015
A Multicenter, Open-label, Noncomparative, Japanese Phase III 
Study to Assess the Efficacy and Safety of Ceftolozane/Tazobactam 
(MK-7625A) in Japanese Patients with Uncomplicated 
Pyelonephritis and Complicated Urinary Tract Infection


Product:  MK-7625A
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Confidential
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 Multicenter, Open-label, Noncomparative, Japanese Phase III Study to Assess the Efficacy 
and Safety of Ceftolozane/Tazobactam (MK-7625A) in Japanese Patients with 
Uncomplicated Pyelonephritis and Complicated Urinary Tract Infection
  
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) .............................................................. 11
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 11
3.2
Exploratory Objectives......................................................................................... 12
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 12
Background ........................................................................................................... 12
4.1
Pharmaceutical and Therapeutic Background .................................................... 12
4.1.1
Clinical Trial results............................................................................................ 15
4.1.2
Ongoing Clinical Trials....................................................................................... 16
4.1.3
Rationale................................................................................................................ 16
4.2
Rationale for the Trial and Selected Subject Population .................................... 16
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 18
4.2.2
Rationale for Endpoints ...................................................................................... 20
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 20
4.2.3.1.1
Definition of Efficacy Endpoints.......................................................... 20
4.2.3.2
Safety Endpoints .......................................................................................... 21
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 21
4.2.3.4
Pharmacodynamic Endpoints....................................................................... 21
4.2.3.5
Planned Exploratory Biomarker Research................................................... 21
4.2.3.6
Future Biomedical Research........................................................................ 21
Benefit/Risk ........................................................................................................... 22
4.3
5.0
METHODOLOGY ................................................................................................... 22
Entry Criteria........................................................................................................ 22
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 22
5.1.1
Subject Inclusion Criteria.................................................................................... 22
5.1.2
 
 
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Subject Exclusion Criteria .................................................................................. 24
5.1.3
Trial Treatment(s) ................................................................................................ 26
5.2
Dose Selection/Modification .............................................................................. 26
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 26
Timing of Dose Administration.......................................................................... 27
5.2.2
Trial Blinding/Masking....................................................................................... 27
5.2.3
Randomization or Treatment Allocation............................................................ 27
5.3
Stratification.......................................................................................................... 27
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 27
5.5
Prohibited medicine ............................................................................................ 27
5.5.1
Allowed medicine ............................................................................................... 28
5.5.2
Rescue Medications & Supportive Care............................................................. 28
5.6
Diet/Activity/Other Considerations..................................................................... 28
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 28
5.8
Subject Replacement Strategy............................................................................. 29
5.9
Beginning and End of the Trial ........................................................................... 29
5.10
Clinical Criteria for Early Trial Termination ................................................... 29
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 30
7.0
TRIAL PROCEDURES ........................................................................................... 32
Trial Procedures ................................................................................................... 32
7.1
Administrative Procedures.................................................................................. 32
7.1.1
7.1.1.1
Informed Consent......................................................................................... 32
7.1.1.1.1
General Informed Consent.................................................................... 32
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 33
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 33
7.1.1.3
Subject Identification Card .......................................................................... 33
7.1.1.4
Medical History ........................................................................................... 33
7.1.1.5
Prior and Concomitant Medications Review ............................................... 33
7.1.1.5.1
Prior Medications.................................................................................. 33
7.1.1.5.2
Concomitant Medications..................................................................... 33
7.1.1.6
Assignment of Screening Number............................................................... 33
 
 
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7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 34
7.1.1.8
Trial Compliance (Medication).................................................................... 34
7.1.1.9
Height and Body Weight ............................................................................. 34
Clinical Procedures/Assessments........................................................................ 34
7.1.2
7.1.2.1
Physical Examination................................................................................... 34
7.1.2.2
Vital Sign ..................................................................................................... 34
7.1.2.3
Assessment of Clinical Sign/Symptom for UTI .......................................... 35
7.1.2.4
Assessment for Clinical Outcome................................................................ 35
7.1.2.4.1
Clinical Response at the EOT, TOC and LFU Visits ........................... 35
Laboratory Procedures/Assessments .................................................................. 35
7.1.3
7.1.3.1
Urine Test for Pyuria ................................................................................... 36
7.1.3.2
Culture (Urine and Blood) ........................................................................... 36
7.1.3.2.1
Urine Culture ........................................................................................ 36
7.1.3.2.2
Blood Culture........................................................................................ 37
7.1.3.3
Assessment for Microbiological Outcome................................................... 37
7.1.3.3.1
Microbiological Response at the EOT, TOC and LFU Visits .............. 37
7.1.3.4
Emergent Infection....................................................................................... 38
7.1.3.5
Composite Microbiological and Clinical Response..................................... 38
7.1.3.6
Blood sampling for Hematology, Coagulation Chemistry, and Urine 
sampling for urinalysis................................................................................. 39
7.1.3.7
Assessment of creatinine clearance ............................................................. 39
7.1.3.8
Urine pregnancy test (females of child bearing potential)........................... 39
7.1.3.9
Pharmacokinetic Evaluations....................................................................... 40
7.1.3.9.1
Blood Collection for Pharmacokinetics................................................ 40
7.1.3.10 Planned Genetic Analysis Sample Collection.............................................. 40
7.1.3.11 Future Biomedical Research Sample Collection ......................................... 40
Other Procedures................................................................................................. 40
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 40
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 41
7.1.4.2
Blinding/Unblinding .................................................................................... 41
7.1.4.3
Calibration of Critical Equipment................................................................ 41
Visit Requirements.............................................................................................. 41
7.1.5
7.1.5.1
Screening (Visit 1) ....................................................................................... 41
 
 
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7.1.5.2
Treatment Period (Visit 2-9)........................................................................ 42
7.1.5.3
Follow-up Period (Visit 10 and 11) ............................................................. 42
Assessing and Recording Adverse Events .......................................................... 42
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 43
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 43
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 44
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 44
7.2.3.2
Events of Clinical Interest............................................................................ 44
Evaluating Adverse Events ................................................................................. 45
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 48
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 48
Statistical Analysis Plan Summary ..................................................................... 48
8.1
Responsibility for Analyses/In-House Blinding ................................................. 49
8.2
Hypotheses/Estimation ......................................................................................... 49
8.3
Analysis Endpoints ............................................................................................... 49
8.4
Efficacy Endpoints.............................................................................................. 49
8.4.1
Safety Endpoints ................................................................................................. 49
8.4.2
Analysis Populations............................................................................................. 50
8.5
Efficacy Analysis Populations ............................................................................ 50
8.5.1
Safety Analysis Populations ............................................................................... 50
8.5.2
Statistical Methods................................................................................................ 51
8.6
Statistical Methods for Efficacy Analyses .......................................................... 51
8.6.1
Statistical Methods for Safety Analyses ............................................................. 52
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 53
8.6.3
8.6.3.1
Demographic and Baseline Characteristics ................................................. 53
8.6.3.2
Population PK Analyses .............................................................................. 53
Interim Analyses ................................................................................................... 53
8.7
Multiplicity ............................................................................................................ 53
8.8
Sample Size and Power Calculations .................................................................. 53
8.9
Sample Size and Power for Efficacy Analyses ................................................... 53
8.9.1
Subgroup Analyses and Effect of Baseline Factors ........................................... 54
8.10
 
 
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Compliance (Medication Adherence).................................................................. 54
8.11
Extent of Exposure................................................................................................ 55
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 55
Investigational Product ........................................................................................ 55
9.1
Packaging and Labeling Information ................................................................. 55
9.2
Clinical Supplies Disclosure................................................................................. 55
9.3
Storage and Handling Requirements.................................................................. 56
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 56
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 56
Confidentiality....................................................................................................... 56
10.1
Confidentiality of Data ....................................................................................... 56
10.1.1
Confidentiality of Subject Records ..................................................................... 56
10.1.2
Confidentiality of Investigator Information........................................................ 57
10.1.3
Confidentiality of IRB/IEC Information............................................................. 57
10.1.4
Compliance with Financial Disclosure Requirements....................................... 57
10.2
Compliance with Law, Audit and Debarment ................................................... 58
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 60
10.4
Quality Management System............................................................................... 60
10.5
Data Management................................................................................................. 60
10.6
Publications ........................................................................................................... 61
10.7
11.0
LIST OF REFERENCES......................................................................................... 62
12.0
APPENDICES........................................................................................................... 63
Merck Code of Conduct for Clinical Trials........................................................ 63
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 65
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 69
Approximate Blood Volumes Drawn by Trial Visit and by Sample Types..... 78
12.4
Clinical Study Conduct System ........................................................................... 79
12.5
13.0
SIGNATURES........................................................................................................... 80
Sponsor's Representative ..................................................................................... 80
13.1
 
 
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Investigator............................................................................................................ 80
13.2
 
 
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LIST OF TABLES
    
Table 1  Summary of Efficacy Endpoints............................................................................... 20
Table 2  Trial Treatment ......................................................................................................... 26
Table 3  The dosage of MK-7625A for every creatinine clearance........................................ 26
Table 4  Clinical Response Definitions at the EOT, TOC and LFU Visits ............................ 35
Table 5  Microbiological Response Definitions at the EOT, TOC and LFU Visits............... 38
Table 6  Emergent Infection Definitions at the TOC and LFU Visits.................................... 38
Table 7  Composite Microbiological and Clinical Response Definitions at the TOC Visit... 38
Table 8  The List of Laboratory Tests .................................................................................... 39
Table 9  Blood Sampling Points for PK ................................................................................. 40
Table 10  Evaluating Adverse Events..................................................................................... 46
Table 11  Analysis Strategy for Key Efficacy Variables........................................................ 52
Table 12  Confidence Interval for MK-7625A Under Various Assumption With 74
Evaluable Subjects in ME Population......................................................................... 54
Table 13  Product Descriptions............................................................................................... 55
 
 
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LIST OF FIGURES
Figure 1  Trial Design............................................................................................................. 11
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A Japanese Phase III, Open-label, Noncomparative Trial of MK-
7625A in Japanese patients with uncomplicated pyelonephritis and 
complicated urinary tract infection
Sponsor Product Identifiers
MK-7625A
Trial Phase
Phase III
Clinical Indication
Uncomplicated pyelonephritis and complicated urinary tract infection
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
MK-7625A
Number of trial subjects
Approximately 115 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
13 months 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 6 weeks 
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase, each subject will 
receive MK-7625A for 7 days.  After the end of treatment, each 
subject will be followed for 4 to 5 weeks.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a nonrandomized, multi-site, open-label trial of MK-7625A in Japanese subjects with 
uncomplicated pyelonephritis and complicated urinary tract infection (cUTI) to be conducted 
in conformance with Good Clinical Practices.
Approximately 115 subjects with a diagnosis of cUTI including pyelonephritis 
(uncomplicated or complicated pyelonephritis, and complicated lower UTI) will be enrolled 
in this trial. The enrollment of the patients with CrCl 30-50 mL/min at screening will be 
restrained from exceeding 15% (18 patients) of the total enrollment due to the rationale 
described in 4.2.1. For patients with a diagnosis of pyelonephritis at screening, the 
enrollment will be restrained from exceeding 80% (92 patients) of the total enrollment. All 
subjects will receive MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) intravenously (IV) 
every 8 hours under unblinded conditions. An adjusted dose [MK-7625A 750 mg 
(ceftolozane 500 mg/tazobactam 250 mg)] will be administered to subjects with creatinine 
clearance (CrCl) 30-50 mL/min. Each subject will be receiving MK-7625A for 7 days.  
Efficacy assessments (microbiological response and clinical response) will be conducted at 
the End of Therapy visit (EOT; within 1 day after the completion of study drug 
administration) and the Test of Cure visit (TOC; 7 days ±2 days after completion of study 
drug administration). Subjects will be followed for Efficacy and Safety evaluations until Late 
Follow-up (LFU; 28 to 35 days after completion of study drug administration). 
 
