Clinical trial NCT02739997
Conditions: Intra-abdominal Infection Complicated Intra-abdominal Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-04-08; Completion date: 2017-07-28
Enrollment: 100 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) plus metronidazole 500 mg for the treatment of Complicated Intra-abdominal Infections (cIAI) in Japanese participants. Efficacy will be primarily assessed by clinical response defined as complete resolution or significant improvement in signs and symptoms of the index infection.

Detailed description:

Arms: arm 1: MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 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 2: metronidazole 500 mg
Intervention descriptions: intervention 1: MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) administered as an intravenous (IV) infusion intervention 2: metronidazole 500 mg administered as an IV infusion

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Multicenter, Open-label, Noncomparative, Japanese Phase III 
Study to Assess the Efficacy and Safety of Ceftolozane/Tazobactam 
(MK-7625A) used in Combination with Metronidazole in Japanese 
Patients with Complicated Intra-abdominal Infection. 
NCT number: 
NCT02739997 
Document Date: 
21-Dec-2015 


Product:  MK-7625A
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THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE 
STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Multicenter, Open-label, Noncomparative, Japanese Phase III Study to Assess the Efficacy 
and Safety of Ceftolozane/Tazobactam (MK-7625A) used in Combination with 
Metronidazole in Japanese Patients with Complicated Intra-abdominal 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......................................................................................... 11
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 12
Background ........................................................................................................... 12
4.1
4.1.1
Pharmaceutical and Therapeutic Background .................................................... 12
4.1.2
Clinical Trials...................................................................................................... 15
4.1.3
Ongoing Clinical Trials....................................................................................... 17
4.1.4
Information on Other Trial-Related Therapy...................................................... 18
Rationale................................................................................................................ 18
4.2
4.2.1
Rationale for the Trial and Selected Subject Population .................................... 18
4.2.2
Rationale for Dose Selection/Regimen/Modification ......................................... 20
4.2.2.1
Rationale for The Use of Concomitant medication ..................................... 22
4.2.3
Rationale for Endpoints ...................................................................................... 22
4.2.3.1
Efficacy Endpoints....................................................................................... 22
4.2.3.2
Definition of Efficacy Endpoints ................................................................. 23
4.2.3.3
Safety Endpoints .......................................................................................... 23
4.2.3.4
Pharmacokinetic Endpoints ......................................................................... 23
4.2.3.5
Pharmacodynamic Endpoints....................................................................... 23
4.2.3.6
Planned Exploratory Biomarker Research................................................... 24
4.2.3.7
Future Biomedical Research........................................................................ 24
Benefit/Risk ........................................................................................................... 24
4.3
5.0
METHODOLOGY ................................................................................................... 24
Entry Criteria........................................................................................................ 24
5.1
 
 
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5.1.1
Diagnosis/Condition for Entry into the Trial ...................................................... 24
5.1.2
Subject Inclusion Criteria.................................................................................... 25
5.1.3
Subject Exclusion Criteria .................................................................................. 26
Trial Treatment(s) ................................................................................................ 29
5.2
5.2.1
Dose Selection/Modification .............................................................................. 29
5.2.1.1
Dose Selection (Preparation) ....................................................................... 29
5.2.2
Timing of Dose Administration .......................................................................... 30
5.2.3
Trial Blinding/Masking....................................................................................... 31
Randomization or Treatment Allocation............................................................ 31
5.3
Stratification.......................................................................................................... 31
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 31
5.5
5.5.1
Prohibited medicine ............................................................................................ 31
5.5.2
Allowed medicine ............................................................................................... 32
Rescue Medications & Supportive Care............................................................. 32
5.6
Diet/Activity/Other Considerations..................................................................... 32
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 32
5.8
Subject Replacement Strategy............................................................................. 33
5.9
Beginning and End of the Trial ........................................................................... 33
5.10
Clinical Criteria for Early Trial Termination ................................................... 33
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 34
7.0
TRIAL PROCEDURES ........................................................................................... 37
Trial Procedures ................................................................................................... 37
7.1
7.1.1
Administrative Procedures.................................................................................. 37
7.1.1.1
Informed Consent......................................................................................... 37
7.1.1.1.1
General Informed Consent.................................................................... 37
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 38
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 38
7.1.1.3
Subject Identification Card .......................................................................... 38
7.1.1.4
Medical History ........................................................................................... 38
7.1.1.5
Prior and Concomitant Medications Review ............................................... 38
7.1.1.5.1
Prior Medications.................................................................................. 38
 
 
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7.1.1.5.2
Concomitant Medications..................................................................... 38
7.1.1.6
Assignment of Screening Number............................................................... 39
7.1.1.7
Assignment of Treatment/Randomization Number..................................... 39
7.1.1.8
Trial Compliance (Medication).................................................................... 39
7.1.1.9
Height and Body Weight ............................................................................. 39
7.1.1.10 APACHE II score ........................................................................................ 39
7.1.2
Clinical Procedures/Assessments........................................................................ 39
7.1.2.1
Physical Examination................................................................................... 40
7.1.2.2
Vital Sign ..................................................................................................... 40
7.1.2.3
Diagnosis of target disease and infection..................................................... 40
7.1.2.4
Assessment of Clinical Sign/Symptom for cIAI.......................................... 41
7.1.2.5
Surgical Wound Examination...................................................................... 41
7.1.2.6
Record summary of operative procedures and operative notes ................... 41
7.1.2.7
Radiographic examination (Ultrasound, X-ray or CT etc) .......................... 42
7.1.2.8
Assessment for Clinical Response............................................................... 42
7.1.3
Laboratory Procedures/Assessments .................................................................. 43
7.1.3.1
Culture for sample at infectious site and determination of pathogen .......... 43
7.1.3.2
Culture for blood sample and determination of pathogen ........................... 44
7.1.3.3
Assessment for Microbiological Response.................................................. 44
7.1.3.3.1
Per Pathogen Microbiological Response .............................................. 44
7.1.3.3.2
Per Subject Microbiological Response................................................. 45
7.1.3.4
Emergent Infection .................................................................................... 45
7.1.3.5
Blood sampling for Hematology, Coagulation Chemistry, and Urine 
sampling for urinalysis................................................................................. 46
7.1.3.6
Assessment of creatinine clearance ............................................................. 46
7.1.3.7
Pharmacokinetic Evaluation ........................................................................ 47
7.1.3.7.1
Blood Sampling for pharmacokinetics ................................................. 47
7.1.3.8
Planned Genetic Analysis Sample Collection.............................................. 47
7.1.3.9
Future Biomedical Research Sample Collection ......................................... 47
7.1.4
Other Procedures................................................................................................. 47
7.1.4.1
Withdrawal/Discontinuation........................................................................ 47
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 48
7.1.4.2
Blinding/Unblinding .................................................................................... 48
 
 
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7.1.4.3
Calibration of Critical Equipment................................................................ 48
7.1.5
Visit Requirements.............................................................................................. 48
7.1.5.1
Screening (Visit 1) ....................................................................................... 48
7.1.5.2
Treatment Period(Visit 2-15)....................................................................... 49
7.1.5.3
Follow-up Period (Visit 16 and 17) ............................................................. 49
Assessing and Recording Adverse Events .......................................................... 49
7.2
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 50
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 50
7.2.3
Immediate Reporting of Adverse Events to the Sponsor.................................... 51
7.2.3.1
Serious Adverse Events ............................................................................... 51
7.2.3.2
Events of Clinical Interest............................................................................ 52
7.2.4
Evaluating Adverse Events ................................................................................. 53
7.2.5
Sponsor Responsibility for Reporting Adverse Events ...................................... 56
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 56
Statistical Analysis Plan Summary ..................................................................... 56
8.1
Responsibility for Analyses/In-House Blinding ................................................. 57
8.2
Hypotheses/Estimation ......................................................................................... 57
8.3
Analysis Endpoints ............................................................................................... 57
8.4
8.4.1
Efficacy Endpoints.............................................................................................. 57
8.4.2
Safety Endpoints ................................................................................................. 57
Analysis Populations............................................................................................. 58
8.5
8.5.1
Efficacy Analysis Populations ............................................................................ 58
8.5.2
Safety Analysis Populations ............................................................................... 58
Statistical Methods................................................................................................ 59
8.6
8.6.1
Statistical Methods for Efficacy Analyses .......................................................... 59
8.6.2
Statistical Methods for Safety Analyses ............................................................. 60
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 61
8.6.3.1
Demographic and Baseline Characteristics ................................................. 61
8.6.3.2
Population PK Analyses .............................................................................. 61
Interim Analyses ................................................................................................... 61
8.7
Multiplicity ............................................................................................................ 61
8.8
 
 
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Sample Size and Power Calculations .................................................................. 61
8.9
8.9.1
Sample Size and Power for Efficacy Analyses ................................................... 61
Subgroup Analyses and Effect of Baseline Factors ........................................... 62
8.10
Compliance (Medication Adherence).................................................................. 63
8.11
Extent of Exposure................................................................................................ 63
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 63
Investigational Product ........................................................................................ 63
9.1
Packaging and Labeling Information ................................................................. 64
9.2
Clinical Supplies Disclosure................................................................................. 64
9.3
Storage and Handling Requirements.................................................................. 64
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 64
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 65
Confidentiality....................................................................................................... 65
10.1
10.1.1 Confidentiality of Data ....................................................................................... 65
10.1.2 Confidentiality of Subject Records ..................................................................... 65
10.1.3 Confidentiality of Investigator Information........................................................ 65
10.1.4 Confidentiality of IRB/IEC Information............................................................. 66
Compliance with Financial Disclosure Requirements....................................... 66
10.2
Compliance with Law, Audit and Debarment ................................................... 66
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 68
10.4
Quality Management System............................................................................... 68
10.5
Data Management................................................................................................. 68
10.6
Publications ........................................................................................................... 69
10.7
11.0
LIST OF REFERENCES......................................................................................... 70
12.0
APPENDICES........................................................................................................... 72
Merck Code of Conduct for Clinical Trials........................................................ 72
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 74
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 78
Approximate Blood Volumes Drawn by Trial Visit and by Sample Types..... 87
12.4
 
 
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ACUTE PHYSIOLOGICAL ASSESSMENT AND CHRONIC HEALTH 
12.5
EVALUATION (APACHE) SCORING SYSTEM............................................ 88
Clinical Study Conduct System ........................................................................... 90
12.6
13.0
SIGNATURES........................................................................................................... 91
Sponsor's Representative ..................................................................................... 91
13.1
Investigator............................................................................................................ 91
13.2
 
