Clinical trial NCT03032380
Conditions: Healthcare-associated Pneumonia (HCAP) Hospital Acquired Pneumonia (HAP) Ventilator Associated Pneumonia (VAP)
Keywords: Hospital-acquired pneumonia (HAP) S-649266 linezolid meropenem Healthcare-associated pneumonia (HCAP) nosocomial pneumonia Ventilator-associated pneumonia (VAP) Gram-negative pathogens pneumonia cefiderocol
Sponsor: Shionogi
Start date: 2017-10-24; Completion date: 2019-04-01
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to compare all-cause mortality at Day 14 in participants receiving cefiderocol with participants receiving the comparator, meropenem, in adults with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative pathogens.

Detailed description:

Arms: arm 1: Participants will receive 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days. arm 2: Participants will receive 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Interventions: intervention 1: Cefiderocol intervention 2: Meropenem intervention 3: Linezolid
Intervention descriptions: intervention 1: 2000 mg intravenously every 8 hours for a period of 7 to14 days (dosage adjustment is necessary based on renal function) intervention 2: 2000 mg intravenously every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function) intervention 3: 600 mg of linezolid administered intravenously over 30 minutes to 2 hours, every 12 hours.

Protocol documents:
Prot_001.pdf: 
 
Shionogi Study Title:  
A Multicenter, Randomized, Double-blind, 
Parallel-group, Clinical Study of S-649266 Compared 
with Meropenem for the Treatment of Hospital-acquired 
Bacterial Pneumonia, Ventilator-associated Bacterial 
Pneumonia, or Healthcare-associated Bacterial 
Pneumonia Caused by Gram-negative Pathogens 
Shionogi Study Number: 
1615R2132  
ClinicalTrials.gov 
Registration No. 
NCT03032380   
Study Document 
Protocol Version 4 (Amendment 3) 22 Feb 2019 
 
History of Protocol Amendments 
Version 1 (Original) 
02 Aug 2016 
This version of the protocol was not used to enroll participants 
Version 2 
21 Dec 2016 
This version of the protocol was not used to enroll participants 
Version 3 
24 Jul 2017 
• Changed the concomitant use of Linezolid to at least 5 days rather than full 
treatment term 
• Contraceptive inclusion criteria added 
• Added inclusion criteria for patients who had failed previous empiric antibiotic 
therapy both clinically and microbiologically 
• Valproic acid was excluded as a concomitant therapy because of meropenem 
dosing instructions 
• Clarification of PK blood sampling times was added 
• Added rescreening criteria for previously screen-failed patients 
• A new appendix provided a flow chart to help investigators determine the 
eligibility of patients failing empiric antibiotic treatment 
 
Version 3.1 
14 Aug 2017 
• The Time and Events Table was edited to better display the  relationship between 
columns and foot notes 
Version 3.2 RUS:  
19 Dec 2017 
• Adds a requirement for only Russian study sites  
Version 3.3 EU  
21 Dec 2018 
• Adds BREXIT required changes to protocol   
Version 3.4 RUS  
11 Jan 2019 
• Adds BREXIT required changes to protocol and phone number change   


Version3.5 EU  
11 Jan 2019 
• Adds change in phone number for BREXIT required changes  
Version 4 
22 Feb 2019 
• Adds address changes required for BREXIT  
• Clarifies that Middle Eastern study sites are under the purview of  SEU personnel 
• Adds a superiority analysis in a fixed sequence for secondary endpoints 
• Notes that resource utilization will be reported outside of the CSR 
• Removes probenecid, methotrexate, and procainamide from the list of prohibited 
medications 
• Specifically allows metronidazole or clindamycin to cover anaerobic bacteria and 
vancomycin for C. difficile 
• Removes the requirement for urinalysis for anuric patients 
• Adds major nonfatal events to the list of items to be reviewed at the prespecified  
times for other evaluations 
  