 
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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 in Figure 1 .
Figure 1  Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective: To estimate the per-subject microbiological response of MK-7625A in 
subjects with uncomplicated pyelonephritis and cUTI in the Microbiologically 
Evaluable (ME) population at TOC. 
2) Objective: To evaluate the safety and tolerability of MK-7625A in subjects with 
uncomplicated pyelonephritis and cUTI.  
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective: To estimate the per-subject microbiological response of MK-7625A in 
subjects with uncomplicated pyelonephritis and cUTI in the ME population at EOT 
and LFU.
2) Objective: To estimate the per-subject and per-pathogen microbiological response of 
MK-7625A in subjects with uncomplicated pyelonephritis and cUTI in the 
microbiological Modified Intent-to-treat (mMITT) population at EOT, TOC, and 
LFU, and to estimate the per-pathogen microbiological response of MK-7625A in 
subjects with uncomplicated pyelonephritis and cUTI in the ME population at EOT, 
TOC and LFU”.
 
 
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3) Objective: To estimate the clinical response of MK-7625A in subjects with 
uncomplicated pyelonephritis and cUTI in the mMITT and Clinically Evaluable (CE) 
populations at EOT, TOC, and LFU.
4) Objective: To estimate the composite response (based on microbiological response 
and clinical response) of MK-7625A in subjects with uncomplicated pyelonephritis 
and cUTI in the ME and mMITT populations at TOC.
Exploratory Objectives
3.3
1) Objective: To summarize the proportion of subjects with superinfections or new 
infections in the mMITT and ME population.
2) Objective: To summarize the proportion of subjects with relapse of clinical cure in 
the mMITT and CE population and recurrence of per-subject and per-pathogen
microbiological eradication in the mMITT and ME population.
3) Objective: To provide the plasma concentrations of ceftolozane and tazobactam for 
updating population pharmacokinetic (POP-PK) model.
4) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered. Variation across the human genome will be analyzed for 
association with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-
7625A.
Pharmaceutical and Therapeutic Background
4.1.1
Summary of MK-7625A
MK-7625A is a fixed-dose combination of a novel antipseudomonal cephalosporin and a 
well-established β-lactamase inhibitor (BLI) that has potent in vitro activity against most 
extended spectrum β-lactamase (ESBL)–producing Enterobacteriaceae and drug-resistant 
Pseudomonas aeruginosa.  
 
 
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Ceftolozane shares the basic chemical and biological attributes and mechanism of action with 
other β-lactam antibiotics [1] [2]. The primary mechanism of action is inhibition of the 
transpeptidation step of bacterial peptidoglycan biosynthesis by inactivation of penicillin 
binding proteins (PBPs). Ceftolozane is a member of the cephalosporin class of antibiotics, 
which are well characterized in terms of their safety, efficacy, and general antimicrobial 
profile. Cephalosporin antibiotics have been widely used in clinical practice for many years 
for their broad antibacterial spectrum, bactericidal activity, and excellent safety profile. A 
number of third and fourth generation parenteral cephalosporin antibiotics continue to be 
widely used (e.g., ceftriaxone, cefepime, and ceftazidime), although expanding resistance 
erodes their reliability. Ceftolozane exhibits time-dependent killing activity against various 
Gram-negative organisms, including drug-resistant P. aeruginosa.  Ceftolozane has been 
shown to be potent against strains of P. aeruginosa that are resistant to carbapenems, 
cephalosporins, fluoroquinolones, and/or aminoglycosides, including the majority of multiple 
drug-resistant (MDR) isolates.  Like most cephalosporins, ceftolozane is poorly active 
against enterococci, ESBL-producing Enterobacteriaceae, and Gram-negative anaerobes.
Tazobactam is a potent inhibitor of chromosomal- and plasmid-mediated bacterial class A 
and some class C β-lactamases that, by binding to the active site of these enzymes, protects 
ceftolozane from hydrolysis, broadening its spectrum to include most ESBL-producing 
Escherichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae, as well as some 
important anaerobic pathogens (i.e., Bacteroides fragilis). 
MK-7625A does not adequately cover certain pathogens, such as Gram-positive pathogens 
(Enterococci, Staphylococcus aureus), and anaerobes other than Bacteroides fragilis.
Epidemiology and Clinical Manifestations of cUTI
The prevalence of urinary tract infections (UTI) is increasing and its financial burden is 
significant. According to a major epidemiological study conducted in the US, UTI accounts 
for more than 100,000 hospital admissions annually and up to 40% of all hospital-acquired 
infections. In addition, the elderly population is now increasing globally. A higher incidence 
of bacteriuria and UTI is observed in elderly patients, both in long-term care facilities and at 
home. The management of elderly patients with UTI is increasing in clinical significance. 
Almost all of UTI in the elderly is cUTI. cUTI is a frequent cause of hospitalization and a 
common health-care associated complication [3] [4].
cUTI is defined as a clinical syndrome in men or women characterized by the development 
of systemic and local signs and symptoms of fever, chills, malaise, flank pain, back pain, and 
costovertebral angle pain or tenderness, occurring in the presence of an abnormality of the 
urinary tract or in the presence of catheterization. cUTI results from a wide variety of 
abnormalities including anatomical, structural, or functional alterations of the urinary tract 
(e.g., urolithiasis, indwelling urethral catheter, intermittent catheterization, stents, prostatic 
hypertrophy), impaired renal function (e.g., acute renal failure from intra, or post-renal 
nephropathies or heart failure), and immunocompromised status (e.g., diabetes mellitus, 
cancer, renal transplant). Clinical presentation can vary, ranging from mild lower urinary 
tract symptoms such as frequency and/or urgency to systemic symptoms associated with 
bacteremia and sepsis.  
 
 
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Pyelonephritis, a subset of UTI, is an infection of one or both kidneys that can occur in 
patients with or without functional or anatomic abnormalities of the urinary tract. 
Pyelonephritis often presents with both local and systemic signs of infection including flank 
pain and/or tenderness, fever, and malaise. Both complicated (associated with functional 
alterations of the urinary tract, impaired renal function or immunocompromised status) and 
uncomplicated pyelonephritis requires antimicrobial treatment for a similar length of time as 
other cUTI.
In cUTI, E.coli remains the predominant organism, but other aerobic Gram-negative rods, 
such as Klebsiella species, Proteus species, Citrobacter species, Acinetobacter species, 
Morganella species, and P. aeruginosa, also are frequently isolated. Gram-positive bacteria 
(e.g. Enterococci and Staphylococcus aureus), and yeasts are also important pathogens in 
cUTI [5]. 
According to a Japanese nationwide epidemiological survey [6], a total of 688 bacterial 
strains were isolated from patients diagnosed with cUTI. Among them, 216 patients were 
hospitalized (31.4%) with preexisting diseases at the time of the study. The following 
bacterial species were isolated from the hospitalized patients: Enterococcus faecalis, 36.4% 
(51/140), E. coli, 22.0% (56/255), K. pneumoniae, 34.4% (32/93), Proteus mirabilis, 23.8% 
(10/42), Serratia marcescens, 29.5% (13/44), and P. aeruginosa, 47.4% (54/114). The 
proportions of fluoroquinolone-resistant E. faecalis, E.coli, P. mirabilis, and S. marcescens
strains were 35.7%, 29.3%, 18.3%, and 15.2%, respectively. The proportions of E. coli, P. 
mirabilis, K. pneumoniae, and S. marcescens strains producing ESBL were 5.1%, 11.9%, 0%, 
and 0%, respectively. The proportions of P. aeruginosa strains resistant to carbapenems, 
aminoglycosides, and fluoroquinolones were 9.2%, 4.4%, and 34.8%, respectively; among 
them, 2 strains (1.8%) were multidrug resistant. 
Treatment of cUTI
Empiric antimicrobial therapy for cUTI should be sufficiently broad spectrum to cover the 
most commonly isolated pathogens. Treatment should be individualized for the subject, 
based on subject tolerance, clinical presentation, prior antimicrobial use and urine culture 
reports, and known or suspected institutional susceptibilities.
The fluoroquinolones and cephalosporins classes have long been widely used for empiric 
treatment of cUTI. According to Japan Nosocomial Infections Surveillance (JANIS), in five 
years from 2009 (the number of medical institutions: 499) to 2013 (the number of medical 
institutions: 745), the percentage of medical institutions that fluoroquinolone- or third 
generation cephalosporin-resistant E. coli was isolated from increased approximately 10%. 
The percentage of medical institutions that fluoroquinolone-resistant E. coli was isolated 
from rose from 84.6% to 94.9%. The percentage of medical institutions that third generation 
cephalosporin-resistant E. coli was isolated from rose from 81.2% to 89.9%. In 2013, the rate 
of resistance of E. coli against levofloxacin was 35.5% (number of specimen: 155998), the 
rate of resistance of E. coli against cefepime was 10.9% (number of specimen: 81456). 
Increasing resistance to fluoroquinolone and cephalosporin antimicrobial drugs poses a major 
medical problem [7].
Although a number of antimicrobial agents are approved for use in cUTI, the emergence of 
resistance to these agents has created a large unmet medical need.
 