 
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LIST OF TABLES
    
Table 1
Summary of Efficacy Endpoints............................................................................. 23
Table 2  Trial Treatment ......................................................................................................... 29
Table 3
The dosage of MK-7625A for every creatinine clearance...................................... 30
Table 4  Treatment period with study drug............................................................................. 30
Table 5
Clinical Response Definitions at the EOT, TOC and LFU Visits .......................... 43
Table 6
Microbiological Response Definitions at the EOT and TOC Visits....................... 45
Table 7
Emergent Infection Definitions .............................................................................. 45
Table 8
The List of Laboratory Tests .................................................................................. 46
Table 9
Blood Sampling Points for PK................................................................................ 47
Table 10 Evaluating Adverse Events...................................................................................... 54
Table 11
Analysis Strategy for Key Efficacy Variables.................................................... 60
Table 12
Confidence Interval for MK-7625A Under Various Assumption With 75
Evaluable Subjects in CE Population ......................................................................... 62
Table 13 Product Descriptions................................................................................................ 64
 
 
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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 Complicated Intra-abdominal 
Infection 
Sponsor Product Identifiers
MK-7625A
Trial Phase
Phase III
Clinical Indication
Complicated Intra-abdominal Infection
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
MK-7625A plus metronidazole
Number of trial subjects
Approximately 100 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 17
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 43 days at 
maximum from the time the subject signs the Informed Consent Form 
(ICF) through the final contact.  After a screening phase of 1 day, each 
subject will receive MK-7625A plus metronidazole for approximately 
4-14 days.  After the initiation of treatment each subject will be 
followed for 42 days.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a nonrandomized, multi-site, open-label trial of MK-7625A plus metronidazole in 
Japanese subjects with complicated intra-abdominal infection (cIAI) to be conducted in 
conformance with Good Clinical Practices.
Approximately 100 subjects with a diagnosis of cIAI will be enrolled in this trial. All 
subjects will receive MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) plus metronidazole 
500 mg intravenously (IV) every 8 hours under unblinded conditions.  The number of 
enrolled patients with CrCl 30-50 mL/min will be restrained from exceeding 15% (15 
patients) of the total enrollment due to the rationale described in Section 4.2.1. An adjusted 
dose [MK-7625A 750 mg (ceftolozane 500 mg/tazobactam 250 mg)] will be administered to 
subjects with creatinine clearance (CrCl) of 30-50 mL/min.  Each subject will receive MK-
7625A plus metronidazole for 4-14 days.  Efficacy assessments (clinical response and 
microbiological response) will be conducted at the End-of-Therapy visit (EOT; completion 
of study drug administration) and the Test-of-Cure (TOC; Day 28+/-2 days).  Subjects will 
be followed for Efficacy and Safety evaluations until Late Follow-up (LFU; Day 42+/-3 
days).
Randomization Ratio
Not Applicable
 
 
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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.
Visit1
†
Visit 2
Visit 3
Visit 4
Visit 5-14
Visit 15
Visit 16
Visit 17
Baseline
Day 1
Day 2
Day 3
Day 4-13
Day 14/EOT
§
Day 28+/- 2 
days/TOC
||
Day 42+/- 3
¶ Late follow-up
|| Test of Cure
days/LFU
¶
Screening
Treatment
‡
Follow-up visit
† Informed consent could be obtained within 2 days of study drug initiation
‡Based on the investigator's discreation, treatment duration could be continued until Day 14 as needed
§ End of Treatment
The treatment can be given for 4-14 days  The daily visits listed as Day 4-13(Visit 5-14) are only performed if treatment extends beyond 4 days
Figure 1 Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective: To estimate the clinical response of MK-7625A plus metronidazole in 
subjects with cIAI in the clinically evaluable (CE) population at TOC.
2) Objective: To evaluate the safety and tolerability of MK-7625A plus metronidazole 
in subjects with cIAI.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective: To estimate the clinical response of MK-7625A plus metronidazole in 
subjects with cIAI in the microbiological intent-to-treat (MITT) population at TOC.
2) Objective: To estimate the per-subject and per-pathogen microbiological response of 
MK-7625A plus metronidazole in subjects with cIAI in the MITT and expanded 
microbiologically evaluable (EME) population at EOT and TOC.
3) Objective: To estimate the clinical response of MK-7625A plus metronidazole in 
subjects with cIAI in the MITT and CE population at EOT and LFU.
Exploratory Objectives
3.3
1) Objective: To summarize the proportion of subjects that develop superinfection and 
new infection in the MITT and EME population.
 
 
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2) Objective: To summarize the proportion of subjects with relapse of clinical cure in 
the MITT and CE 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)/approved labeling for detailed background 
information on MK-7625A.
4.1.1
Pharmaceutical and Therapeutic Background
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.
Ceftolozane shares the basic chemical and biological attributes and mechanism of action with
other β-lactam antibiotics. 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 [1]. 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 extended-spectrum β-
lactamase (ESBL) -producing Escherichia coli, Klebsiella pneumoniae, and other 
Enterobacteriaceae, as well as some important anaerobic pathogens (i.e., Bacteroides 
fragilis). 
 
 
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MK-7625A does not adequately cover some pathogens implicated in cIAIs, such as Gram-
positive pathogens (Enterococci, Staphylococcus aureus), and anaerobes other than 
Bacteroides fragilis.
Epidemiology and Clinical Manifestations of Complicated Intra -Abdominal Infection
Complicated intra-abdominal infection (cIAI) encompasses a wide variety of serious 
infections ranging from appendiceal abscesses to more severe conditions such as intestinal
perforation with diffuse fecal peritonitis. In cIAI, the infectious process proceeds beyond the 
organ that is the source of the infection, and causes either localized peritonitis, also referred 
to as abdominal abscess, or diffuse peritonitis, depending on the ability of the host to contain 
the process within a part of the abdominal cavity [2].
Complicated IAIs, those requiring both operative intervention and antimicrobial therapy, are 
very common infections encountered in general surgery [3], and cIAIs are an important cause 
of morbidity and are frequently associated with a poor prognosis. According to a global 
epidemiological survey of bacterial pathogens in patients with cIAI (the complicated intra-
abdominal infections worldwide observational study, CIAOW study) which was conducted 
worldwide including Japan, the overall mortality rate was 10.1% [4]. The immediate post-
operative clinical course was a significant parameter for predicting mortality: the rate of 
patient mortality was 54.9% among critically ill patients (patients presenting with septic 
shock and severe sepsis post-operatively), but the mortality rate was only 3.3% for clinically 
stable patients [4].
Although the bacteriology of cIAI depends on the anatomic origin of the infection, these 
infections are usually polymicrobial and involve a wide variety of Gram-negative and Gram-
positive aerobic and anaerobic organisms. Pathogens most commonly encountered in cIAI 
are E. coli, other common Enterobacteriaceae, P. aeruginosa, and B. fragilis [5].
The threat of antimicrobial resistance is one of the major challenges associated with the 
antimicrobial management of cIAI. The growing emergence of MDR bacteria and the limited 
availability of new antibiotics to counteract them have brought about an impending crisis 
with alarming implications (especially regarding Gram-negative microorganisms).
The main resistance threat in intra-abdominal infections is posed by ESBL-producing 
Enterobacteriaceae, which are becoming increasingly common in community acquired 
infections. The furequency
of ESBL-positive E. coli
isolates and ESBL-positive 
K. pneumoniae isolates collected from patients with IAI increased from 2002 to 2011 as a 
world trend [6]. According to the CIAOW study, among the intra-operative isolates, ESBL-
positive E. coli isolates comprised 13.7% of all E. coli isolates, while ESBL-positive K. 
pneumoniae isolates represented 18.6% of all K. pneumoniae isolates [4].
 
 
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Distributions of the isolates from surgical infections were investigated in a multicenter study
in Japan. In the 1057 isolates from secondary peritonitis, 59.4% anaerobes and 37.4% 
aerobes were isolated. Gram-negative anaerobes, Bacteroides spp. including Bacteroides 
fragilis (5.4%) were observed most frequently (18.8%). This was followed by E. coli (10.2%), 
Streptococcus spp. (6.3%) and Enterococcus spp. (6.0%) in this order. On the other hand, in 
the 242 isolates from hepatobiliary infection (including cholecysitis and cholangitis), 19.8% 
anaerobes and 78.1% aerobes were isolated. Gram-positive aerobes, Enterococcus spp.
including  Enterococcus faecalis (10.7%) were observed most frequently (21.4%). This was 
followed by Klebsiella spp. (15.7%) including Klebsiella pneumoniae (11.6%) and E. coli
(14.5%) in this order [7].
Treatment of Complicated Intra-Abdominal Infection
While cIAI is an important cause of morbidity and frequently associated with a poor 
prognosis, an early diagnosis, followed by adequate source control to stop ongoing 
contamination and restore anatomical structures and physiological function, as well as 
prompt initiation of appropriate empirical therapy, can limit the associated mortality [2].
Surgery is the most important therapeutic recourse for controlling IAI. The choice of the 
procedure depends on the anatomical source of infection, on the degree of peritoneal 
inflammation, on the generalized septic response and on the patient’s general conditions [2].
Antimicrobial therapy plays an integral role in the management of cIAI. Empiric antibiotic 
therapy should account for the most frequently isolated microorganisms as well as local 
trends of antibiotic resistance [1].
In general, primary peritonitis is typically monomicrobial (e. g., due to streptococci, E. coli, 
staphylococci), whereas secondary and tertiary peritonitis are polymicrobial mixtures of 
aerobic and anaerobic bacteria, and occasionally fungi (in case of tertiary peritonitis). In 
community-acquired secondary peritonitis, Gram-positive and Gram-negative and aerobic 
organisms often are implicated in infections derived from the stomach, duodenum, biliary 
system, and proximal small bowel. On the other hand, in hospital-acquired peritonitis, 
nosocomial isolates particular to the site of previous surgery and to the specific hospital and 
unit may determine which organisms are responsible. In Japan, the treatment with penicillins,
cephalosporins, carbapenems, monobactams, or new quinolones based on the classification 
and extent of peritonitis and pathogens are recommended in The Japanese Association for 
Infectious Diseases (JAID)/Japanese Society of Chemotherapy (JSC) Guide to Clinical 
Management of Infectious Diseases 2014 [8].
For treatment of acute cholecystitis and cholangitis, clinical guidelines (GLs) for cIAI 
including diagnosis and management have already been established in the United States and 
Europe. The international GL (TG13: Updated Tokyo Guidelines for acute cholangitis and 
acute cholecystitis), which was developed in Japan with overseas specialists for acute 
cholangitis and cholecystitis, provides a framework for selecting antimicrobial agents, with 
class-based definitions of appropriate therapy [9]. Recommendations for treatment 
modification based upon local microbiological findings, referred to as an antibiogram, are 
also made in the GL. Based on the data of bacterial pathogens isolated from biliary 
infections, the treatment with penicillins, cephalosporins, carbapenems, monobactams, or 
new quinolones with or without metronidazole are recommended.
 