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CLINICAL STUDY PROTOCOL: 1615R2132 
Study Title:  
A Multicenter, Randomized, Double-blind, 
Parallel-group, Clinical Study of S-649266 
Compared with Meropenem for the Treatment of 
Hospital-acquired Bacterial Pneumonia, Ventilator-
associated Bacterial Pneumonia, or Healthcare-
associated Bacterial Pneumonia Caused by 
Gram-negative Pathogens 
Study Number: 
1615R2132 
EudraCT Number: 
2016-003020-23 
Study Phase: 
3  
IND Number: 
116,787 
Product Name:  
S-649266 (INN name: cefiderocol) 
Sponsor* for North America, 
South America: 
Shionogi Inc. 
300 Campus Drive, Florham Park, NJ 07932 USA 
Sponsor* for Europe/Middle 
East: 
Shionogi B.V. 
Kingsfordweg 151,  
1043 GR Amsterdam  
Netherlands 
Sponsor* for Asia-Pacific: 
Shionogi & Co., Ltd. 
(Head Office) 1-8 Doshomachi, 3 Chrome, Chuo-
ku, Osaka 541-0045, Japan 
(Development Office) 12F, Hankyu Terminal Bldg., 
1-4, Shibata 1-chome, Kita-ku, Osaka 530-0012, 
Japan 
Sponsor Contact: 
 
Shionogi Inc. 
300 Campus Drive 
Florham Park, NJ 07932 USA 
 
 
 
Shionogi B.V. 
Kingsfordweg 151,  
1043 GR Amsterdam  
Netherlands 
 
 
 
Clinical Research Department, Shionogi & Co., Ltd. 
1-1-4, Shibata, Kita-ku, Osaka 530-0012, Japan 
 


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Medical Monitor in 
Shionogi: 
  
 
  
300 Campus Drive 
Florham Park, NJ 07932, USA 
 
Medical Monitor CRO:  
 
 
 
 
 
 
 
 
Issue Date: 
 
Version 1: (Original) 
02 Aug 2016 
Version 2: (Amendment 1) 
21 Dec 2016 
Version 3: (Amendment 2) 
24 Jul 2017 
Version 3.1: (Amendment 
2.1) 
14 Aug 2017 
Version 3.2 RUS: 
(Amendment 2.2) 
19 Dec 2017 
Version 3.3 EU  
(Amendment 2.3) 
21 Dec 2018 
Version 3.4 RUS 
(Amendment 2.4) 
11 Jan 2019 
Version3.5 EU  
(Amendment 2.5) 
11 Jan 2019 
Version 4: (Amendment 3) 
22 Feb 2019 
* The study sponsor may be 1 or more of the above companies. Throughout the 
protocol, the term “sponsor” represents the various legal entities identified in the 
“Sponsor List of the Study Administrative Structure” in the protocol. The above 
companies are referred to as Shionogi. 
Confidentiality Statement 
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi. This Confidential Material 
should only be viewed by those individuals or companies that have been given prior 
written authorization to do so by Shionogi (“Authorized Users”). This Confidential 
Material should not be made available in any form to any person or company, other 
than the Authorized Users and their respective employees or associates on a need-to-
know basis, without the written consent from Shionogi.  
 
 