 
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Clinical Trial results
4.1.2
The prior global cUTI Phase 2 and 3 studies were conducted outside of Japan; hence, there is 
a need for an additional trial in Japan for this indication.
Phase 1 Trial in Japanese Subjects (CXA-EB-13-05)
An open-label Phase 1 single ascending dose trial (CXA-EB-13-05) was conducted to 
evaluate pharmacokinetics (PK), safety and tolerability of MK-7625A after a single 1 hr IV 
infusion of MK-7625A at 1.5 g and 3 g doses. A total of 29 healthy subjects were enrolled 
(Japanese: 10 subjects, Chinese: 9 subjects and Caucasian: 10 subjects). 
The PK of ceftolozane and tazobactam were comparable between the 3 ethnic groups. After 
dose normalization, the PK parameters were comparable between the 1.5 and 3 g doses for 
each ethnic group. These findings suggest that the PK is dose independent and similar across 
the three ethnic groups. 
A total of 4 subjects experienced adverse events (AEs) with the single-dose administration of 
MK-7625A 1.5 g and 1 AE (drug eruption) lead to discontinuation in a Chinese subject 
[Chinese: 3 subjects (constipation: 2 subjects; faeces discoloured: 1 subject; headache: 1 
subject: and drug eruption: 1 subject), Japanese: 1 subject (pharyngitis)]. 
A total of 3 subjects experienced AEs with the single-dose administration of MK-7625A 3 g 
[Caucasian: 1 subject (dry mouth and dizziness), Chinese: 2 subjects (abdominal pain: 1 
subject; decreased appetite: 1 subject, and yellow skin: 1 subject)]. All AEs in both dosing 
groups were mild in severity. 
Phase 2 Trial in Subjects with cUTI including pyelonephritis (CXA-101-03)
Phase 2 trial (CXA-101-03) evaluated the comparative efficacy and safety of IV ceftolozane 
(1 g every 8 hours) versus IV ceftazidime (1 g every 8 hours) for 7 to 10 days in hospitalized 
adult subjects with cUTI including pyelonephritis.  
The microbiological response of ceftolozane at TOC (test-of-cure) was comparable to 
ceftazidime in complicated lower UTI and pyelonephritis. Moreover, ceftolozane was well-
tolerated and the incidence of AEs and drug related AEs of ceftolozane was comparable to 
ceftazidime.
Phase 3 Trials in Subjects with cUTI including pyelonephritis (CXA-cUTI-10-04 and CXA-
cUTI-10-05)
In two Phase 3 trials (CXA-cUTI-10-04 and CXA-cUTI-10-05) for cUTI including 
pyelonephritis, the efficacy and safety of MK-7625A (1.5 g every 8 hours) was compared 
with levofloxacin (0.75 g once daily).  The treatment period was 7 days.
MK-7625A achieved high composite microbiological and clinical cure rates at the TOC visit 
in the primary (mMITT) and secondary (ME) efficacy populations. For both populations, the 
lower bound of the 95% CI (2.31, 14.57) around the treatment difference (MK-7625A minus 
levofloxacin) was greater than -10%, indicating noninferiority. Notably, the 2-sided 99% CI 
around the treatment differences excluded zero in both primary and key secondary analysis 
populations indicating superiority over levofloxacin. 
 
 
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The microbiological response rate of MK-7625A at TOC in ME population was 86.2% and 
95% CI was (82.2, 89.5). The difference of microbiological response (MK-7625A minus 
levofloxacin) was 8.6% and 95% CI was (2.87, 14.26). 
MK-7625A was well-tolerated. The type, incidence and degree of AEs were comparable 
between MK-7625A and levofloxacin in the integrated Phase 3 analysis.
Ongoing Clinical Trials
4.1.3
The Phase 3 global trial (Protocol 008) for ventilated nosocomial pneumonia, the Phase 1 PK 
trial (Protocol 007) for intensive care unit subjects, and the Phase 1 pediatric PK trial
(Protocol 010) are on-going. Additional details may be found in the accompanying 
Investigators Brochure (IB).
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
This open-label trial is planned to estimate the efficacy and safety of MK-7625A for 
uncomplicated pyelonephritis and cUTI in Japanese patients. The prior global cUTI Phase 2 
and 3 studies were conducted outside of Japan; hence, there is a need for an additional trial in 
Japan for this indication.
Rationale for trial design
The primary data that support the efficacy of MK-7625A in the cUTI indications were 
derived from 2 large, identical, global, multicenter, randomized, double-blind, active-
controlled Phase 3 trials (CXA-cUTI-10-04 and CXA-cUTI-10-05) subsequently pooled to 
form one submission dataset.
In the cUTI indication, subjects were randomized 1:1 to receive either MK-7625A (1.5 g [1 g 
of ceftolozane and 0.5 g tazobactam] every 8 hours) or levofloxacin (0.75 g once daily) 
administered as IV infusions for 7 days. The results indicated MK-7625A was noninferior to 
levofloxacin for the primary and key secondary efficacy variables. Additionally, the lower 
bound of the 2-sided 99% CI excluded zero in both the primary and secondary analysis 
populations, indicating superiority over levofloxacin. 
The purpose of this trial is to further demonstrate the safety and efficacy of MK-7625A in 
only Japanese patients with cUTI for Japanese registration. Therefore, the design of this trial
is open-label, non-comparative design for the purpose of collecting safety and efficacy data 
without statistical verification and assess use of MK-7625A in Japanese patients with cUTI.
Rationale for sample size
A sample size of 74 evaluable patients in the microbiological evaluable (ME) population is 
applied to the Japanese cUTI trial to achieve a similar microbiological response to that in two 
global cUTI Phase 3 trials. 
The estimated microbiological response rate at TOC for the Japanese subjects is 85.1% with 
a 95% confidential interval (75.0%, 92.3%) in the ME population. The estimated upper and 
lower limits of the interval are comparable with the microbiological response rate (86.2%) 
observed in the global cUTI Phase 3 trials (CXA-cUTI-10-04 and CXA-cUTI-10-05).
 
 
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The estimation is based on the assumption that microbiological efficacy of MK-7625A is 
similar between Japanese and non-Japanese subjects. The assumption is supported by the 
similarity in the MIC distributions for MK-7625A between the clinical isolates collected in 
Japan and the US & EU, the comparability in PK exposures, and the expected PK-PD 
relationships between Japanese and non-Japanese subjects. Assuming there will have a 35% 
dropout rate (from enrollment to who qualifies for the ME population), a total of 115 subjects
will be enrolled.
Rationale for Selected Subject Population
The activity of ceftolozane alone and MK-7625A has been well characterized in a 
comprehensive series of in vivo and in vitro microbiology studies. MK-7625A displays 
potent time-dependent antibacterial activity against select Gram-positive pathogens, 
especially streptococci, and common Gram-negative aerobic pathogens commonly involved 
in cUTI, such as E. coli, other Enterobacteriaceae, and P. aeruginosa. The BLI activity of 
tazobactam protects ceftolozane from the majority of common ESBL-producing 
Enterobacteriaceae, an increasing problem in patients with cUTI that is associated with 
poorer microbiological outcomes compared with patients with ESBL-negative isolates. In 
addition, MK-7625A is active against strains of P. aeruginosa that are resistant to 
carbapenems, cephalosporins, fluoroquinolones, and aminoglycosides, including isolates 
exhibiting multidrug resistance.
The primary data that support the safety and efficacy of MK-7625A in cUTI including 
pyelonephritis indications were derived from 2 large, identical, multicenter, randomized, 
double-blind, active-controlled Phase 3 trials (CXA-cUTI-10-04 and CXA-cUTI-10-05), 
subsequently pooled to form 1 submission dataset. The efficacy (composite response based 
on microbiological response and clinical response) of MK-7625A was non-inferior to 
levofloxacin which is a comparator drug. 
From the above, MK-7625A shows antimicrobial activity against main offending bacterium 
of cUTI, and the efficacy of MK-7625A in subjects with cUTI including pyelonephritis was 
shown in overseas trials. 
To keep the comparability of safety and efficacy assessment of MK-7625A in Japanese 
patients to the non-Japanese patients in the global trials, the proportion of patients with 
moderate renal insufficiency (CrCl 30-50 mL/min) will be capped at 15%. In a subgroup 
analysis of the Phase 3 cUTI trials (CXA-cUTI-10-04 and CXA-cUTI-10-05), clinical cure 
rates were lower in patients with baseline creatinine clearance (CrCl) of 30 to ≤50 mL/min
(61.8%, 21/34 subjects) compared to those with CrCl >50 mL/min (78.5%, 285/363 subjects). 
Patients with moderate renal insufficiency are expected to be at worse baseline health and 
require dose adjustment of MK-7625A. Therefore, the enrollment of the patients with CrCl 
30-50 mL/min is limited to 15% (18 patients) of the total enrollment in this study to keep the 
similar proportion of these patients as the global studies. Similarly, for patients with a 
diagnosis of pyelonephritis at screening, the enrollment will be restrained from exceeding 
80% (92 subjects) of the total enrollment to be comparable to the global trial data 
[pyelonephritis: 82.4% (328/398 subjects)].
 
 
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Rationale for the Trial
MIC distributions for MK-7625A against Enterobacteriaceae and P. aeruginosa, which 
represent the target pathogens of MK-7625A, were compared between the clinical isolates 
collected in Japan (cryopreservation stock strain of the epidemiological purpose) and North 
America/EU (Clinical Isolates from US, EU, British and Canadian Surveillance Programs 
showed in IB). The result shows similar MIC distribution among the tested clinical isolates 
both in Japan and in North America/EU [E. coli: MIC50 and MIC90 are 0.12 µg/mL and 
0.5µg/mL in the clinical isolates in Japan (N=100), 0.25 µg/mL and 0.5µg/mL in the clinical 
isolates in North America/EU (N=9429) respectively. P. aeruginosa: MIC50 and MIC90 are 
0.5 µg/mL and 2 µg/mL in the clinical isolates in Japan (N=100), 0.5 µg/mL and 4µg/mL in 
the clinical isolates in North America/EU (N=6316) respectively].
A single-dose, open-label, parallel-group trial
(CXA-EB-13-05) to evaluate the 
pharmacokinetics, safety and tolerability of MK-7625A after single intravenous infusion to 
adult Japanese, Chinese and Caucasian healthy subjects, was conducted. After dose and/or 
weight normalization, AUC and Cmax values were similar between ethnic groups. Thus, it can 
be concluded that no clinically relevant difference in PK behavior is observed for ceftolozane, 
tazobactam and tazobactam M1 in all the healthy subjects investigated. 
From the above, it was thought possible to use overseas study results as reference data. In 
Japan, the Japanese Phase 3 trial (Protocol 014) is planned to examine and confirm the 
efficacy (microbiological response and clinical effect) and safety of the overseas Phase 3 
studies for cUTI including pyelonephritis.
Rationale for Dose Selection/Regimen/Modification
4.2.2
In this Japanese Phase 3 trial (Protocol 014), subjects with CrCl > 50 mL/min will receive 
MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) and subjects with CrCl 30 - 50 mL/min 
will receive MK-7625A 750 mg (ceftolozane 500 mg/tazobactam 250 mg).
The dose selection of the ceftolozane component of MK-7625A was mainly based on the PK 
of ceftolozane and all known relevant pharmacokinetic/pharmacodynamic (PK/PD) 
principles for cephalosporins. The dose of tazobactam was based on prior experience with 
BLIs and aimed to achieve a dose known to be well-tolerated. Based on the combined plasma 
concentration-time data from Phase 1 and 2 trials, a population PK analysis was conducted to 
characterize the PK of ceftolozane, and using these data, Monte Carlo simulations were 
conducted to evaluate the expected efficacy of different dosing regimens of ceftolozane. Like 
other β-lactam antibiotics, the PK/PD parameter that most closely correlates with efficacy is 
the time, as a percentage of the dosing interval, that the plasma concentration of ceftolozane 
exceeds the minimum inhibitory concentration (MIC) of the infecting organism (%T>MIC). 
Monte Carlo simulation analysis of clinical PK data revealed that using 30% T>MIC, an IV 
1-hour infusion of 1.5 g MK-7625A administered every 8 hours would provide sufficient 
drug concentrations to cover target pathogens, with a probability of target attainment (PTA) 
of 100% for pathogens with an MIC of up to 8 μg/mL. 
 