 
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Product:  MK-7625A
16
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
MK-7625A plus metronidazole was well tolerated and generally safe in this trial. Three 
subjects died in the MK-7625A plus metronidazole group (namely urosepsis, pulmonary 
embolism, and renal failure with cardiopulmonary arrest), all following study drug 
discontinuation. All deaths were reported as unrelated to study treatment. A similar 
proportion of subjects in the MK-7625A plus metronidazole (41 of 82 subjects, 50%) and 
meropenem (19 of 39 subjects, 48.8%) groups experienced at least one AE. The incidence of 
serious AEs (SAEs) was higher in the MK-7625A plus metronidazole group (14 subjects, 
17.1%) compared to the meropenem group (2 subjects, 5.1%). All SAEs were reported in 1 
subject each and all were assessed as unrelated to study treatment. Serious AEs reported in 
the MK-7625A plus metronidazole-treated subjects included: pancreatitis acute, seroma, 
atrial flutter, shock, urosepsis, haematoma, postoperative wound infection, intestinal 
perforation, colitis ischaemic, pulmonary embolism, pneumonia, peridiverticular abscess, 
cholelithiasis, atrial fibrillation, hyponatraemia, female genital tract fistula, renal failure, and 
cardiorespiratory arrest. The most common post-baseline shifts in clinical laboratory 
parameters in both treatment groups were elevated liver enzymes (GGT, AST, and ALT), 
which were consistent with known experience with β-lactam therapy. Details are in the 
investigator brochure.
A Phase 3 Trial in patients with complicated intra-abdominal infection（CXA-cIAI-10-08 
and CXA-cIAI-10-09）
Two large, identical, global, multicenter, randomized, double-blind, active-controlled 
Phase 3 trials were initiated in subjects with cIAI (CXA-cIAI-10-08 and CXA-cIAI-10-09). 
The data for these 2 trials were prospectively pooled to form a single adequately powered 
Phase 3 dataset, reported in a single clinical study report. 
Adult subjects with a diagnosis of cIAI requiring surgical intervention were randomly 
assigned in a 1:1 ratio to receive MK-7625A (1.5 g IV every 8 hours) plus metronidazole 
(500 mg IV every 8 hours) or meropenem (1 g IV every 8 hours) with placebo (IV every 8 
hours) for 4 to 10 days. Subjects were stratified at randomization by primary site of infection 
(bowel versus other site of IAI).
A total of 970 subjects were included in the ITT population, of which 476 subjects were 
randomized to receive MK-7625A plus metronidazole and 494 subjects randomized to 
receive meropenem. 472 and 485 subjects received at least 1 dose of MK-7625A plus 
metronidazole and meropenem, respectively. 
 
 
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Product:  MK-7625A
17
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
In both the FDA and EMA analyses, MK-7625A plus metronidazole demonstrated 
noninferiority compared to meropenem for the primary and key secondary efficacy variables 
in the treatment of adult subjects with cIAI. Clinical cure rates at the TOC visit in the 
primary efficacy analysis population (MITT) were 83.0% (323/389) and 87.3% (364/417) for 
MK-7625A plus metronidazole and meropenem with placebo, respectively. Clinical cure 
rates at the TOC visit in the CE population were 94.1% (353/375) and 94.0% (375/399) for 
MK-7625A plus metronidazole and meropenem with placebo, respectively. Clinical cure 
rates at the TOC visit in the ITT population were 83.6% (407/487) and 86.2% (436/506) for 
MK-7625A plus metronidazole and meropenem with placebo, respectively. Microbiological 
response rate at the TOC visit in MITT population were 85.3% (332/389) and 88.7%
(370/417) for MK-7625A plus metronidazole and meropenem with placebo, respectively. 
Additionally, MK-7625A plus metronidazole demonstrated high clinical cure rates in 
subjects with common intra-abdominal pathogens including Enterobacter cloacae, 
Escherichia 
coli, 
Klebsiella 
oxytoca, 
Klebsiella 
pneumoniae, 
Proteus 
mirabilis, 
Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus 
constellatus, and Streptococcus salivarius.
MK-7625A plus metronidazole was well tolerated and generally safe in this trial. The 
proportion of subjects who had one or more AEs was similar in both treatment groups 
[44.0 % (212/482) for MK-7625A plus metronidazole, 42.7% (212/497) for meropenem with 
placebo].  The proportion of subjects who had one or more SAEs was comparable in both 
treatment groups [2.7% (13/482) for MK-7625A plus metronidazole, 2.2% (11/497) for 
meropenem with placebo]. The proportion of subjects who had AEs that led to death was 
comparable in both treatment groups [2.3% (11/482) for MK-7625A plus metronidazole, 
1.6% (8/497) for meropenem with placebo]. 
Results of the subgroup analyses based on demographic characteristics, prognostic factors, 
disease characteristics, and geographical region suggested that MK-7625A
plus 
metronidazole maintained its efficacy across various subpopulations, including high-risk 
subjects.
The most common intra-abdominal Gram-negative aerobic baseline pathogens were E. coli, 
K. pneumoniae, and P. aeruginosa, in addition to other pathogens such as B. fragilis and 
Streptococcus spp., with approximately 70% of subjects having a polymicrobial infection. 
In the cIAI trial, there was no emergence of decreased susceptibility or resistance in either 
treatment arm.
4.1.3
Ongoing Clinical Trials
The Phase 3 global trial (Protocol 008) for ventilated nosocomial pneumonia, the Phase 1
trial (Protocol 007) for intensive care unit subjects and the pediatric PK trial (Protocol 010)
are on-going. Additional details may be found in the accompanying Investigators Brochure 
(IB).
 
 
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Product:  MK-7625A
18
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
4.1.4
Information on Other Trial-Related Therapy
Intravenous metronidazole will be used for all subjects in this trial (Refer to domestic 
package insert of metronidazole). An appropriate surgical intervention for target diseases will 
be done for all subjects based on the investigators’ decision, as inclusion in this trial requires 
surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous draining of an 
abscess) within 24 hours of (before or after) the first dose of MK-7625A.
Rationale
4.2
4.2.1
Rationale for the Trial and Selected Subject Population
This open-label trial is planned to estimate the efficacy and safety of MK-7625A in Japanese 
patients with complicated intra-abdominal infection. The prior global cIAI 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 cIAI indication was derived 
from 2 large, identical, global, multicenter, randomized, double-blind, active-controlled 
Phase 3 trials (CXA-cIAI-10-08 and CXA-cIAI-10-09).
The efficacy of MK-7625A was demonstrated in these 2 global Phase 3 trials. In the cIAI 
indication, subjects were randomized 1:1 to receive either MK-7625A 1.5 g (ceftolozane 1 
g/tazobactam 0.5 g) every 8 hours plus metronidazole 500 mg every 8 hours or meropenem 1 
g every 8 hours administered as IV infusions for 4-10 days (14 days at maximum). The 
results indicated that MK-7625A plus metronidazole was non-inferior to meropenem for the 
primary and key secondary efficacy variables. 
The purpose of this trial is to further demonstrate the safety and efficacy of MK-7625A in 
only Japanese patients with cIAI for Japanese registration. Therefore, the design of this trial
is an open-label, non-comparative design for the purpose of collecting safety and efficacy 
data without statistical verification to assess the use of MK-7625A in Japanese patients with 
cIAI.
Rationale for sample size
A sample size of 100 patients is applied to the Japanese cIAI trial to evaluate the safety and 
efficacy in Japanese patients with cIAI. As efficacy and safety of MK-7625A has already 
been established in two large Phase 3 global trials, the purpose of this trial is to establish 
safety and efficacy in Japanese patients. A sample size of approximately 100 Japanese 
patients receiving MK-7625A plus metronidazole will provide the Japanese data needed to 
establish safety and efficacy of MK-7625A compared to the global Phase 3 trials. In addition, 
there was a past example that enrolled approximately 100 Japanese patients with IAI for the 
local registration in Japan [10]. Therefore, this sample size is considered adequate for the 
local registration in Japan.
 
 
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Product:  MK-7625A
19
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
Rationale for Selected Subject Population
Gram-negative pathogens, including ESBL producing organisms, are important causes of 
cIAI. The most commonly isolated pathogens in cIAI are E. coli, Enterobacteriaceae, 
Pseudomonas spp. and B. fragilis. These infections are typically polymicrobial, also 
involving anaerobes such as B. fragilis.  The spectrum of activity of MK-7625A in 
combination with metronidazole supports its use in treatment of pathogens commonly 
isolated in cIAI.
The safety and efficacy of MK-7625A in combination with metronidazole for the treatment 
of cIAI was demonstrated in 2 large, identical, multicenter, randomized, double-blind, active-
controlled Phase 3 trials (CXA-cIAI-10-08 and CXA-cIAI-10-09), subsequently pooled to 
form 1 submission dataset. MK-7625A plus metronidazole demonstrated non-inferiority to 
meropenem, a standard of care for the treatment of cIAIs. 
As described previously, MK-7625A is active against the most common infecting pathogens 
encountered in cIAIs, and the efficacy and safety of MK-7625A in subjects with cIAI was 
demonstrated in global, active-controlled Phase 3 trials. Based on the efficacy and safety of 
MK-7625A demonstrated in the global Phase 3 trials, it is considered appropriate to conduct 
a cIAI trial in a Japanese patient population. 
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. In a subgroup analysis of 
Phase 3 cIAI trials (CXA-cIAI-10-08 and CXA-cIAI-10-09), clinical cure rates were lower in 
patients with baseline creatinine clearance (CrCl) of 30 to ≤50 mL/min (47.8%, 11/23 
patients) compared to those with CrCl >50 mL/min (85.2%, 312/366 patients). A similar 
trend was also seen in the cUTI trials. 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 up to 15% (15 
patients) of the total enrollment in this study to keep the similar proportion of these patients 
as the global studies.
The underlying infection type causing cIAI will be captured in this trial. It is recommended
that at least the following number of subjects in each infection type be enrolled in the trial 
according to the domestic guideline for intra-abdominal infection (Koukinyaku-no-rinsho-
hyoka guideline, 1998) [11]. Although desirable, the recommended number may not be 
reached as this is not a large clinical trial. 
・Cholangitis: 3 patients or more
・Peritonitis: 5 patients or more
・Intra-abdominal abscess: 5 patients or more
・Liver abscess: 5 patients or more
 