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SYNOPSIS 
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel-group, Clinical Study of S-649266 
Compared with Meropenem for the Treatment of Hospital-acquired Bacterial Pneumonia, 
Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial 
Pneumonia Caused by Gram-negative Pathogens 
Study Number: 1615R2132 
Study Phase: 3  
Primary Objective: 
• To compare all-cause mortality at Day 14 of subjects who receive S-649266 with 
that of subjects who receive the comparator, meropenem, in adults with hospital-
acquired bacterial pneumonia (HABP),ventilator-associated bacterial pneumonia 
(VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by 
Gram-negative pathogens  
Secondary Objectives: 
Key Secondary Objectives: 
• To compare the clinical outcome of treatment with S-649266 with that of 
meropenem in subjects at Test of Cure (TOC)1 
• To compare the microbiologic outcome of treatment with S-649266 with that of 
meropenem at TOC 
• To compare Day 14 all-cause mortality of S-649266 with that of meropenem for 
superiority of S-649266 
Other Secondary Objectives: 
Efficacy:  
• To compare the clinical outcome of treatment with S-649266 with that of 
meropenem in subjects at Early Assessment (EA)2, End of Treatment (EOT)3, and 
Follow-up (FU) 
• To compare the microbiologic outcome of treatment with S-649266 with that of 
meropenem at EA, EOT, and FU 
• To compare the all-cause mortality at Day 28 of subjects treated with S-649266 
with that of subjects treated with meropenem  
• To compare the all-cause mortality during treatment and the follow-up period 
(until End of Study [EOS])4 of S 649266 with that of meropenem  
 
1  TOC is defined as End of Treatment (EOT) + 7 days (± 2 days). 
2  EA is defined as start of treatment + 3 days to 4 days. 
3  EOT is defined as the last day of study treatment. 
4 
EOS is defined as the last day of the study 


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• To compare the resource utilization required for the 2 study treatments for the 
study-qualifying infection. This end point will not be included in the CSR, but it 
will be analyzed based upon a separate analytical plan after the conclusion of the 
study. 
Safety:  
• To assess the safety of S-649266 
Study Design: 
This is a Phase 3, multicenter (multinational), double-blind, parallel-group, randomized, 
active-controlled study in approximately 300 subjects with documented nosocomial 
pneumonia caused by Gram-negative bacteria. Subjects meeting eligibility criteria and 
assessed by the investigator as requiring 7 to 14 days of intravenous treatment in the 
hospital will be randomized (1:1) to either S-649266, 2 g, administered intravenously 
over 3 hours every 8 hours (q8h) or meropenem, 2 g, administered intravenously over 
3 hours, q8h. Linezolid will be administered for at least 5 days to subjects in both arms to 
provide coverage for methicillin-resistant Staphylococcus aureus (MRSA) and to 
maintain the study blind and, in the S-649266 arm, to provide coverage for Gram-positive 
bacteria. 
Study Population: 
Subjects with documented nosocomial pneumonia caused by a suspected Gram-negative 
pathogen(s) will be enrolled. 
Key Inclusion Criteria: 
Subjects who fulfill the following criteria at Screening will be included in the study: 
1. Subjects 18 years or older at the time of signing informed consent  
2. Subjects who have provided written informed consent or their informed consent 
has been provided by a legally authorized representative (Note: Country-specific 
rules and local ethics committee approval for legally authorized representative 
informed consent will determine whether or not and how a subject unable to 
comprehend or sign the informed consent is allowed to be enrolled in the study) 
3. Subjects who meet the clinical diagnosis criteria for HABP/VABP/HCABP  
4. All subjects must fulfill at least 1 of the following clinical criteria at Screening:  
a. New onset or worsening of pulmonary symptoms or signs, such as cough, 
dyspnea, tachypnea (eg, respiratory rate > 25 breaths/minute), expectorated 
sputum production, or requirement for mechanical ventilation 
b. Hypoxemia (eg, a partial pressure of oxygen [PaO2] < 60 mm Hg while the 
subject is breathing room air, as determined by arterial blood gas [ABG], or 
worsening of the ratio of the PaO2 to the fraction of inspired oxygen 
[PaO2/FiO2]) 
c. Need for acute changes in the ventilator support system to enhance 
oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2) 
or needed changes in the amount of positive end-expiratory pressure 