 
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MK-7625A 1.5 g every 8 hours intravenously demonstrated non-inferiority of efficacy to 
levofloxacin 0.75 g once daily intravenously in Phase 3 trials (CXA-cUTI-10-04 and CXA-
cUTI-10-05) for cUTI including pyelonephritis.  Additionally, MK-7625A 1.5 g every 8 
hours intravenously demonstrated non-inferiority of efficacy to meropenem 1 g every 8 hours
intravenously in Phase 3 trials (CXA-cIAI-10-08 and CXA-cIAI-10-09) for complicated 
intra-abdominal infectious. MK-7625A 1.5 g every 8 hours intravenously was generally well-
tolerated. 
The PK of MK-7625A has also been evaluated in subjects with mild, moderate, and severe 
renal impairment, as well as subjects with end-stage renal disease on hemodialysis (CXA-
101-02, CXA-201-02, and CXA-REN-11-01). Each trial evaluated a single-dose based on the 
linear and time independent PK profile of MK-7625A. 
Relative to MK-7625A exposures in subjects with normal renal function (CrCl ≥90 mL/min), 
no clinically relevant differences in exposure were observed in subjects with mild renal 
impairment, whereas exposures increased approximately 2-fold in subjects with moderate 
renal impairment.
Based on these results, no dose adjustment is recommended for subjects with mild renal 
impairment (CrCl >50 to 89 mL/min). However the MK-7625A dose in subjects with 
moderate renal impairment (CrCl >30 to 50 mL/min) is recommended to be reduced by 2-
fold (i.e., 750 mg MK-7625A every 8 hours).  
The results of the PK/PD target attainment analyses for MK-7625A 1.5 g (ceftolozane 1 
g/tazobactam 0.5 g) and dosing regimens adjusted for renal function described below, which 
are based on non-clinical PK/PD targets for ceftolozane alone and as appropriate, in 
combination with those for tazobactam, against Enterobacteriaceae from the clinical trial 
program, support in vitro susceptibility test interpretive criteria for MK-7625A against 
Enterobacteriaceae of 2-4 μg/mL:
‧
For patients with normal renal function administered MK-7625A 1.5 g (ceftolozane 
1 g/tazobactam 0.5 g) q8h, a PK/PD MIC cutoff value of as high as 4 μg/mL was 
identified;
‧
For patients with mild renal impairment administered MK-7625A 1.5 g (ceftolozane 
1 g/tazobactam 0.5 g) q8h, a PK/PD MIC cutoff value of as high as 8 μg/mL was 
identified; and
‧
For patients with moderate renal impairment administered MK-7625A 750 mg 
(ceftolozane 500 mg/tazobactam 250 mg) q8h, a PK/PD MIC cutoff value of as high 
as 8 μg/mL was identified.
The treatment period of MK-7625A for this Japanese Phase 3 trial (Protocol 014) is 7 days, 
based on 2 overseas Phase 3 studies (CXA-cUTI-10-04 and CXA-cUTI-10-05) for cUTI 
including pyelonephritis and the US package insert.
 
 
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Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
In this Japanese Phase 3 trial (Protocol 014), microbiological response (primary endpoint) 
and clinical response are set as efficacy endpoints.  Clinical response and microbiological 
response are the efficacy endpoints that will be used to estimate the efficacy of MK-7625A 
based on the clinical signs and symptoms (Section 7.1.2.3), microbiological outcome
(Section 7.1.3.3), and clinical outcome (Section 7.1.2.4).
In order to estimate the efficacy of MK-7625A to the uropathogen isolated from subjects
with uncomplicated pyelonephritis and cUTI which are target diseases of this clinical trial, 
the evaluation criteria of the microbiological response is set as the index of bacterial colony 
forming unit by urine culture. Moreover, in this clinical trial, in order to observe change of 
clinical signs and symptoms for uncomplicated pyelonephritis and cUTI, the evaluation 
criteria of clinical response are set. 
In addition, there is also the condition of asymptomatic bacteriuria without clinical 
signs/symptom of infection in cUTI. Therefore, microbiological response is set as primary 
endpoint for efficacy. 
Based on the Japanese guideline (the 1st edition) for urinary tract/genital infection, TOC is 
set as primary time point for efficacy. Moreover, in order to estimate the efficacy at the end 
of treatment of MK-7625A, EOT is set as secondary time point for efficacy. The analysis 
populations in the study objectives are comparable to those of global cUTI studies (CXA-
cUTI-10-04 and CXA- cUTI-10-05). The same mMITT, CE and ME population definitions 
included in both the global trial and this trial are used for the analysis of clinical 
response/microbiological response.
4.2.3.1.1 Definition of Efficacy Endpoints
Refer to Table 1 for efficacy endpoints by timing and analysis population.  Details of the 
endpoints are presented in the referenced sections.
Table 1  Summary of Efficacy Endpoints
Objective
Endpoint
Timing
Analysis Population
References
(Section)
Primary
Per-subject 
Microbiological response
TOC
ME
7.1.3.3
Secondary
Per-subject 
microbiological response
EOT, LFU
ME
7.1.3.3
EOT, TOC and LFU
mMITT
Per-pathogen 
microbiological response
EOT, TOC and LFU
ME
EOT, TOC and LFU
mMITT
Clinical Response
EOT, TOC and LFU
CE
7.1.2.4
EOT, TOC, and LFU
mMITT
Composite 
(microbiological and 
clinical) response
TOC
ME
7.1.3.5
mMITT
 
 
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4.2.3.2
Safety Endpoints
In this Japanese Phase 3 trial (Protocol 014), vital signs, AEs (clinical AEs and laboratory 
AEs) and laboratory test (hematology test, coagulation test, blood biochemistry test and urine 
test) are set as safety endpoints in order to evaluate the safety and tolerability of MK-7625A.  
The broad clinical and laboratory AE categories consisting of the percentage of patients with 
any AE, a drug-related AE, a serious AE, and an AE which is both drug-related and serious, 
and who discontinued the study drug due to an AE will be considered key safety endpoints.
4.2.3.3
Pharmacokinetic Endpoints
Plasma samples for pharmacokinetic analyses will be drawn from all patients that receive 
MK-7625A. The Plasma concentrations of ceftolozane, tazobactam and its metabolite, 
tazobactam M1 will be summarized and the plasma concentration data of ceftolozane and
tazobactam will be used for POP-PK analysis.  All available data for the POP-PK analysis 
will be used for the analysis.  The parameters to be evaluated for the POP-PK analysis will be 
specified in a separate POP-PK protocol.
4.2.3.4
Pharmacodynamic Endpoints
The pharmacokinetic/pharmacodynamic analyses will be specified in a separate protocol.
4.2.3.5
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
4.2.3.6
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA specimens collected for 
future biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
 
 
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Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
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
Japanese Male/Female subjects with uncomplicated pyelonephritis or cUTI of at least 18 
years 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. Provided written informed consent prior to any study-related procedure not part of 
normal medical care (a legally acceptable representative may provide consent if the 
subject is unable to do so, provided this is approved by local country and institution 
specific guidelines). The subject may also provide consent for Future Biomedical 
Research.  However, the subject may participate in the main trial without 
participating in Future Biomedical Research. The written informed consent should 
also be obtained from a legally acceptable representative if the subject is < 20 years 
of age.
2. Be Japanese males or females ≥ 18 years of age who needs hospitalization.
3. Pyuria (white blood cell [WBC] count > 10/μL in unspun urine or ≥ 10 per high 
power field in spun urine) at screening visit.
4. Clinical signs and/or symptoms of UTI at screening visit, either of 1) or 2):
1) Pyelonephritis (uncomplicated or complicated), as indicated by at least 2 of 
the following:
a. Documented fever (oral temperature > 38°C or axillary temperature 
>37.5°C) accompanied by patient symptoms of rigors, chills, or 
warmth
b. Flank pain
c. Costovertebral angle tenderness or suprapubic tenderness on physical
exam
d. Nausea or vomiting
 
 
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2) Complicated lower UTI, as indicated by the following 2 symptoms and 1 
complicating factor:
a. At least 2 of the following new or worsening symptoms of 
complicated lower UTI:
i.
Dysuria; urinary frequency or urinary urgency
ii.
Documented fever (oral temperature > 38.0°C or axillary 
temperature >37.5°C) accompanied by patient symptoms of 
rigors, chills, or warmth
iii.
Suprapubic pain or flank pain
iv.
Costovertebral angle tenderness or suprapubic tenderness on
physical exam
v.
Nausea or vomiting
b. And at least 1 of the following complicating factors:
i.
Males with documented history of urinary retention
ii.
Indwelling urinary catheter that is scheduled to be removed
during IV study therapy and before the EOT
iii.
Current obstructive uropathy that is scheduled to be medically
or surgically relieved during IV study therapy and before the
EOT
iv.
Any functional or anatomical abnormality of the urogenital
tract (including anatomic malformations or neurogenic bladder)
with voiding disturbance resulting in at least 100 mL residual
urine.
5. Have a pretreatment baseline urine culture specimen obtained within 24 hours before
the start of administration of the first dose of study drug.
NOTE: Subjects may be enrolled in this study and start IV study drug therapy before 
the Investigator knows the results of the baseline urine culture.
6. Require IV antibacterial therapy for the treatment of the presumed UTI.
7. If female, subject is either:
1) Not of childbearing potential, defined as postmenopausal for at least 1 year or 
surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy, no possibility of pregnancy based on pregnancy tests (urine 
hCG, etc.) or lactating.
 
 
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2) Of childbearing potential and is practicing a barrier method of birth control 
[e.g., a diaphragm or contraceptive sponge (unapproved in Japan)] along with 
1 of the following methods: oral or parenteral (unapproved in Japan)
contraceptives (for 3 months prior to study drug administration), or a 
vasectomized partner. Or, the subject is practicing abstinence from sexual 
intercourse. Subjects must be willing to practice these methods for the 
duration of the trial and for at least 35 days after last dose of study medication.
8. Males are required to practice reliable birth control methods (practicing abstinence 
from sexual intercourse, condom or other barrier device) during the conduct of the 
study and for at least 75 days after last dose of study medication.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Subject with history of recent or recurrent Gram-positive organism UTI suggesting 
colonization, or subject with UTI that shows or suspects the presence of a Gram-
positive organism only. 
2. Have a documented history of any moderate or severe hypersensitivity or allergic
reaction to any β-lactam antibacterial including cephalosporins, carbapenems and 
penicillins, or tazobactam.
3. Have a concomitant infection at the time of randomization, which requires non-study
systemic antibacterial therapy in addition to IV study drug therapy [vancomycin, 
linezolid, daptomycin and teicoplanin (i.e. drugs with only Gram-positive activity) 
are allowed]. 
4. Subject who are currently receiving probenecid.
5. Subject who are currently receiving bladder infusions with topical urinary antiseptics 
or antibacterial agents.
6. Receipt of any dose of a potentially therapeutic systemic antibacterial agent for the 
treatment of the current UTI within 48 hours before the study-qualifying pretreatment 
baseline urine is obtained.
(exceptions: subjects with an active UTI who have received prior systemic antibiotics 
may be enrolled provided a minimum of 48 hours have elapsed between the last dose 
of the prior systemic antibiotic and the time of obtaining the baseline urine specimen). 
7. Receipt of any amount of potentially therapeutic systemic antibacterial therapy after 
collection of the pretreatment baseline urine culture and before administration of the 
first dose of study drug.
8. Intractable urinary infection at baseline that the Investigator anticipates would require
more than 7 days of study drug therapy.
9. Complete, permanent obstruction of the urinary tract.
10. Confirmed fungal urinary tract infection at time of randomization (with ≥ 103 fungal
CFU/mL).
 