 
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Product:  MK-7625A
20
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
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 in 
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, the 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 trial results as reference data. In 
Japan, the Japanese Phase 3 trial (Protocol 013) is planned to examine and confirm the 
efficacy (microbiological response and clinical effect) and safety of the overseas Phase 3 
trials for cIAI.
4.2.2
Rationale for Dose Selection/Regimen/Modification
In this Japanese Phase 3 trial (Protocol 013), 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/pharmacodynamics (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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Product:  MK-7625A
21
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
In Phase 3 trials (CXA-cIAI-10-08 and CXA-cIAI-10-09), IV MK-7625A 1.5 g every 8 
hours plus metronidazole demonstrated non-inferiority to IV meropenem 1000 mg every 8 
hours for the treatment of cIAIs. Additionally, in Phase 3 trials of complicated urinary tract 
infections (cUTI) including pyelonephritis (CXA-cUTI-10-04 and CXA-cUTI-10-05), IV 
MK-7625A 1.5 g every 8 hours demonstrated non-inferiority to IV levofloxacin 750 mg once 
daily. In both indications,  IV MK-7625A 1.5 g every 8 hours 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 (Study 
CXA-101-02, Study CXA-201-02, and Study CXA-REN-11-01). Each study 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 for MK-7625A in this Japanese Phase 3 trial (Protocol 013) will be 4-
14 days. This duration was determined based on 2 overseas phase 3 trials (CXA-cIAI-10-08
and CXA-cIAI-10-09) and the US package insert.
 
 
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Product:  MK-7625A
22
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
4.2.2.1
Rationale for The Use of Concomitant medication
Metronidazole will be used in combination with MK-7625A for all subjects in this trial. MK-
7625A demonstrates activity against the major pathogens implicated in cIAIs such as Gram-
negative bacteria including Enterobacteriaceae (including E.coli, K. pneumoniae) and P. 
aeruginosa, some of Gram-positive bacteria such as Streptococci spp., and the anaerobe B. 
fragilis. However, MK-7625A lacks activity against non-B. fragilis anaerobes. Thus,
Bacteroides species beyond B. fragilis are major pathogens in IAIs necessitating the need for 
an antibacterial agent with activity against a range of anaerobic organisms. Metronidazole, a 
limited-spectrum, anaerobe-specific antibiotic, is commonly used in the treatment of cIAI in 
combination with a cephalosporin, and its use is recommended in the evidence-based 
guidelines developed by an expert panel for the treatment of cIAI at 500 mg every 8 hours
[12]. Metronidazole is approved and marketed for the treatment of anaerobe infections in 
Japan and overseas. Taking into consideration this background, IV metronidazole will be 
used concomitantly in this trial in order to appropriately treat the target pathogens associated 
with cIAI.
4.2.3
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
In this Japanese Phase 3 trial (Protocol 013), clinical response and microbiological response
are the efficacy endpoints that will be used to estimate the efficacy of MK-7625A plus 
metronidazole based on the vital signs (7.1.2.2), clinical signs and symptoms (7.1.2.3-
7.1.2.5), microbiological examination (7.1.3.3) and laboratory tests (7.1.3.5).  
Based on the FDA guidance (2015) for cIAI and to conduct a comparable analysis to the 
global cIAI trials (CXA-cIAI-10-08 and CXA-cIAI-10-09), TOC is the primary time point 
for efficacy. Moreover, for the same reason, in order to estimate the efficacy at the end of 
treatment and late follow-up visit of MK-7625A, EOT and LFU are set as secondary time 
points for efficacy. The analysis populations in the study objectives are comparable to those 
of global cIAI trials (CXA-cIAI-10-08 and CXA-cIAI-10-09). The same MITT, CE and 
EME population are included in both the global trials and this Japan trial and used for the 
analysis of clinical response/microbiological response.
 
 
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4.2.3.2
Definition of Efficacy Endpoints
Refer to Table 1 for efficacy endpoints by timing and analysis population. Details regarding 
the endpoints are presented in the referenced sections.  
Table 1
Summary of Efficacy Endpoints
Objective
Endpoint
Timing
Analysis Population
References
(Section)
Primary
Clinical response
TOC
CE
7.1.2.8
Secondary
Clinical response
EOT and LFU
CE
7.1.2.8
EOT, TOC and LFU
MITT
Per-subject
microbiological 
response
EOT and TOC
EME
7.1.3.3
EOT and TOC
MITT
Per-pathogen 
microbiological 
response
EOT and TOC
EME
EOT and TOC
MITT
4.2.3.3
Safety Endpoints
In this Japanese Phase 3 trial (Protocol 013), vital signs, adverse events (clinical AEs and 
laboratory AEs) and laboratory tests (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 plus metronidazole.
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.
4.2.3.4
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.
4.2.3.5
Pharmacodynamic Endpoints
The pharmacokinetic/pharmacodynamic analyses will be specified in a separate protocol.
 
 
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4.2.3.6
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.
4.2.3.7
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.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination 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
5.1.1
Diagnosis/Condition for Entry into the Trial
Japanese male/female subjects with complicated intra-abdominal infection of at least 18 
years will be enrolled in this trial.
 
 
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5.1.2
Subject Inclusion Criteria
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.
3. One of the following diagnoses (in which there is evidence of intraperitoneal 
infection) including:
a.
Cholecystitis with rupture, perforation, or progression of the infection beyond 
the gallbladder wall or gangrenous cholecystitis;
b. Acute gastric or duodenal perforation;
c.
Traumatic perforation of the intestine;
d. Appendiceal perforation or periappendiceal abscess;
e.
Diverticular disease with perforation or abscess;
f.
Intraabdominal abscess (including liver or spleen); or 
g. Peritonitis due to other perforated viscus or following a prior operative 
procedure.
Note: Subjects with inflammatory bowel disease or ischemic bowel disease 
are eligible provided there is bowel perforation.
4. Evidence of systemic infection including one or more of the following at screening 
visit:
a.
Axillary temperature greater than 37.5°Celsius (C) or oral temperature greater 
than 38.0°Celsius;
b. Elevated white blood cells (WBC; >10,500/mm3);
c.
Abdominal pain, flank pain, or pain likely due to cIAI that is referred to 
another anatomic area such as back or hip; or
d. Nausea or vomiting.
5. Subject had or plans to have surgical intervention (e.g., laparotomy, laparoscopic 
surgery, or percutaneous draining of an abscess) within 24 hours of (before or after) 
the first dose of study drug.
6. If subject is to be enrolled preoperatively, perforation or abscess should be seen or 
strongly suspected on the radiologic exam.
 
 
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7. Subject whose intra-abdominal specimen could be taken at baseline for the 
microbiological assessment (pre-operative enrollment and dosing is acceptable, 
provided that the sample from the site of infection is obtained during the 
interventional procedure).
8. If female, subject is either:
a.
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.
b. 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.
9. 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.
5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Acute gastric or duodenal perforation operated on ≤24 hours after perforation 
occurred
2. Traumatic perforation of the intestine operated on ≤12 hours after perforation 
occurred
3. Subject who has the following diagnoses as the target diseases for the study:
a.
Simple appendicitis (other than appendiceal perforation or periappendiceal 
abscess);
b. Diagnosis of abdominal wall abscess; 
c.
Small bowel obstruction or ischemic bowel disease without perforation;
d. Spontaneous (primary) bacterial peritonitis associated with cirrhosis and 
chronic ascites; or
e.
Pelvic infections.
4. Subject who has the following diseases:
a.
Acute suppurative cholangitis; 
b. Infected necrotizing pancreatitis; 
c.
Pancreatic abscess;  
 
 
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d. Infectious mononucleosis; or
e.
Cystic fibrosis.
5. Subject who has complicated intra-abdominal infection managed by staged 
abdominal repair (STAR) or, open abdomen drainage.
6. Subject who is expected to be cured by only surgical intervention (e.g., drainage)
without use of systemic antibiotic therapy.
7. Use of systemic antibiotic therapy for IAI for more than 24 hours during the previous 
72 hours prior to the first dose of study drug, unless there is a documented treatment 
failure† with such therapy.
† The definition of subjects considered to have failed a previous antibiotic regimen
Should meet all of the following criteria
1)
The systemic antibacterial treatment was given for at least 48 hours;
2)
There are clinical and operative or radiographic findings clearly indicating ongoing 
infection;
3)
Operative intervention or re-intervention (if previous surgical procedure) is intended no 
more than 24 hours after first dose of study drug;
4)
No further non-study antibiotics were administered postoperatively; and
5)
Current positive baseline bacterial culture from intra-abdominal site. 
・
Specimens for bacterial culture and susceptibility testing are to be taken at operative 
intervention. Culture results do not need to be known before randomization.
・
It may be useful to obtain a Gram-stain of fluid from the site of infection; if there are 
minimal WBCs and no or rare bacteria seen, the likelihood of a positive culture is low 
and such a subject should usually not be enrolled.
8. Subjects who meet the following criteria with regard to the use of systemic 
antibacterial therapy:
a.
Use of any postoperative non-study antibacterial therapy in a subject enrolled 
preoperatively; or
b. Use of more than 1 dose of an active non-study antibacterial therapy following 
the surgical operation in a subject enrolled postoperatively.
9. Subject who have a concomitant infection at the time of the randomization, which 
requires a non-study systemic antibacterial therapy in addition to study drug therapy 
[vancomycin, teicoplanin, linezolid and daptomycin (i.e., drugs with only Gram-
positive activity) are allowed]
10. Severe impairment of renal function (estimated CrCl <30 mL/min), or requirement 
for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (<20 mL/h urine 
output over 24 hours) at screening visit. (Refer to 5.2.1.1, where the formula for the 
calculation of CrCl can be found)
11. The presence of hepatic disease at screening visit as defined by any of the following:
a.
Total bilirubin >2 × upper limit of normal (ULN);
b. Alkaline phosphatase (ALP), ALT (SGPT) or AST (SGOT) > 4 × ULN; or
c.
ALT (SGPT) or AST (SGOT) ≥3 × ULN and total bilirubin ≥2 × ULN and, at 
the same time, Alkaline phosphatase (ALP)
< 2 × ULN
 
 
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d. Acute or chronic hepatitis, cirrhosis, acute hepatic failure, acute 
decompensation of chronic hepatic failure.
12. Subject who has any of the following values at screening visit:
a.
Hematocrit <25%;
b. Hemoglobin <8 g/dL;
c.
Neutropenia with absolute neutrophil count <1,000/mm3.; or
d. Platelet count <75,000/mm3.
13. Subject who meet any of the following conditions:
a.
Considered unlikely to survive the 4- to 5-week study period.
b. Organic brain or spinal cord disease
c.
Any rapidly-progressing disease or immediately life-threatening illness.
d. Immunocompromising condition, including established acquired immune 
deficiency 
syndrome, 
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.
14. Subject who has a history of any moderate or severe hypersensitivity or allergic 
reaction to any beta-lactam (β-lactam) antibacterial, including cephalosporins, 
carbapenems, penicillins, or
β-lactamase inhibitors, or metronidazole, or 
nitroimidazole derivatives.
15. Subject who is receiving or received disulfiram within 14 days before the proposed 
first day of study drug or who are currently receiving probenecid.
16. Participation in any clinical study of an investigational product within 30 days prior 
to the proposed first day of study drug.
17. Subject who has joined a ceftolozane or  MK-7625A clinical trial in the past
18. Any condition or circumstance that, in the opinion of the Investigator, would 
compromise the safety of the subject or the quality of study data.
19. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
 
 
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Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 2.
Table 2 Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route 
of 
Administration
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/4-14days
Experimental
Metronidazole 
500 
mg 
metronidazole
Every 
8
hours
intravenous
60 
(±10)
min 
intravenous 
infusion/4-14days 
Concomitant 
drug
† 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.
5.2.1
Dose Selection/Modification
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. Careful monitoring of renal function is important, especially during the 
first few days following intra-abdominal surgery, as there are often fluctuations in CrCl
following surgery. Therefore, daily 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 14, obtain serum creatinine and 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.
 
 
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The dosage of metronidazole IV is administered 500 mg every 8 hours based on the package 
insert in Japan regardless of the calculation of creatinine clearance. 
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
5.2.2
Timing of Dose Administration
After all the study procedures at visit 1 (baseline) are completed, MK-7625A 1.5 g 
(ceftolozane 1 g/tazobactam 0.5 g) followed by metronidazole 500 mg is administered 
intravenously every 8 hours starting on visit 2 (Day 1), respectively. The dosage of MK-
7625A is adjusted for subjects with creatinine clearance 30 - 50 mL/min. Preparation of MK-
7625A is referred to a separate manual.
In this trial, MK-7625A 1.5 g is administered intravenously 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 intervals 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. Metronidazole 500 mg is administered intravenously 60 (±10) minutes based on the 
package insert in Japan.
Treatment period for MK-7625A plus metronidazole is 4 to 14 days with duration at the 
investigator’s discretion (described in Table 4).
Table 4  Treatment period with study drug
Treatment period with study drug and decision of treatment completion
Subjects should receive study drug for a minimum of 4 days (unless subjects meet the 
discontinuation criteria defined in 5.8, for example, clinical failure occurs earlier or an AE 
necessitating early discontinuation occurs), and end the treatment of study drug within 14 
days. After 3 days and at the discretion of the Investigator, study drug administration may be
discontinued if the subject has shown signs and symptoms of clinical resolution or significant 
improvement such as:
・
WBC count is < 12,500/μL;
・
Maximum axillary temperature has been < 99.5 °F / 37.5 °C or maximum oral 
temperature has been < 100.4 °F / 38.0 °C for > 24 hours, without the influence of 
antipyretic agents, such as aspirin, acetaminophen, non-steroidal anti-inflammatory
drugs, or corticosteroids;
・
Improvement of abdominal signs and symptoms manifested at study entry;
・
Return of bowel function and restoration of oral/enteral intake; and
・
No further antibiotic therapy is required. 
 
 
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5.2.3
Trial Blinding/Masking
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 number of enrolled patients with CrCl 30-50 mL/min will be restrained from exceeding 
15% (15 patients) of the total enrollment due to the rationale described in 4.2.1.
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
5.5.1
Prohibited medicine
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.
Listed below are specific restrictions for concomitant therapy during the course of the trial:
1)
Systemic antibiotics (except for MK-7625A and metronidazole): From the timing of first 
study drug administration to LFU visit (Exception: subjects with clinical or 
microbiological failure can receive systemic antimicrobial drugs).
2)
Disulfiram: From 14 days before the first study drug administration to TOC visit 
3)
Probenecid: From the timing of first study drug administration to EOT visit
4)
Other investigational drugs (except for MK-7625A and metronidazole): From 30 days 
prior to the proposed first day of study drug to LFU visit
5)
Peritoneal irrigation with antibiotic-containing solutions: From the timing of first study 
drug administration to LFU visit
 
 
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5.5.2
Allowed medicine
Vancomycin, teicoplanin, linezolid (IV and PO) and daptomycin are allowed in case an
infection with MRSA or Enterococcus is suspected(for the index infection of complicated 
intra-abdominal infection or a concomitant infection). However, these drugs should be 
discontinued in case these pathogens are not isolated. Guidelines outline patients at risk for 
Enterococcus as those with health care–associated intra-abdominal infection, particularly 
those with postoperative infection, those who have previously received cephalosporins or 
other antimicrobial agents selecting for Enterococcus species, immunocompromised patients, 
and those with valvular heart disease or prosthetic intravascular materials are at risk of 
enterococcal infection [1]).
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
No special restriction for diet or daily activities are specified in this trial.
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:

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 cIAI.

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)
 
 
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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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X: must be done. X in the Day 4-13 visits (Visits 5-14) signifies that the procedure should be performed daily.
(X): may be done if 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.
Throughout Day 2 to 13, assessment will be done at approximately the same timing in principle.
2.
It can be done within 2 days prior to study drug initiation.
3.
Study drug will be administered for 4 to 14 days and Visits 5-14 may not be needed.
4.
Any operative procedures and operative notes for complicated intra-abdominal infection must be recorded if surgical intervention is conducted for complicated intra-
abdominal infection during the trial[including operative procedures at screening or a surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous draining of 
an abscess) within 24 hours of (before or after) the first dose of study drug].
5.
Culture for blood sample at screening is conducted as indicated in subjects with hospital-acquired infections, for those who have failed prior antibacterial therapy, or who have 
signs of sepsis. Two sets (from two separate blood draws) of blood cultures (each set consisting of an aerobic and an anaerobic bottle for a total of four bottles) are conducted. 
Blood culture is conducted at appropriate frequency until negative if blood culture at screening is positive. In addition, if signs of sepsis appear or the subject is assessed as a 
treatment failure at any time on study(including EOT, TOC and LFU visit), a blood culture should be taken. When blood cultures are indicated, two sets (each consisting of 
aerobic and anaerobic bottles) should be obtained for a total of four bottles.
6.
Radiographic examination is conducted for the subject who is enrolled prior to surgical intervention, perforation or abscess should be seen or strongly suspected. Radiological 
result should be entered in the eCRF in the all subjects who have radiological examination during the trial(Radiological result of subjects who are enrolled postoperatively 
should also be entered in the eCRF).
7.
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). 
8.
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 14, obtain serum creatinine value and monitor CrCl at least daily and adjust the dosage of MK-7625A accordingly based on local laboratory results.
9.
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]
10.
A urine pregnancy test (urine hCG) is performed in each investigational institution. After ensuring the urine hCG is negative, a subject may be enrolled in this study.
11.
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.
12.
‘Culture for sample of infectious site and determination of pathogen’ at EOT/TOC/LFU is needed in case of additional abdominal intervention (e.g., collection during the 
additional surgery in the subjects with clinical failure) to evaluate the microbiological assessment.
13.
LFU can be conducted by telephone by conducting only ‘X14’ items specified in LFU visit to assess subject’s safety and clinical outcome if subject had a TOC visit with 
clinical cure and no abnormalities requiring follow-up assessment; otherwise, the LFU visit must be made at the study center to conduct all items specified in LFU visit. If 
symptoms of relapse of clinical cure are noted during the telephone interview, the subject should be immediately scheduled for an in-person visit.
14.
These porocedures ‘X14’ items should be conducted and recorded in the source document and eCRF regardless of visit type(i.e. telephone interview or in-person visit)
 
 
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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.
7.1.1
Administrative Procedures
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, a 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, disulfiram from 14 days before the first dose of trial medication, other 
investigational drugs from 30 days before the first dose of trial medication). Record any 
blood or blood product transfusions in the previous 48 hours before 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).
 
 
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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.
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 at screening. 
7.1.1.10 APACHE II score
The investigator or qualified designee will record pre-surgical APACHE II score based on
Appendix 12.5 at screening. 
7.1.2
Clinical Procedures/Assessments
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.
 
 
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7.1.2.1
Physical Examination
The investigator or qualified designee will perform a physical examination at the visits 
specified in 6.0 TRIAL FLOW CHART. The screening physical examination will be 
complete; the EOT visit physical examinations 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. The LFU can be conducted by 
telephone to assess subject’s safety and clinical outcome if subject had a TOC visit with 
clinical cure and no abnormalities requiring follow-up assessment; otherwise, the LFU visit 
must be made at the study center to conduct all items specified in LFU visit, including 
physical exam. If symptoms of clinical relapse are noted during the telephone interview, the 
subject should be immediately scheduled for an in-person visit.
7.1.2.2
Vital Sign
The investigator or qualified designee will record vital signs (oral or axillary temperature, 
blood pressure, pulse rate and respiratory rate) at the visit specified in 6.0 TRIAL FLOW 
CHART. The method of body temperature(oral or axillary) should be consistent during the 
trial. The highest daily body temperature should be recorded in the eCRF from those values 
taken that day. Systolic and diastolic blood pressure will be measured on the same arm 
(preferentially on the left arm). Pulse will be recorded simultaneously with blood pressure 
measurements.
7.1.2.3
Diagnosis of target disease and infection
Assess and record the diagnosis of target disease, anatomic site of infection, the presence and 
extent of abscesses (i.e. presence or absence of a abscess, single or multiple abscess), the 
presence and extent of peritonitis (i.e. presence or absence of peritonitis, local or diffuse), the 
etiological mechanism (i.e., postoperative/hospital acquired infection, trauma, spontaneous 
rupture, malignancy or other) and infection history (i.e. new infection or failure of prior 
antibiotic therapy) at screening. ‘Postoperative/hospital acquired infection’ in the etiological 
mechanism should be selected if the subject meet one or more of the following criteria; 1) 
intra-abdominal infection following a prior surgery, 2) ≧72 hours of hospitalization prior to 
surgical intervention, 3) failure of prior antibiotic therapy for cIAI, or 4) surgical or medical 
procedure within 90 days prior to receipt of study drug.
 