 
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11. Permanent indwelling bladder catheter or urinary stent including nephrostomy.
12. Suspected or confirmed perinephric or intrarenal abscess.
13. Suspected or confirmed prostatitis, urethritis or epididymitis.
14. Ileal loop or known vesico-ureteral reflux.
15. Severe impairment of renal function including an estimated CrCl < 30 mL/min,
requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 
20 mL/h urine output over 24 hours) at screening visit. (Refer to Section 5.2.1.1, 
where the formula for the calculation of CrCl can be found).
16. Current urinary catheter that is not scheduled to be removed before the EOT
(intermittent straight catheterization during the IV study drug administration period is
acceptable).
17. Any condition or circumstance that, in the opinion of the Investigator, would 
compromise the safety of the subject or the quality of study data.
18. Subject is judged inappropriate for study by the investigator or sub-investigator.
19. Any rapidly progressing disease or immediately life-threatening illness including
acute hepatic failure, respiratory failure, and septic shock.
20. Immunocompromising condition, including established AIDS, hematological
malignancy, or bone marrow transplantation, or immunosuppressive therapy 
including cancer chemotherapy, medications for prevention of organ transplantation 
rejection, or the administration of corticosteroids equivalent to or greater than 40 mg 
of prednisone per day administered continuously for more than 14 days preceding 
randomization.
21. One or more of the following laboratory abnormalities at screening visit:
1) aspartate aminotransferase (AST [SGOT]), alanine aminotransferase (ALT 
[SGPT]), alkaline phosphatase, or total bilirubin level greater than 3 times the 
upper limit of normal (ULN)
2) ALT (SGPT) or AST (SGOT) ≥3 × ULN and total bilirubin ≥2 × ULN and, 
at the same time, Alkaline phosphatase (ALP) < 2 × ULN
3) Absolute neutrophil count less than 500/μL
4) Platelet count less than 40,000/μL
5) Hematocrit less than 20%.
22. Participation in any clinical study of an investigational product within 30 days prior
to the proposed first day of study drug.
23. Previous participation in any study of ceftolozane or MK-7625A.
24. 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.
 
 
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Trial Treatment(s)
5.2
The treatment to be used in this trial is outlined below in Table 2.
Table 2  Trial Treatment
Drug
Dose/Potency
Dose 
Freque
ncy
Route of 
Administrat
ion
Regimen/Treatment 
Period
Use
MK-
7625A
1.5 g (ceftolozane 1 g/tazobactam 0.5 g)
750 mg†(ceftolozane 500 mg/tazobactam 250 mg)
Every 8 
hours
Intravenous
60 (±10) min 
intravenous  
infusion/7 days
Experimental
† For subjects with CrCl:30-50 mL/min.
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
5.2.1.1
Dose Selection (Preparation)
For the subject to whom the renal function decreased, it is necessary to adjust dosage based 
on the grade of a renal function (creatinine clearance: CrCl). Estimate the subject’s CrCl 
using the subject’s serum creatinine value, actual body weight, and the appropriate Cockroft-
Gault formula below. For patients with changing renal function (creatinine clearance is either 
close to 30 or close to 50 mL/min), monitor CrCl at least daily and adjust the dosage of MK-
7625A accordingly (dose reduction or dose increase after dose reduction). 
For serum creatinine reported in mg/dL:
Males:     CrCl (mL/min) =
(140 – age in years) × weight (kg)
72 × serum creatinine (mg/dL)
Females: CrCl (mL/min) =
0.85 ×
(140 – age in years) × weight (kg)
72 × serum creatinine (mg/dL)
The dosage of MK-7625A for each creatinine clearance category is shown in Table 3.
Table 3  The dosage of MK-7625A for every creatinine clearance
Creatinine clearance
Dosage of MK-7625A
CrCl > 50 mL/min
1.5 g (ceftolozane 1 g/tazobactam 0.5 g) IV q8h
CrCl 30 – 50 mL/min
Decrease dose to 750 mg (ceftolozane 500 mg/tazobactam 250 mg) IV q8h
CrCl < 30 mL/min
Discontinue study drug
 
 
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Timing of Dose Administration
5.2.2
After all the study procedures at visit 1 (baseline) are completed, MK-7625A 1.5 g 
(ceftolozane 1 g/tazobactam 0.5 g) is administered intravenously every 8 hours starting on 
visit 2 (Day 1). The dosage of MK-7625A is adjusted for subjects with creatinine clearance 
30 - 50 mL/min. Preparation of MK-7625A is referred to in a separate manual.
In this trial, MK-7625A 1.5 g is administered intravenously over 60 (±10) minutes. The 
second dose is administrated at interval of 8 hour (±4 hours) following the initial dose of 
study drug. The 3rd dose or subsequent ones are administrated at interval of 8 hour (±2 
hours) following the previous infusion. Allowance of administration interval is permitted to
facilitate adjustment of the q8h dosing schedule to be carried out throughout the dosing 
period.
Study drug should be administered daily for exactly 7 full days. This translates to 21 doses of 
MK-7625A for every 8 hour (q8h) dosing. In addition, a switch to another oral antimicrobial 
drug during MK-7625A treatment period is not allowed. 
Trial Blinding/Masking
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. Assignment 
of treatment/randomization number (see Section 7.1.1.7) will occur centrally using an 
interactive voice response system/integrated web response system (IVRS/IWRS). In addition, 
the enrollment of the patients with CrCl 30-50 mL/min at screening will be restrained from 
exceeding 15% (18 patients) of the total enrollment. For patients with a diagnosis of 
pyelonephritis at screening, the enrollment will be restrained from exceeding 80% (92
patients) of the total enrollment.
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
Prohibited medicine
5.5.1
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.  
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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Concomitant use of the following medicines is prohibited. 
1) Systemic antimicrobial (except for MK-7625A): from the time that the pretreatment 
baseline urine culture is obtained to LFU visit. (Exception: subjects with clinical or 
microbiological failure can receive systemic antimicrobial drugs). 
2) Other investigational drugs (except for MK-7625A): from 30 days prior to the 
proposed first day of study drug to LFU visit. 
3) Bladder infusions with topical urinary antiseptics or antibacterial agents: from initial 
dose of study drug to LFU visit.
4) Probenecid: from initial dose of study drug to EOT visit.
Allowed medicine
5.5.2
Systemic medicines (IV or PO) with only Gram-positive activity (i.e., vancomycin, linezolid, 
daptomycin and teicoplanin) are allowed as concomitant drug: from the pretreatment baseline 
urine culture to LFU visit.
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
Special care won't be needed for diet and activity.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent. 
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

Lack of a qualifying baseline urine culture, as defined in Section 7.1.3.2 (e.g. 
bacterial counts in urine are < 105 CFU/mL or coagulase-negative staphylococci is 
isolated).
 
 
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
Lack of qualifying baseline uropathogen: The subject with Gram-positive organism 
only at baseline urine culture

Development of severe impairment of renal function (estimated CrCl <30 mL/min), 
oliguria 
(<20 mL/h 
urine 
output 
over 
24 
hours) 
or 
requirement 
for 
hemodialysis/hemofiltration.

Lack of efficacy: New signs and symptoms that develop after 48 hours of study 
therapy and require additional or alternative antimicrobial therapy [excluding 
medicines with only Gram-positive activity (i.e., vancomycin, linezolid, daptomycin 
and teicoplanin)] for the current UTI.

The case that subject experiences significant adverse event(s) (clinical signs & 
symptoms or abnormal clinical laboratory test) that is considered study drug-related 
by investigators and precludes the continuation of study therapy.

Others (i.e., the subject become pregnant)
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Screening
Treatment
Follow-up
Visit
1
2
3
4
5-8
9
10
11
Scheduled Day
Baseline
Day 1
Day 21
Day 31
Day 4~71
End of 
Therapy
(EOT)
7 days after 
completion of 
study drug 
administration
(TOC)
28-35 days after 
completion of 
study drug 
administration
(LFU)
Allowance Day
-1 to the first dose 
of study drug
-
-
-
-
+1
±2
-
Administrative Procedures
Informed Consent2
X
Informed Consent for Future Biomedical 
Research2
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Height and body weight
X
Medical history
X
Prior and concomitant medication
X
X
X
X
X
X
X
X
Allocation of treatment assignment
X
Administration of MK-7625A3
X
X
X
X
X
Monitor compliance with Trial Medication
X
X
X
X
X
Clinical Procedures/Assessments
Vital sign (oral or axillary body 
temperature, blood pressure, pulse rate and 
respiratory rate)
X
X
X
X
X
X
X
X
Physical examination
X
(X)
(X)
(X)
(X)
X
(X)
(X)
Clinical sign/symptom assessment for UTI
X
X
X
X
X
X
X
X
Assess clinical outcome
X
X
X
Assess for adverse events
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments
Urine culture and assess pathogen
X
X4
(X)
X
X
X
Blood culture and assess pathogen
X5
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Urine test for pyuria
X
 
 
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Hematology test, blood biochemistry test 
and urine test
X6
X
X
X
X
Coombs test (direct)
X
X
Assessment of CrCl and Daily Adjustment 
of Study Therapy Dose as Needed
X
X
X
X
(X)7
(X)7
Collect the blood sample for PK8
X
X
Urine pregnancy test (females for child 
bearing potential)9
X
Blood for Genetic Analysis10
X
X: must be done. X in the Day 4-7 (Visits 5-8) signifies that the procedure should be performed daily. 
(X): may be done in case of clinically necessary by primary or sub investigator, and items should be recorded in the source document and eCRF.
Assessment or test result done in ‘Day -1 to pre-treatment’ can be used as screening result/baseline data even if those are done before informed consent is obtained. 
If the Visit 1 and 2 occur on the same day, the procedures required in both Visit 1 and 2 do not need to be repeated.
1.
For study Day 2 through 7 all study assessments are to be performed at a consistent time of day for the study patient for each calendar day.
2.
It can be done within 2 days prior to study drug initiation.
3.
Study drug should be administered daily for 7 full days. This translates to 21 doses of MK-7625A for every 8 hour (q8h) dosing.
4.
In case that bacterial count is ≥104 CFU/mL in urine culture at Day 3 [allowance: +2 days (Day 4 or Day 5)], the urine specimens for culture will be collected and urine culture will be performed. 
The same procedure is repeated at the following visit if bacterial count is ≥104 CFU/mL in urine culture during treatment period. 
5.
Culture for blood sample at screening is conducted as indicated in subjects who present with clinical signs and/or symptoms of pyelonephritis or bacteremia (OR subjects with indwelling catheters 
whose baseline urine specimen are obtained through the catheter). Two sets (from two separate blood draws) of blood cultures (each set consisting of an aerobic bottle) are conducted. Blood culture 
is conducted at appropriate frequency until negative if the previous blood culture was positive. In addition, if signs of sepsis appear at any time on study, a blood culture should be taken. When 
blood cultures are indicated, two sets (each set consisting of an aerobic bottle) should be obtained for a total of two aerobic bottles.
6.
Local laboratory data is used for enrollment criteria of laboratory test. The samples for laboratory tests of baseline are collected separately, and a sample is sent to a central laboratory. The sampling
on Day 3 has allowance: +2 days (Day 4 or Day 5).
7.
During this study period, serum creatinine value to determine dose adjustment will be collected in local laboratory. CrCl assessments are set on Day 1 to 3 for all subjects and dose adjustment
should be done as appropriate. In addition, for patients with changing renal function (creatinine clearance is either close to 30 or close to 50 mL/min) during the period of Day 4 to 7, obtain serum 
creatinine value and monitor CrCl at least daily and adjust the dosage of MK-7625A accordingly based on local laboratory results.
8.
Blood sample for pharmacokinetics is collected at Day 1 (prior to first dose of study drug) and Day 3 [allowance: +2 days (Day 4 or Day 5)].  6 samples in total are collected [Day 1: pre-treatment, 
Day 3: pre-treatment (15 minutes prior to infusion), just before the completion of infusion, 30-90 minutes after the completion of infusion, 2.5-3.5 hours after the completion of infusion and 5.5-7 
hours after the completion of infusion]. At least 3 samples must be collected in total if it is difficult to collect all blood samples at Day 3 [Any one of 30-90 minutes after the completion of infusion, 
2.5-3.5 hours after the completion of infusion or 5.5-7 hours after the completion of infusion will be collected in addition to pre-treatment (15 minutes prior to infusion) and just before the 
completion of infusion]
9.
A urine pregnancy test (urine hCG) is performed in each investigational institution in female subjects.  After checking the urine hCG negative, a subject may be enrolled in this trial.
10.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation prohibiting collection, or 
if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is collected, leftover extracted DNA will be stored for 
future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the 
purpose of FBR.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. 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. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
At baseline, medical history will be obtained by the investigator or qualified designee. Obtain 
recent (within past 5 years) medical history.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
At baseline, the investigator or qualified designee will review prior medication use, and 
record prior medication taken by the subject within 7 days before first dose of trial 
medication (for all antibacterial agents within 14 days before the first dose of trial medication, 
other investigational drugs from 30 days before the first dose of trial medication).
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial (from the first dose of trial medication to LFU).
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
 
 
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7.1.1.7
Assignment of Treatment/Randomization Number
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/randomization.   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.
7.1.1.8
Trial Compliance (Medication)
Interruptions from the protocol specified treatment plan for compliance <80% require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff.
7.1.1.9
Height and Body Weight
The investigator or qualified designee will record height and body weight. Body weight (kg) 
will be measured without shoes or jacket. 
Clinical Procedures/Assessments
7.1.2
In order to minimize variability, it is preferred that the same individual(s) perform the same 
procedure(s)/evaluation(s) for all subjects at each trial site.
7.1.2.1
Physical Examination
The investigator or qualified designee will perform a physical examination. The screening 
physical examination will be complete; the EOT visit physical examination may be targeted. 
At other times, the investigator or qualified designee always can perform a complete or 
targeted physical examination if they suspect an AE or abnormality. A complete physical 
examination includes examination of body systems (including, but not limited to, general 
appearance, skin, neck, eyes, ears, nose, throat, breast, lungs, heart, abdomen, back, lymph 
nodes, extremities, and nervous system). The targeted physical examination should be 
focused, at the investigator’s discretion, based on the subject’s condition and circumstances. 
The targeted physical examination should note any changes in the subject’s condition (body 
systems) since the last assessment and does not preclude examination of any of the body 
systems as clinically indicated. Clinically significant changes, in the judgment of the 
Investigator, in physical examination findings (abnormalities) will be recorded as AEs.
7.1.2.2
Vital Sign
The investigator or qualified designee will record vital sign (body temperature (oral or 
axillary), blood pressure, pulse rate and respiratory rate). Systolic and diastolic blood 
pressure will be measured on the same arm. Pulse will be recorded simultaneously with 
blood pressure measurements. 
 
 
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7.1.2.3
Assessment of Clinical Sign/Symptom for UTI
The clinical sign/symptoms of uncomplicated pyelonephritis and cUTI (dysuria, frequency, 
urgency, flank pain, suprapubic pain/tenderness, chills or rigors, costovertebral angle 
tenderness, nausea or vomiting) will be evaluated and graded as none, mild, moderate, or 
severe at the visits specified in the flowchart (Section 6.0).
The definition of grade
1)
None: sign or symptom absent
2)
Mild: awareness of sign or symptom, but easily tolerated
3)
Moderate: sign or symptom of enough intensity to cause interference with usual activity
4)
Severe: sign or symptom of enough intensity to incapacitate
7.1.2.4
Assessment for Clinical Outcome
7.1.2.4.1 Clinical Response at the EOT, TOC and LFU Visits
Clinical outcomes will be assessed at both the EOT, TOC and LFU visits. The definition of 
clinical response is shown in Table 4.
The Investigator will classify clinical outcome as “clinical cure”, “clinical failure”, or
“indeterminate”. A favorable clinical response is “clinical cure”. 
Relapse of clinical cure is defined as a response of clinical failure at LFU for subjects who 
have a response of clinical cure at TOC.
Table 4  Clinical Response Definitions at the EOT, TOC and LFU Visits
Outcome
Definition
Clinical Cure
Complete resolution of, marked improvement in (where clinical improvement was 
defined as a reduction in severity of all baseline signs and symptoms with 
worsening of none and with no requirement for additional antibiotic therapy after 
EOT), or return to pre-infection signs and symptoms and no use of additional or 
nonstudy antimicrobial therapy for the treatment of the current UTI.
Clinical Failure
Persistence of 1 or more sign or symptom of infection or reappearance of or new 
signs and symptoms that requires additional or alternative antimicrobial therapy 
for the current UTI
OR
Adverse event leading to study drug discontinuation and the subject required 
nonstudy antimicrobial therapy for the current UTI.
Indeterminate
Study data were not available for the evaluation of clinical outcome for any reason 
or the outcome assessment was confounded.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.
 
 
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7.1.3.1
Urine Test for Pyuria
Urine test for pyuria will be conducted and pyuria (white blood cell [WBC] count >10/μL in 
unspun urine ≥ 10 per high power field in spun urine) will be checked in each investigational 
institution.
7.1.3.2
Culture (Urine and Blood)
7.1.3.2.1 Urine Culture
A study-qualifying pretreatment baseline urine culture specimen must be obtained within 1
day before the start of administration of the first dose of study drug and at least 48 hours after 
the last dose of a potentially therapeutic antibacterial agent administered for treatment of the 
current UTI. If more than 1 appropriately collected urine culture specimen is obtained before 
the initiation of study drug therapy, the specimen obtained closest to the time of the 
administration of the first dose of study drug will be considered the baseline specimen.
Urine must be collected either by an adequate midstream clean catch, by catheterization, or
by suprapubic aspiration. Urine specimens obtained from Foley bags are not allowed. A 
study-qualifying pretreatment baseline urine culture must grow at least 1 and not more than 2 
bacterial isolates at ≥105 CFU/mL each, as follows: 

For non-catheterized subjects, if more than 2 bacterial isolates are identified from a 
single urine specimen, the culture will be suspected contaminated. Reconfirm the 
appropriateness of a urine specimen and make an effort to specify a causative
uropathogen. If a pathogen of ≥105 CFU/mL at baseline urine culture is isolated also 
from the blood culture at baseline, that pathogen will be considered as a causative 
pathogen.

For catheterized subjects, if more than 1 bacterial isolates are identified from a single 
urine specimen, the culture will be suspected
contaminated. Reconfirm the 
appropriateness of a urine specimen and make an effort to specify a causative 
uropathogen. If a pathogen of ≥105 CFU/mL at baseline urine culture is isolated also 
from the blood culture at baseline, that pathogen will be considered as a causative 
pathogen.

The following pathogens will not be considered causative pathogens of cUTI in this trial.

Coagulase-negative Staphylococci

non-Group D Streptococci
Note: The Lancefield8 category is shown below as reference.

Group A: Streptococcus pyogenes

Group B: S. agalactiae

Group C and G: S. equi, S. canis
 
 
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Urine culture, isolation of uropathogen(s), initial identification of pathogen(s) and bacterial 
counts in urine will be conducted in local laboratory. The result of culture, initial 
identification of pathogen(s) and bacterial counts at local laboratory should be recorded in 
the source document and eCRF. The sites should ship the isolated pathogen(s) to the central 
laboratory because re-identification of uropathogen(s) and MIC test will be performed by 
central laboratory. Further details of the procedures to be followed for sample collection,
storage, and shipment will be documented in the Laboratory Manual.
7.1.3.2.2 Blood Culture
Culture for blood sample at screening is conducted as indicated in subjects with indwelling 
catheters whose baseline urine specimen are obtained through the catheter or in subjects who 
present with clinical signs and/or symptoms of pyelonephritis or bacteremia. In addition, if 
signs of sepsis appear at any time on study, a blood culture should be taken. Blood culture is 
conducted at appropriate frequency until negative if the previous blood culture was positive.
Blood specimen will be obtained from 2 separate sites, and will be added to each aerobic 
bottle (a total of 2 aerobic bottles). Culture of the blood specimen, isolation of pathogen(s) 
and initial identification of pathogen(s) will be conducted in local laboratory. The result of 
culture and initial identification of pathogen(s) at local laboratory should be recorded in the 
source document and eCRF. The sites should ship the isolated pathogen(s) to the central 
laboratory because re-identification and MIC test of pathogen(s) will be performed by central 
laboratory. Further details of the procedures to be followed for sample collection, storage, 
and shipment will be documented in a Laboratory Manual.
7.1.3.3
Assessment for Microbiological Outcome
7.1.3.3.1 Microbiological Response at the EOT, TOC and LFU Visits
Microbiological outcomes will be assessed at both the EOT, TOC and LFU visits. The 
definition of microbiological response is shown in Table 5.
The per-pathogen microbiological outcome will be determined for each uropathogen isolated
at baseline from a pretreatment study-qualifying culture. Microbiological outcome is 
classified as "Eradication", "Persistence" or "Indeterminate." A favorable microbiological 
response is "Eradication". 
The per-subject microbiological response will be determined based on individual outcomes 
for each baseline uropathogen. In order for a subject to have an overall outcome of
microbiological eradication, the outcome for each baseline uropathogen must be eradication. 
If the outcome for any uropathogen is persistence, the subject will be considered to have an
overall microbiological response of persistence.
Recurrence of per-pathogen microbiological eradication is defined as a response of 
persistence at LFU for subjects who have a response of eradication at TOC.  Recurrence of 
per-subject microbiological eradication is defined as a response of persistence at LFU for 
subjects who have a response of eradication at TOC.
 