 
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7.1.2.4
Assessment of Clinical Sign/Symptom for cIAI
The cIAI symptoms will be assessed at baseline by clinical examination of the abdomen and 
at the visits specified in 6.0 TRIAL FLOW CHART. Specific findings such as abdominal 
pain, tenderness to palpation, rebound tenderness, guarding, or presence of ascites and mass, 
will be assessed and graded as none, mild, moderate or severe according to the following 
definitions:
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
Other pertinent findings should be recorded, including ability to tolerate oral or enteral intake 
and presence of ileus.
On each study day thereafter, each cIAI symptom will be assessed by the Investigator by 
using above definitions. 
7.1.2.5
Surgical Wound Examination
Conduct surgical wound examination at the visits specified in 6.0 TRIAL FLOW CHART to 
assess signs of infection such as skin erythema, induration, tenderness, swelling, and wound 
pain (superficial). If signs of infection are present, findings will be recorded and graded as 
mild, moderate, or severe according to the definitions provided above. Warmth and 
fluctuance will be assessed as absent or present. The nature of any discharge (non-purulent or 
purulent) will also be assessed. Surgical wound examination should be conducted at the 
baseline visit if subject already had surgical intervention before the allocation. It is preferred
that this assessment should be performed approximately at the same time each day (e.g., 
every morning).
7.1.2.6
Record summary of operative procedures and operative notes
During the trial, record summary of initial and any subsequent interventional operative 
procedure and operative note for complicated intra-abdominal infection (e.g., laparotomy, 
laparoscopic surgery, or percutaneous draining of an abscess) in the eCRF and retain source 
records of all operative procedure and notes at study sites. The initial interventional 
procedure must intend to achieve adequate source control, (i.e., all communications between 
the GI tract and the peritoneal cavity are closed), no necrotic intestine (or other tissue) is left, 
and all infected collections are drained).
 
 
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7.1.2.7
Radiographic examination (Ultrasound, X-ray or CT etc)
Specific radiographic examinations are not required for this study unless the subject is 
enrolled pre-operatively (Radiographic examination is conducted for the subject who is 
enrolled prior to surgical intervention, perforation or abscess should be seen or strongly 
suspected). Radiological examinations should only be performed as required for routine 
subject management. Radiologic evaluations might include plain abdominal radiograph, 
computerized tomography (CT) scan, ultrasound, and/or magnetic resonance imaging (MRI) 
scan, with or without contrast. The results of any such studies should be recorded in the 
eCRF and retained at the sites appropriately. Radiological result should be entered in the 
eCRF in the all subjects who have radiological examination druing the trial (Radiological 
result of subjects who are enrolled postoperatively should also be entered in the eCRF).
7.1.2.8
Assessment for Clinical Response
Clinical response is assessed at the EOT, TOC and LFU visits. The definition of clinical 
response at the EOT, TOC and LFU is shown in Table 5.
The Investigator will classify clinical outcome as “cure”, “failure”, or “indeterminate”. A 
favorable clinical response is “cure”. An unfavorable response is “failure”.
Failure will be carried forward; subjects who are assessed as a failure prior to the TOC/LFU 
visit should have“failure” recorded on the TOC/LFU outcome visit eCRF, regardless of 
their final outcome at that time. Subjects who are assessed as a failure prior to the TOC/LFU
should attend the TOC/LFU visit but will not have a clinical outcome assessment at the 
TOC/LFU visit. 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.
 
 
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Table 5
Clinical Response Definitions at the EOT, TOC and LFU Visits
Outcome
Definition
Clinical Cure
Complete resolution or significant improvement in signs and symptoms of the 
index infection, such that no additional antibacterial therapy or surgical or
drainage procedure is required for the index infection.
Clinical Failure
・
Death related to IAI at any time point prior to each assessment point (EOT,
TOC and LFU)
・
Persisting or recurrent infection within the abdomen requiring additional 
intervention to cure the infection*
・
Need for treatment with additional antibiotics for ongoing symptoms of IAI 
prior to each assessment point (EOT, TOC and LFU), or
・
Post-surgical wound infection, defined as an open wound with signs of local 
infection, such as purulent exudate, erythema, or warmth that requires 
additional antimicrobial therapy and/or non-routine wound care (such as 
incision and drainage or re-opening of the wound).**
Note: Closure of a colostomy or an enterocutaneous fistula is not considered a 
failure. Wherever possible, failures should be documented microbiologically by 
obtaining an appropriate deep wound or intraabdominal site culture. Blood 
cultures should also be obtained.
* Repeat percutaneous aspiration of an abscess within 72 hours of the original 
aspiration, without worsening clinical signs and symptoms, is not considered a 
failure. However, the need to repeat any procedure after 72 hours of study therapy 
to cure the infection should be considered a failure. Exploratory or diagnostic
procedures with no evidence of an ongoing infection are not considered a failure.
**Use of vacuum-assisted wound closure following fascial closure is acceptable 
and such procedure must be reported on the abdominal intervention page. Daily 
wound assessments must be conducted according to schedule of events.
Indeterminate
・
Study data are not available for evaluation of efficacy for any reason, 
including death during the study period unrelated to the index infection, or
・
Extenuating circumstances that preclude classification as cure or failure (e.g., 
subject lost to follow-up).
7.1.3
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
7.1.3.1
Culture for sample at infectious site and determination of pathogen
Obtain intraabdominal specimens for culture of aerobic and anaerobic organisms during the 
interventional procedure as a screening sample; specimens should be collected at the 
beginning of the interventional procedure prior to debridement, removal or disinfection of the 
primary site of infection. Aspirates (collected with a needle or syringe) or tissue or biopsy 
samples are recommended, swabs of purulent material are discouraged. 
 
 
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Thereafter, obtain specimens for culture from the site of infection, if clinically indicated (e.g., 
if reintervention is required, collection during the additional surgery in the subjects with 
clinical failure) to evaluate the microbiological assessment. Do not obtain specimens from in 
situ abdominal drains. Culture of the intraabdominal 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.
7.1.3.2
Culture for blood sample and determination of pathogen
Obtain two sets (from two separate blood draws) of blood cultures (each set consisting of an 
aerobic and an anaerobic bottle) for a total of four bottles as indicated in subjects with 
hospital-acquired infections, for those who have failed prior antibacterial therapy, or who 
have signs of sepsis at screening. Thereafter, obtain blood sample for culture until at least 
one negative result is obtained if screening blood culture was positive. If signs of sepsis 
appear or the subject is assessed as a treatment failure at any time on study (including EOT, 
TOC or LFU visit), a blood culture should be taken. When blood cultures are indicated, two 
sets (each consisting of aerobic and anaerobic bottles) should be obtained for a total of four 
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 Response
7.1.3.3.1 Per Pathogen Microbiological Response
A microbiological response will be determined by the Sponsor for each pathogen isolated at 
baseline. Microbiological response categories are eradication, presumed eradication,
persistence, persistence acquiring resistance, presumed persistence, and indeterminate, as
defined in Table 6. Favorable microbiological responses include “eradication” or “presumed
eradication”. “Persistence,” “persistence acquiring resistance,” and “presumed persistence”
are considered unfavorable responses. Microbiological response is assessed at both the EOT 
and TOC visits.
 
 
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Table 6
Microbiological Response Definitions at the EOT and TOC Visits
Outcome
Definition
Eradication
Absence of the baseline pathogen in a specimen appropriately obtained from the 
original site of infection
Presumed Eradication
Absence of material to culture in a subject who is assessed as a clinical cure
Persistence
Presence of the baseline pathogen in a culture of an appropriately obtained 
specimen from the site of infection or surgical wound. Cultures from indwelling 
drains are not considered appropriate.
Persistence acquiring
resistance
As above [Persistence], and the baseline pathogen that was susceptible to study 
drug pretreatment is resistant to study drug post-treatment.
Presumed persistence
Absence of material to culture in a subject who is assessed as a clinical failure
Indeterminate
Baseline culture either not obtained or has an assessment of no growth
Any other circumstance that makes it impossible to define the
microbiological response (e.g., patient lost to follow-up)
7.1.3.3.2 Per Subject Microbiological Response
An overall microbiological response will be determined by the Sponsor for each subject
based on individual microbiological responses for each baseline pathogen. In order for the
subject to have a favorable overall microbiological response (i.e., eradication or presumed
eradication), each baseline pathogen must have a favorable microbiological outcome. If the
outcome for any pathogen is unfavorable, the subject will be considered an overall
microbiological failure. Microbiological response is assessed at both the EOT and TOC visits. 
7.1.3.4
Emergent Infection
Emergent infections (intra-abdominal pathogens other than the baseline intra-abdominal 
pathogen) will be evaluated. Isolation of intra-abdominal pathogen other than the baseline 
intra-abdominal pathogen is classified as “superinfection” or “new infection”. The definition 
of emergent infection is shown in Table 7. Subjects with new pathogens will be considered to 
have an unfavorable microbiologic response.
Table 7
Emergent Infection Definitions
Outcome
Definition
Superinfection
Isolation of a pathogen, other than the original baseline pathogen(s), from an intra-
abdominal specimen taken from a subject with signs or symptoms of infection 
while on study drug
New infection
Isolation of a pathogen, other than the original baseline pathogen(s), from an intra-
abdominal specimen in a subject with signs or symptoms of infection after 
treatment with study drug
 
 
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7.1.3.5
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 6.0 TRIAL FLOW CHART 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(fresh urine)
Red blood cell count (RBC)
Total protein
Presence or absence of nitrites
Hemoglobin
Albumin
Specific gravity
Hematocrit
Total bilirubin
pH
White blood cell count (WBC)
Aspartate aminotransferase (AST)
Protein
WBC 
differential 
(neutrophil, 
eosinophil, basophil, lymphocyte, 
monocyte)
Alanine aminotransferase (ALT)
Glucose
Alkaline phosphatase
Ketones
Gamma-glutamyl transferase
Bilirubin
Platelet count
Blood urea nitrogen
Occult blood
Prothrombin time
Serum creatinine†
Urobilinogen
Direct Coombs test
Uric acid
Urine pregnancy test (urine hCG) †
Bicarbonate
Calcium
Chloride
Magnesium
Potassium
Phosphorous
Sodium
Non-fasting serum glucose
C-reactive protein(CRP)
† Test is performed locally in each investigational institution.
7.1.3.6
Assessment of creatinine clearance
During this study period, serum creatinine value to determine dose adjustment will be 
collected in 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 5.2.1.1 at the visit specified in 6.0 TRIAL FLOW CHART.
Careful monitoring of renal function is important, especially during the first few days 
following intra-abdominal surgery, as there are often fluctuations in CrCl following surgery. 
Therefore, daily 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 14, obtain serum creatinine value and monitor CrCl at least daily and adjust the dosage of 
MK-7625A accordingly. Obtained serum creatinine values should be recorded in the eCRF.
 
 
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7.1.3.7
Pharmacokinetic Evaluation
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 departments. The collected sparse pharmacokinetic 
samples will be included in a future cross study POP-PK analysis.
7.1.3.7.1 Blood Sampling for pharmacokinetics
Blood for pharmacokinetic analysis will be collected from all subjects who received MK-
7625A (approximately 100 subjects). 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.
7.1.3.8
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.
7.1.3.9
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
DNA for future research.
7.1.4
Other Procedures
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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PPD


Product:  MK-7625A
49
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
7.1.5.2
Treatment Period(Visit 2-15)
For study Day 1 (Visit 2) through Day 14 (Visit 15) all study assessments are recommended 
to be performed at an approximately consistent time of day for the study subject (e.g. every 
morning) for each calendar day.
7.1.5.3
Follow-up Period (Visit 16 and 17)
Subjects will be required to return to the investigational institution at Day 28+/-2days and 
Day 42+/-3days after the last dose of MK-7625A for post-trial visits. Visit 17 (LFU, 
Day42+/-3days), can be conducted by telephone by conducting ‘X14’ items specified in LFU 
visit in section 6.0 to assess subject’s safety and clinical outcome if subject had a TOC visit 
with clinical cure and no abnormalities requiring follow-up assessment; otherwise, the LFU 
visit must be made at the study center to conduct all items specified in LFU visit. If 
symptoms of clinical relapse are noted during the telephone interview, the subject should be 
immediately scheduled for an in-person visit.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
 
 
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All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 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.
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).
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than the dose below. MK-7625A: 3 g/dose or 9 
g/day.  Metronidazole: 500 mg/dose or 2000 mg/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).
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor
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.
 
 
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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).
7.2.3
Immediate Reporting of Adverse Events to the Sponsor
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.
 
 
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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.
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).
 
 
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7.2.4
Evaluating Adverse Events
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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7.2.5
Sponsor Responsibility for Reporting Adverse Events
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) used in Combination with Metronidazole in Japanese Patients 
with Complicated Intra-abdominal Infection
Treatment Assignment
Non-randomized, open-label and single arm
Analysis Populations
Efficacy: Clinically Evaluable (CE), expanded Microbiologically
Evaluable (EME) and microbiological intent-to-treat (MITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Clinical response at TOC
Secondary Endpoints
Clinical response at EOT and LFU
Microbiological response (Per-subject and per-pathogen 
microbiological response) at EOT and TOC
Statistical Methods for Key 
Efficacy Analyses
For the primary and secondary efficacy endpoints, point estimates 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 100 subjects to receive MK-7625A, and will 
allow estimation of the clinical response rate at TOC among subjects 
receiving MK-7625A in the CE population with a 95% confidence 
interval of (86.9%, 98.5%). This is based on the following 
assumptions: 1) an approximately 25% dropout and/or protocol 
deviation rate excluding subjects from the CE population, and 2) an 
observed response rate of 94 .7% 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 study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as a non-randomized, open-label study, i.e., subjects, 
investigators, and SPONSOR personnel will be aware of subject treatment assignments after 
each subject is enrolled and treatment is assigned.
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.
8.4.1
Efficacy Endpoints
The primary efficacy endpoint is clinical response rate at TOC, defined as the proportion of 
subjects in the analysis population who have a response of clinical cure at TOC.
The secondary efficacy endpoints include:

Clinical response rate at EOT and LFU.

Per-subject microbiological response rate at EOT and TOC, defined as the proportion
of subjects in the analysis population who have a favorable overall microbiological 
response at the visit interest (i.e. EOT or TOC).  Favorable microbiological responses 
will include eradication or presumed eradication.  In order for the subjects to have a 
favorable microbiological response, each baseline pathogen, must have a favorable 
microbiological outcome.  If the outcome for any pathogen was unfavorable, the 
subject will be considered an overall microbiological failure.

Per-pathogen microbiological response rate at EOT and TOC, defined as the 
proportion of subjects in the analysis population who have an outcome of 
microbiological eradication or presumed eradication for each pathogen isolated at 
baseline.
8.4.2
Safety Endpoints
An initial description of the safety measures is included in Sections 4.2.3.2.
 
 
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Analysis Populations
8.5
8.5.1
Efficacy Analysis Populations
The clinically evaluable (CE) population will serve as the primary population for the analysis 
of clinical response data in this study.  The CE population consists of all allocated subjects 
who:

receive study therapy for a minimum of 3 days,

have 80-120% study drug treatment compliance,

meet the protocol-specific disease definition of cIAI,

adhere to study procedures,

have a clinical response at the visit of interest within the specified visit window.
In addition, the expanded microbiologically evaluable (EME) population will serve as the
primary population for the analysis of microbiological response data.  The EME population 
consists of all allocated subjects who have cIAI as evidenced by identification of at least 1 
baseline intra-abdominal pathogen, regardless of susceptibility to study drug and meet all CE 
population criteria.
A supportive analysis using the microbiological intent-to-treat (MITT) population will be 
performed for the primary and secondary efficacy endpoints.  The MITT population consists 
of all allocated subjects who have cIAI as evidenced by identification of at least 1 baseline 
intra-abdominal pathogen, regardless of susceptibility to study drug.
The final determination on major protocol deviations, and thereby the composition of the CE, 
EME and MITT 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.
8.5.2
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all 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
8.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory endpoints will be described in the sSAP.
For the primary efficacy endpoint of clinical 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 clinical and microbiological responses, missing data will be primarily handled with a 
data-as-observed approach for the CE or EME population and a treatment failure approach 
for the MITT populations which is defined as follows:

For the analysis of clinical response and microbiological response in the MITT 
population, the subjects with a missing clinical response or microbiological response 
(e.g., including indeterminate) will be categorized as treatment failures.

For the analyses in the CE, or EME population, the subjects with a missing clinical 
response or microbiological response (e.g., including indeterminate) will be excluded 
from the population.

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.

A missing microbiological outcome at the TOC visit will be considered an 
indeterminate outcome if the clinical outcome at the TOC visit was indeterminate as 
well.  Microbiological response will be presumed from clinical response when there 
will be no suitable intra-abdominal specimen to culture on/after the EOT through the 
TOC 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
Clinical response rate at TOC
P
Clopper-Pearson 
method
CE
Data As Observed
Secondary Endpoints
Clinical response rate at TOC
S
Clopper-Pearson 
method
MITT
Treatment Failure 
Approach
Clinical response rate at EOT and 
LFU
P
Clopper-Pearson 
method
CE
Data As Observed
Clinical response rate at EOT and 
LFU
S
Clopper-Pearson 
method 
MITT
Treatment Failure 
Approach
Per-subject microbiological 
response rate at EOT and TOC
P
Clopper-Pearson 
method
EME
Data As Observed
Per-subject microbiological 
response rate at EOT and TOC
S
Clopper-Pearson 
method
MITT
Treatment Failure 
Approach
Per-pathogen microbiological 
response rate at EOT and TOC
P
Clopper-Pearson 
method 
EME
Data As Observed
Per-pathogen microbiological 
response rate at EOT and TOC
S
Clopper-Pearson 
method 
MITT
Treatment Failure 
Approach
†
P=Primary approach; S=Supportive approach. 
8.6.2
Statistical Methods for Safety Analyses
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 
methods 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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8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
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 study, 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 study.
Multiplicity
8.8
No multiplicity adjustment is planned for this study. 
Sample Size and Power Calculations
8.9
8.9.1
Sample Size and Power for Efficacy Analyses
This is an estimation study. This study will enroll 100 subjects to receive MK-7625A (the 
rationale for the enrollment of 100 subject is referred to Section 4.2.1), and will allow 
estimation of the clinical response rate at TOC among subjects receiving MK-7625A in the 
CE population with a 95% confidence interval of (86.9%, 98.5%). This is based on the 
following assumptions: 1) an approximately 25% dropout and/or protocol deviation rate
excluding subjects from the CE population, and 2) an observed response rate of 94.7% in the 
MK-7625A group based on the study results conducted outside of Japan (from protocol 
CXA-cIAI-10-08 and CXA-cIAI-10-09). The calculation is based on the exact binomial 
method proposed by Clopper and Pearson with 75 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 75
Evaluable Subjects in CE Population
Number of Subjects with a 
Response of Clinical Cure
Estimate of Clinical 
Response Rate
95% Confidence Interval
60
80.0%
(69.2%, 88.4%)
64
85.3%
(75.3%, 92.4%)
68
90.7%
(81.7%, 96.2%)
71
94.7%
(86.9%, 98.5%)
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 CE population for the primary endpoint will be estimated within each subgroup.  
The following are classification variables: 

Primary Site of Infection (bowel [small or large], other site of infection)

Anatomic Site of Infection

Etiological mechanism [nosocomial infection
(postoperative/hospital acquired 
infection), community acquired infection (trauma, spontaneous rupture, malignancy 
or other)]

APACHE II Category

Age categories (≥18 to <65 years, ≥65 to <75 years, ≥75 years)

Sex

CrCl (≤50 mL/min, >50 mL/min)

Number of Abscesses (single, multiple)

Peritonitis Type (local, diffuse)

Procedure Type (percutaneous aspiration, laparoscopy, laparotomy, other)

Prior Antibiotic Use (yes, no)

Site of infection (appendix, non-appendix)

Baseline Bacteremia

Number of Baseline Pathogens (polymicrobial, monomicrobial)

Pathogen MIC and Pathogen Classification
 
 
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
ESBL status of Enterobacteriaceae

AmpC overexpression status of P. aeruginosa (for subject with baseline P. 
aeruginosa)
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 and metronidazole 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).
The “Total Number of Expected Doses on Therapy” is the total scheduled number of doses
from allocation to the last scheduled day for treatment administration for that subject. 
Compliance (%) will be categorized as: < 80%, ≥80% to ≤120%, and > 120%. 
Summaries of percent compliance and compliance (%) categories will be provided for the CE 
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 3 days, 4 to 7
days, 8 to 10 days, 11-14 days and >14 days] for the “Actual Number of Days on Therapy”, 
and frequencies [by 3 doses] for the “Actual Number of Doses 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.
 