 
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Table 5  Microbiological Response Definitions at the EOT, TOC and LFU Visits
Outcome
Definition
Eradication
A urine culture shows all uropathogens found at baseline at ≥105 CFU/mL were 
reduced to <104 CFU/mL.
Persistence
A urine culture, taken any time after the completion of therapy, grows ≥104
CFU/mL of the uropathogen found at baseline.
Indeterminate
No interpretable urine culture available.
7.1.3.4
Emergent Infection
Emergent infections (uropathogens other than the baseline uropathogens) will be evaluated at 
TOC and LFU visit. Uropathogens other than the baseline uropathogens will be classified as
“superinfection” or “new infection”. The definition of emergent infection is shown in Table 6. 
Table 6  Emergent Infection Definitions at the TOC and LFU Visits
Outcome
Definition
Superinfection
A urine culture that grew ≥105 CFU/mL of a bacterial uropathogen other than the 
baseline uropathogen(s) during the course of study drug therapy
New infection
A urine culture that grew ≥105 CFU/mL of a bacterial uropathogen other than the 
baseline uropathogen(s) at any time between the last administration of the last 
dose of study drug therapy and the LFU visit.
7.1.3.5
Composite Microbiological and Clinical Response
Composite response (based on microbiological response and clinical response) will be
assessed at TOC. The definition of microbiological response is shown in Table 7. 
The composite response will be classified as “cure”, “failure”, or “indeterminate”. A 
favorable clinical response is “cure”. 
Table 7  Composite Microbiological and Clinical Response Definitions at the TOC Visit
Outcome
Definition
Cure
By-subject microbiological response was microbiological success and the clinical 
response was clinical cure.
Failure
By-subject microbiological response was microbiological failure or the clinical 
response was clinical failure.
Indeterminate
By-subject microbiological response was indeterminate and/or the clinical 
response was indeterminate.
 
 
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7.1.3.6
Blood sampling for Hematology, Coagulation Chemistry, and Urine sampling 
for urinalysis
Obtain blood samples for hematology, coagulation and chemistry, and urine samples for 
urinalysis listed in Table 8 at the visits specified in the flow chart (Section 6.0) and send the
samples to the central laboratory designated by the Sponsor. Serum creatinine (for the 
monitoring of CrCl) and urine hCG (ensure negative before randomization in females of 
child bearing potential) test are performed in each investigational institution but not in the 
central laboratory. At screening, local laboratory data is used for enrollment criteria of 
laboratory test but the blood/urine samples for Hematology, Coagulation and Chemistry test, 
and urinalysis of baseline are collected separately, and sent to a central laboratory.
Table 8  The List of Laboratory Tests
Hematology
Chemistry
Urinalysis
Red blood cell count (RBC)
Total protein
Nitrite 
Hemoglobin
Albumin
Leukocyte esterase
Hematocrit
Total bilirubin
Urine pregnancy test (urine hCG) †
White blood cell count (WBC)
Aspartate aminotransferase (AST)
WBC 
differential 
(neutrophil, 
eosinophil, basophil, lymphocyte, 
monocyte)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Blood urea nitrogen
Platelet count
Sodium
Prothrombin time
Potassium
Direct Coombs test
non-fasting serum glucose
Serum creatinine†
C-reactive protein (CRP)
† Test is performed locally in each investigational institution.
7.1.3.7
Assessment of creatinine clearance
During this study period, serum creatinine value to determine dose adjustment will be
collected in the local laboratory. Obtain serum creatinine value and estimate the subject’s 
CrCl using the subject’s serum creatinine value, actual body weight, and the appropriate 
Cockroft-Gault formula described in Section 5.2.1.1. For patients with changing renal 
function (creatinine clearance is either close to 30 or close to 50 mL/min) while on study 
therapy, obtain serum creatinine value and monitor CrCl at least daily and adjust the dosage 
of MK-7625A accordingly. Obtained serum creatinine value should be recorded in the eCRF.
7.1.3.8
Urine pregnancy test (females of child bearing potential)
Obtain urine sample for serum pregnancy test (women of child bearing potential and those 
who are less than 1 years postmenopausal only) to be assessed at the study sites (ensure that 
the test is negative before randomization).
 
 
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7.1.3.9
Pharmacokinetic Evaluations
The decision as to which plasma samples collected will be assayed for evaluation of
pharmacokinetics will be collaboratively determined by the Departments of Drug
Metabolism and the other appropriate department. The collected sparse pharmacokinetic 
samples will be included in a future cross study POP-PK analysis.
7.1.3.9.1 Blood Collection for Pharmacokinetics
Blood for pharmacokinetic analysis will be collected from all subjects who received MK-
7625A (approximately 115). Table 9 shows the time points of blood collection.
Sample collection, storage and shipment instructions for plasma samples will be provided in 
a separate Operation/Laboratory Manual.
Table 9  Blood Sampling Points for PK
pre-treatment
(15 minutes 
prior to 
infusion)
just before the 
completion of 
infusion
30-90 minutes 
after the 
completion of 
infusion
2.5-3.5 hours 
after the 
completion of 
infusion
5.5-7 hours 
after the 
completion of 
infusion
Day 1
X†
Day 3
[allowance: +2 
days (Day 4 or 
Day 5)]
X
X
X‡
X‡
X‡
X: Collection of specimen
† A sample will be collected before initial administration of study drug.
‡ When sample collection of five points will be difficult, the sample of at least one point will be collected among the latter 
three points.
7.1.3.10 Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Laboratory Manual.
7.1.3.11 Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
 
 
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7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
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:

Clinical testing equipment relevant to inclusion/exclusion criteria and clinical evaluation.
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.
7.1.5.1
Screening (Visit 1)
Baseline (screening) assessments are to be performed as close as possible to the start of study
therapy and at most within 1 day before the start of administration of the first dose of MK-
7625A. Potential subjects will be evaluated to determine that they fulfill the entry 
requirements as set forth in Section 5.1. All baseline assessment results except the results of 
the urine culture must be available before registration of this study.
 
 
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7.1.5.2
Treatment Period (Visit 2-9)
For study Day 2 through 7 all study assessments are recommended to be performed at a
approximately consistent time of day for the study patient (e.g. every morning) for each 
calendar day. End-of-therapy assessments are to be performed within 1 day after completion 
of administration of the last dose of study drug.
7.1.5.3
Follow-up Period (Visit 10 and 11)
Test-of-cure visit assessments are to be performed 7 days (± 2 days) after completion of
administration of the last dose of study drug. Subjects will be required to return to the 
investigational institution at 28 to 35 days after the last dose of MK-7625A for post-trial 
visits. 
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
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 LFU visit, 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.
 
 
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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 is any dose higher than MK-7625A 3 g/dose or 9 g/day.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through LFU visit 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).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
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 10 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through LFU visit, 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.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
 
 
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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 LFU visit, 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.*
*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).
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 10. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 10 for instructions in evaluating adverse events.
 
 
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Table 10  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 trial.  Changes to 
analyses made after the protocol has been finalized, but prior to data base 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 Multicenter, Open-label, Noncomparative, Japanese Phase III Study to 
Assess the Efficacy and Safety of Ceftolozane/Tazobactam (MK-7625A) 
in Japanese Patients with Uncomplicated Pyelonephritis and 
Complicated Urinary Tract Infection
Treatment Assignment
Non-randomized, open-label and single arm
Analysis Populations
Efficacy: Microbiologically Evaluable (ME), Clinical Evaluable (CE) 
and microbiological modified intent-to-treat (mMITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Per-subject microbiological response at TOC
Secondary Endpoints
Per-subject microbiological response at EOT and LFU
Per-pathogen microbiological response at EOT, TOC, and LFU
Clinical response at EOT, TOC, and LFU
Composite (clinical and microbiological) response at TOC
Statistical Methods for Key 
Efficacy Analyses
For the primary and secondary efficacy endpoints, point estimate and 
two-sided 95% confidence intervals of response rate will be calculated 
using the Clopper-Pearson method.
Statistical Methods for Key 
Safety Analyses
All adverse events will be tabulated. The 95% confidence interval will 
be provided using the Clopper-Pearson method for key safety endpoints.
Summary statistics for baseline, on-treatment, and change from baseline 
values will be provided for the continuous measures such as laboratory, 
and vital signs parameters.
Interim Analyses
No interim analyses are planned for this trial.
Multiplicity
No multiplicity adjustment is planned for the trial.
Sample Size and Power 
This trial will enroll 115 subjects to receive MK-7625A, and will allow 
estimation of the microbiological response rate at TOC among subjects 
receiving MK-7625A in the ME population with a 95% confidence 
interval of (75.0%, 92.3%). This is based on the following assumptions: 
1) an approximate 35% dropout and/or protocol deviation rate excluding 
subjects from the ME population, and 2) an observed response rate of 
85.1% in the MK-7625A group.
 
 
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Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as a non-randomized, open-label trial, i.e., subjects, 
investigators, and Sponsor personnel will be aware of subject treatment assignments after 
each subject is enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule(s) for study 
treatment assignment.
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
8.4.1
The primary efficacy endpoint is microbiological response rate at TOC, defined as the
proportion of subjects in the analysis population who have an overall outcome of 
microbiological eradication at TOC.  For subjects with more than 1 uropathogen isolated at
baseline, an overall outcome of microbiological eradication will be based on eradication of 
all baseline uropathogens.
The secondary efficacy endpoints include:

Per-subject microbiological response rate at EOT and LFU.

Per-pathogen microbiological response rate at EOT, TOC and LFU, defined as the 
proportion of subjects in the analysis population who have an outcome of 
microbiological eradication for each uropathogen isolated at baseline.

Clinical response rate at EOT, TOC and LFU, defined as the proportion of subjects in 
the analysis population who have a response of clinical cure. 

Composite (clinical and microbiological) response at TOC, defined as the proportion 
of subjects in the analysis who have an overall outcome of microbiological 
eradication and the response of clinical cure at TOC.
Safety Endpoints
8.4.2
An initial description of the safety measures is included in Sections 4.2.3.2.
 
 
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Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
The microbiological modified intent-to-treat (mMITT) population consists of all allocated 
subjects who receive at least one dose of study treatment and have at least 1 acceptable 
causative uropathogen from a baseline urine specimen (≥105 CFU/mL).
The clinically evaluable (CE) population will be a subset of the mMITT population who 
adhere to study procedures and have a clinical response at the visit interest within the 
specified visit window.  All subjects in the CE population have to have an evaluable clinical 
outcome; an indeterminate response is excluded from this population.
The microbiologically evaluable (ME) population will be a subset of the CE population who 
have an appropriately collected urine culture specimen and interpretable urine culture result 
at the visit interest.
The ME population will serve as the primary population for the analysis of the 
microbiological response and composite endpoints in this trial.  In addition, the CE
population will serve as the primary population for the analysis of the clinical response 
endpoints.
A supportive analysis using the mMITT population will be performed for the primary and 
secondary endpoints.  
The final determination on major protocol deviations, and thereby the composition of the 
ME, CE and mMITT populations, will be made prior to the final 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.
Safety Analysis Populations
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this trial.  The ASaT population consists of all allocated subjects who received at least one 
dose of study treatment. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 Statistical Methods.
 