 
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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.
Metronidazole 500 mg
Solution 
for 
I.V. infusion
Provided by the trial site.
All supplies indicated in Table 13 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 13 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed 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.
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.
 
 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
10.1.1 Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the 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.
10.1.2 Confidentiality of Subject Records
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.
10.1.3 Confidentiality of Investigator Information
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.
 
 
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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.
10.1.4 Confidentiality of IRB/IEC Information
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.
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.
 
 
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
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. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJC, Baron EJ, et at.
Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and 
Children: Guidelines by the Surgical Infection Society and the Infectious Diseases.
Society of America. Clinical Infectious Diseases 2010; 50:133–64.
2. Sartelli M, Viale P, Catena F, Ansaloni L, Moore E, Malangoni M. 2013 WSES 
guidelines for management of intra-abdominal infections. World Journal of Emergency 
Surgery 2013, 8:3
3. Solomkin JS, Yellin AE, Rotstein OD, et al. Ertapenem versus piperacillin/tazobactam in 
the treatment of complicated Intra-abdominal infections. Results of a double-blind, 
randomized comparative phase III trial. Ann Surg 2003; 237(2):235-245.
4. Sartelli M, Catena F, Ansaloni L, Coccolini F, Corbella D, Moore EE, Malangoni M, et 
al. Complicated intra-abdominal infections worldwide: the definitive data of the CIAOW 
Study. World Journal of Emergency Surgery 2014, 9:37
5. Tellado J, Woods GL, Gesser R, et al. Ertapenem versus piperacillin-tazobactam for 
treatment of mixed anaerobic complicated Intra-abdominal, complicated skin and skin 
structure, and acute pelvic infections. Surg Infect 2002; 3(4):303-314.
6. Morrissey I, Hackel M, Badal R, Bouchillon S, Hawser S, Biedenbach D. A Review of Ten 
Years of the Study for Monitoring Antimicrobial Resistance Trends (SMART) from 2002 to 
2011. Pharmaceuticals 2013, 6, 1335-1346.
7. Shinagawa N, Osanai H, Hirata K, Furuhata T, Mizukuchi T, Yanai Y, et al. Bacteria 
isolated from surgical infections and its susceptibilities to antimicrobial agents--special 
references to bacteria isolated between April 2009 and March 2010. The Japanese Journal 
of Antibiotics. 2011. 64:125-169.
8. Japanese Association for Infectious Diseases/Japanese Society of Chemotherapy. The 
JAID/JSC Guide to Clinical Management of Infectious Diseases 2014.
9. Takada T, Strasberg SM, Solomkin JS, Pitt HA, Gomi H, Yoshida M, et al. TG13: 
Updated Tokyo Guidelines for acute cholangitis and acute cholecystitis. J Hepatobiliary 
Pancreat Sci (2013) 20:1–109.
 
 
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10. Hiroshige Mikamo, Yoshio Takesue, Shinya Kusachi, Masahito Kotaka, Yasuyuki 
Kawachi, Naoki Aikawa. An open-label multicenter study of tazobactam/piperacillin in 
the treatment of patients with intra-abdominal infections. Japanese Journal of 
Chemotherapy. 2012. 60: 560-72.
11. Sunagawa K, Yamaguchi K, Shiba K, Onodera S, Hanatani Y, Chiba K. Koukinyaku-no-
rinsho-hyoka guideline. Japanese Journal of Chemotherapy. 1998. 46: 408-37.
12. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, O’Neill PJ, et al.
Diagnosis and management of complicated intra-abdominal infection in adults and
children: guidelines by the Surgical Infection Society and the Infectious Diseases Society 
of America. Clin Infect Dis. 2010; 50:133-64.
 
 
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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 7.1.3.9 – 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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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
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Product:  MK-7625A
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Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
 
 
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Product:  MK-7625A
85
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
 
 
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Product:  MK-7625A
86
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
 
 
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Product:  MK-7625A
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Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
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Confidential
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.
Approximate Blood Volume
Scr
Treatment
Post-Treatment
Trial Visit:
1
2
3
4
5-14
15
16
17
Blood Parameter 
Approximate Blood Volume (mL)
APACHE II SCORE†
5.0
Hematology
2.0
2.0
2.0
2.0
2.0
Coagulation
1.8
1.8
1.8
1.8
1.8
Serum Chemistry
5.0
5.0
5.0
5.0
5.0
Glucose
2.0
2.0
2.0
2.0
2.0
Coombs
2.0
2.0
Serum creatinine†
1.0
1.0
1.0
1.0
Culture for blood sample†
40.0‡
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)
62.8
11.5
1.0
21.8
12.8
10.8
10.8
† Test is performed locally in each investigational institution.
‡ Culture for blood sample at screening is conducted as indicated in subjects with hospital-acquired infections, for those who have 
failed prior antibacterial therapy, or who have signs of sepsis. Two sets (from two separate blood draws) of blood cultures (each 
set consisting of an aerobic and an anaerobic bottle for a total of four bottles) are conducted. Blood culture is conducted at 
appropriate frequency until negative if blood culture at screening is positive. In addition, if signs of sepsis appear or the subject is 
assessed as a treatment failure at any time on study(including EOT, TOC and LFU visit), a blood culture should be taken. When
blood cultures are indicated, two sets (each consisting of aerobic and anaerobic bottles) should be obtained for a total of four 
bottles.
 
 
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Product:  MK-7625A
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Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
ACUTE PHYSIOLOGICAL ASSESSMENT AND CHRONIC HEALTH 
12.5
EVALUATION (APACHE) SCORING SYSTEM
Physiologic Variable
POINT SCORE
+4
+3
+2
+1
0
+1
+2
+3
+4
1 Temperature, core (°C) †
≥41°
39–40 9°
—
38 5–38 9°
36–38 4°
34–35 9°
32–33 9°
30–31 9°
≤29 9
2 Mean arterial pressure
(mm Hg)
≥160
130–159
110–129
—
70–109
—
50–69
—
≤49
3 Heart rate
≥180
140–179
110–139
—
70–109
—
55–69
40–54
≤39
4
Respiratory
rate
(nonventilated
or
ventilated)
≥50
35–49
—
25–34
12–24
10–11
6–9
—
≤5
5 Oxygenation:
a) FIO2 ≥0 5: use A-
aDO2
≥500
350–499
200–349
—
<200
—
—
—
—
b) FIO2 <0 5: use PaO2 (mm
Hg)
—
—
—
—
>70
61–70
—
55–60
<55
6 Arterial pH
≥7 7
7 6–7 69
—
7 5–7 59
7 33–7 49
—
7 25–7 32
7 15–
7 24
<7 15
7 Serum Na (mmol/L)
≥180
160–179
155–159
150–154
130–149
—
120–129
111–119
≤110
8 Serum K (mmol/L)
≥7
6–6 9
—
5 5–5 9
3 5–5 4
3–3 4
2 5–2 9
—
<2 5
9
Serum
Creatinine
(mg/dL);
Double
point
score
for 
Acute
renal
failure
≥3 5
2–3 4
1 5–1 9
—
0 6–1 4
—
<0 6
—
—
10 Hct (%)
≥60
—
50–59 9
46–49 9
30–45 9
—
20–29 9
—
<20
11 WBC (in 1000s)
≥40
—
20–39 9
15–19 9
3–14 9
—
1–2 9
—
<1
12 Glasgow Coma score
(GCS)
Score =15 minus actual GCS
Acute physiology score is the sum of the 12 individual variable points
Add 2 points for age 45–54 yr; 3 points, 55–64 yr; 5 points, 65–74 yr; 6 points ≥ 75 yr
Add chronic health status points: 5 points for immunocompromiseor severe organ insufficiency ‡
(13)§ Serum HCO3
(venous–mmol/L)
≥52
41–51 9
—
32–40 9
22–31 9
—
18–21 9
15–17 9
<15
APACHE II score = acute physiology score + age points + chronic health points  Minimum score = 0; maximum score = 71  Increasing 
score is associated with increasing risk of hospital death Choose worst pre-surgical value in the past 24 h
†Axillary temperature could be used based on ‘Axillary temperature + 1 0 (°C)= Core temperature’ if core temperature cannot be obtained  
‡Chronic health status: Organ insufficiency (e g , hepatic, cardiovascular, renal, pulmonary) or immunocompromised state must have 
preceded current admission
§Optional variable; use only if no ABGs
A-a DO2 = Alveolar–arterial oxygen gradient; FIO2 = fractional inspired O2
Adapted from Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: A severity of disease classification system  Critical Care 
Medicine 13:818–829, 1985
 
 
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Product:  MK-7625A
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Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
ACUTE 
PHYSIOLOGICAL 
ASSESSMENT 
AND 
CHRONIC
HEALTH 
EVALUATION (APACHE) SCORING SYSTEM (CONT'D)
Glasgow Coma Scale
(Circle appropriate
response)
B Age Points
C
Chronic
Health
Points
Apache-II 
Score
(sum of 
A+B+C)
Eyes open
4 - spontaneously
3 - to speech
2 - to pain
1 - no response
Motor response
6 - to verbal command
5 - localizes to pain
4 - withdraws to pain
3 – flexion to pain
2 – extension to pain
1 - no response
verbal - nonintubated
5 - oriented
4 - confused
3 – inappropriate words
2 – incomprehensible sounds
1 - no response
verbal - intubated
5 - seems able to talk
3 – questionable ability to talk
1 – generally unresponsive
Age
≤44
45-54
55-64
65-74
≥75
Age points =
Points
0
2
3
5
6
Refer to bottom 
of the chart above 
for:
Chronic Health
Status Points =
A APS points
+ B Age points
+ C Chronic
Health Points
__________
= Total Apache II
 
 
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Product:  MK-7625A
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Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
Clinical Study Conduct System
12.6
Clinical study conduct system is shown in attachment 1 and 2.
 
 
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Product:  MK-7625A
91
Protocol/Amendment No.: 013-00
MK-7625A-013-00 Final Protocol
21-Dec-2015
Confidential
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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