 
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Statistical Methods
8.6
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the sSAP.
For the primary efficacy endpoint of per-subject microbiological response rate at TOC, the 
point estimate and two-sided 95% confidence intervals of response rate will be calculated 
using the Clopper-Pearson method.  
For the secondary endpoints, the same method will be applied as primary endpoint.
For microbiological, clinical and composite responses, missing data will be primarily 
handled with a treatment failure approach for the mMITT populations and a data-as-observed 
approach for the ME or CE population which is defined as follows:

For analyses of clinical response and microbiological response, including the 
composite response, in the mMITT population, the subjects with a missing clinical 
response or microbiological response (e.g., indeterminate) will be categorized as 
treatment failures.

For the analyses in the ME or CE population, the subjects with a missing clinical 
response or microbiological response (e.g., including indeterminate) will be excluded 
from the population.

A missing per-pathogen microbiological outcome at the TOC visit will be considered 
an indeterminate outcome unless the per-pathogen microbiological outcome at EOT is
persistence. A per-pathogen microbiological outcome of persistence at EOT will be
carried forward to the TOC visit.

A missing per-pathogen microbiological outcome at the LFU visit will be considered 
an indeterminate outcome unless the per-pathogen microbiological outcome at TOC
is persistence. A per-pathogen microbiological outcome of persistence at TOC will 
be carried forward to the LFU visit.

A missing clinical outcome at the TOC visit will be considered an indeterminate 
outcome unless the clinical outcome at EOT is failure.  A clinical response of failure 
at EOT will be carried forward to the TOC visit.

A missing clinical outcome at the LFU visit will be considered an indeterminate 
outcome unless the clinical outcome at TOC is failure.  A clinical response of failure 
at TOC will be carried forward to the LFU visit.
Table 11 summarizes the key efficacy analyses.
 
 
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Table 11  Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Per-subject microbiological response 
rate at TOC
P
Clopper-Pearson 
method
ME
Data As Observed
Secondary Endpoints
Per-subject microbiological response 
rate at TOC
S
Clopper-Pearson 
method
mMITT
Treatment Failure 
Approach
Per-subject microbiological response 
rate at EOT and LFU
P
Clopper-Pearson 
method 
ME
Data As Observed
Per-subject microbiological response 
rate at EOT and LFU
S
Clopper-Pearson 
method 
mMITT
Treatment Failure 
Approach
Per-pathogen microbiological response 
rate at EOT, and TOC and LFU
P
Clopper-Pearson 
method 
ME
Data As Observed
Per-pathogen microbiological response 
rate at EOT, TOC, and LFU
S
Clopper-Pearson 
method 
mMITT
Treatment Failure 
Approach
Clinical response rate at EOT, TOC
and LFU
P
Clopper-Pearson 
method
CE
Data As Observed
Clinical response rate at EOT, TOC,
and LFU
S
Clopper-Pearson 
method 
mMITT
Treatment Failure 
Approach
Composite (clinical and 
microbiological) response rate at TOC
P
Clopper-Pearson 
method
ME
Data As Observed
Composite (clinical and 
microbiological) response rate at TOC
S
Clopper-Pearson 
method
mMITT
Treatment Failure 
Approach
  †
P=Primary approach; S=Supportive approach. 
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests and vital signs measurements.
To address the primary objective of safety and tolerability, all adverse events (preferred
terms as well as system organ class terms) will be tabulated.
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, a drug related AE, a serious AE, and an AE which is both drug-related 
and serious, and who discontinued the study drug due to an AE will be considered as key 
safety endpoints.  The 95% confidence interval will be provided using the Clopper-Pearson 
method for key safety endpoints.
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided for the continuous measures such as laboratory and vital signs parameters.
 
 
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Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
8.6.3.1
Demographic and Baseline Characteristics
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables, baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical 
tables.
8.6.3.2
Population PK Analyses
For the plasma concentration data of ceftolozane, tazobactam and tazobactam M1, summary 
statistics will be provided.
Based on the plasma concentration data obtained within this trial, a separate population 
Pharmacokinetics (PK) analysis will be performed.  The prospective details of this analysis 
will be specified in a separate population PK analysis plan.
Interim Analyses
8.7
No interim analyses are planned for this trial.
Multiplicity
8.8
No multiplicity adjustment is planned for the trial. 
Sample Size and Power Calculations
8.9
Sample Size and Power for Efficacy Analyses
8.9.1
This is an estimation study. This study will enroll 115 subjects to receive MK-7625A (the 
rationale for the enrollment of 115 subject is referred to Section 4.2.1), and will allow 
estimation of the per-subject microbiological response rate at TOC among subjects receiving 
MK-7625A in the ME population with a 95% confidence interval of (75.0%, 92.3%).  This is 
based on the following assumptions: 1) an approximately 35% dropout and/or protocol 
deviation rate excluding subjects from the ME population, 2) an observed response rate of 
85.1% in the MK-7625A group based on the study results conducted outside of Japan (from 
protocol CXA-cUTI-10-04 and CXA-cUTI-10-05).  The calculation is based on the exact 
binomial method proposed by Clopper and Pearson with 74 subjects in MK-7625A expected 
to be included in the analysis, and is carried out using PASS2008. Table 12 summarizes 
estimates of the confidence interval for the MK-7625A group under various assumptions. 
 
 
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Table 12  Confidence Interval for MK-7625A Under Various Assumption With 74 Evaluable 
Subjects in ME Population
Number of Subjects with a 
eradication response
Estimate of Response 
Rate
95% Confidence Interval
55
74.3%
(62.8%, 83.8%)
59
79.7%
(68.8%, 88.2%)
63
85.1%
(75.0%, 92.3%)
67
90.5%
(81.5%, 96.1%)
71
95.9%
(88.6%, 99.2%)
Subgroup Analyses and Effect of Baseline Factors
8.10
To determine whether the response rate is consistent across various subgroups, the response 
rate in the ME at TOC population for the primary endpoints will be estimated within each 
category of each subgroup.  The following are classification variables: 

Baseline diagnosis (pyelonephritis vs. cLUTI)

CrCl (≤50 mL/min, >50 mL/min)

Age categories (≥18 to <45 years, ≥45 to <65 years, ≥65 years)

ESBL status of Enterobacteriaceae

Presence of bacteremia at baseline

Subject with/without indwelling catheter

Subject with/without complicated factors for pyelonephritis

Number of uropathogens present at baseline
The consistency of the response rate will be assessed descriptively via summary statistics by 
category for the classification variables listed above.
Compliance (Medication Adherence)
8.11
Drug accountability data for MK-7625A will be collected during the study.  These results 
will be used to calculate subject compliance.
For each subject, percent compliance will then be calculated using the following formula:
Compliance (%) = 100 times (Actual Number of Doses on Therapy) / (Total Number of 
Expected Doses on Therapy).
 
 
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For a subject who is followed for the entire study period, the “Total Number of Expected 
Doses on Therapy” is 21.  For a subject who discontinued from the study permanently, the 
“Total Number of Expected Doses on Therapy” is the total scheduled number of doses from 
allocation to the date of the last dose of study medication. Compliance (%) will be 
categorized as: < 80%, ≥80% to ≤120%, and > 120%. 
Summaries of percent compliance and compliance (%) categories will be provided for the 
ME at TOC population.
Extent of Exposure
8.12
The extent of exposure to study treatment will be evaluated by summary statistics (n, mean, 
median, standard deviation, minimum, and maximum) and frequencies [1 to 4 days, 5 to 6 
days, 7 days and >7 days] for the “Number of Days on Therapy”, and frequencies [by 3 
doses] for the “Number of Does on Therapy” for 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 13.
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 13  Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional 
Information
MK-7625A 1.5 g (ceftolozane 
1 g/tazobactam 0.5 g) 
Lyophilized Powder for I.V. 
infusion
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.
Investigator will receive open label vials of MK-7625A.
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/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
 
 
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The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
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.
 
 
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According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  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 FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
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.
 
 
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Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
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.
 
 
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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.
Takeda S, Ishii Y, Hatano K, Tateda K, Yamaguchi K. Stability of FR264205 against 
AmpC β- lactamase of Pseudomonas aeruginosa. Int J Antimicrob Agents. 2007; 
30(5):443-45.
2.
Takeda S, Nakai T, Wakai Y, Ikeda F, Hatano K. In vitro and in vivo activities of a new 
cephalosporin, FR264205, against Pseudomonas aeruginosa. Antimicrob Agents 
Chemother. 2007; 51(3):826-30.
3.
Wagenlehner FME, Naber KG. Current challenges in the treatment of complicated 
urinary tract infections and prostatitis. Clin Microb Infect 2006;12(S3):67-80.
4.
Nicolle LE, AMMI Canada Guidelines Committee. Complicated urinary tract infection 
in adults. Can J Infect Dis Med Microbiol 2005; 16 (6): 349-60.
5.
The Japanese Association for Infectious Diseases/ Japanese Society of Chemothrapy. 
Guideline on Use of Antibiotics 2005: 186-92. 
6.
Ishikawa K, Hamasuna R, Uehara S, Yasuda M, Yamamoto S, Hayami H, et al. Japanese 
nationwide surveillance in 2011 of antibacterial susceptibility patterns of clinical isolates 
from complicated urinary tract infection cases. J Infect Chemother. 2015: 1-11.
7.
Ministry of Health, Labour and Welfare.  Japan Nosocomial Infections Surveillance 
(Annual report January to December 2013). 
8.
Lancefield RC, A serological differentiation of human and other groups of hemolytic 
streptococci. J Exp Med 1933; 57: 571-95.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.11 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by 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 Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
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 Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, 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 for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository 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.
 
 
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6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from 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 (e.g., ISO17799) to protect against unauthorized access.
 
 
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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 any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by 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
 
 
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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
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Approximate Blood Volumes Drawn by Trial Visit and by Sample Types
12.4
Approximate blood volume is shown in the table below. There is a possibility to be different 
volume by subject’s condition etc.
Trial Visit:
Screening
Treatment
Follow-up
1
2
3
4
5-8
9
10
11
Blood Parameter
Approximate Blood Volume (mL)
Hematology
2.0
2.0
2.0
2.0
2.0
Coagulation
1.8
1.8
1.8
1.8
1.8
Serum Chemistry
3.0
3.0
3.0
3.0
3.0
Coombs
2.0
2.0
Glucose
2.0
2.0
2.0
2.0
2.0
Serum creatinine†
1.0
1.0
1.0
1.0
Culture for blood sample†
20.0
‡
Hematology†
2.0
Chemistry†
2.0
Blood for Genetic Analysis 
8.5
Collection of sample to measure 
MK-7625A plasma concentration
2.0
10.0
Expected Total (mL)
35.8
11.5
1.0
19.8
10.8
8.8
8.8
† Test is performed locally in each investigational institution.
‡ Culture for blood sample is conducted as indicated in subjects who present with clinical signs and/or symptoms of 
pyelonephritis or bacteremia (OR subjects with indwelling catheters whose baseline urine specimen are obtained through 
the catheter).
 
 
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Clinical Study Conduct System
12.5
Clinical study conduct system is shown in attachment 1 and 2.
 
 
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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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