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d. New onset of or increase in (quantity or characteristics) suctioned respiratory 
secretions, demonstrating evidence of inflammation and absence of 
contamination 
5. All subjects must have at least 1 of the following signs: 
a. Documented fever (ie, core body temperature [tympanic, rectal, esophageal] 
≥ 38°C [100.4°F], oral temperature ≥ 37.5°C, or axillary temperature ≥ 37°C) 
b. Hypothermia (ie, core body temperature [tympanic, rectal, esophageal] ≤ 35°C 
[95.0°F], oral temperature ≤ 35.5°C and axillary temperature ≤ 36°C)  
c. Leukocytosis with a total peripheral white blood cell (WBC) count 
≥ 10,000 cells/mm3 
d. Leukopenia with total peripheral WBC count ≤ 4500 cells/mm3 
e. Greater than 15% immature neutrophils (bands) noted on peripheral blood 
smear  
6. All subjects must have a chest radiograph during Screening or have a previous 
chest radiograph within 48 hours prior to randomization showing the presence of 
new or progressive infiltrate(s) suggestive of bacterial pneumonia. A computed 
tomography (CT) scan in the same time window showing the same findings could 
also be acceptable.  
7. All subjects must have a suspected Gram-negative infection involving the lower 
respiratory tract by 1 or more of the following: 
a. Gram stain of lower respiratory secretions showing Gram-negative bacteria, 
either alone or mixed with Gram-positive bacteria at or within 72 hours prior 
to randomization 
b. Microbiologic culture of respiratory tract secretions within 72 hours prior to 
randomization identifying Gram-negative aerobic bacteria 
c. Other diagnostic tests, including molecular tests, which provide evidence of 
Gram-negative bacterial infection of the lower respiratory tract  
d. Pneumonia highly suspected to be due to Gram-negative bacteria based on 
prior antibiotic use or local epidemiologic evidence of Gram-negative 
infection outbreak 
8. Subject is male (no contraception required) or female and meets 1 of the 
following criteria: 
a. Surgically sterile (has had a hysterectomy and/or bilateral oophorectomy, or a 
bilateral salpingectomy or tubal ligation for the purpose of contraception for at 
least 6 weeks with appropriate documentation of such surgery) 
b. Postmenopausal (defined as older than 45 years of age with cessation of 
regular menstrual periods for at least 6 months and a follicle-stimulating 
hormone level of > 40 mIU/mL, or amenorrhea for at least 12 months) 
c. Of childbearing potential and using combined (estrogen and progestogen) or 
progestogen-only hormonal contraception associated with inhibition of 
ovulation (including oral, intravaginal, injectable, implantable, and 


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transdermal contraceptives), or an intrauterine device, or intrauterine 
hormone-releasing system for the entire duration of the study 
d. Of childbearing potential and practicing abstinence as a preferred and usual 
life style and agrees to continue practicing abstinence from screening for the 
entire duration of the study 
e. Of childbearing potential and whose sole heterosexual partner has been 
successfully vasectomized and agrees to not have other heterosexual partners 
for the entire duration of the study 
9. Subjects who failed empiric therapy will be allowed in this study. However, 
confirmation of both clinical and microbiological failure is necessary. 
a. Clinical failure: An investigator needs to confirm clinical failure of empiric 
treatment by clinically available information such as vital signs, physical 
examinations, laboratory data, and/or imaging 
b. Microbiological failure: Respiratory specimens from a subject need to meet 
either i OR ii: 
i. 
The lower respiratory tract specimen taken at the time of or before empiric 
therapy shows that the pathogen cultured is a Gram-negative aerobic 
bacteria, and the pathogens are resistant or intermediate to all the empiric 
antibiotics used 
ii. 
The pathogen from a specimen obtained after at least 2 calendar days of 
the empiric antibiotic regimen demonstrates that it is a Gram-negative 
aerobe, or shown in Gram stain as Gram-negative bacteria 
Exclusion Criteria  
Subjects who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Subjects who have known or suspected community-acquired bacterial pneumonia, 
atypical pneumonia, viral pneumonia, or chemical pneumonia (including 
aspiration of gastric contents, inhalation injury) 
2. Subjects who have a history of any hypersensitivity to cephalosporins or to 
carbapenems, or severe hypersensitivity to any other type of β-lactams other than 
cephalosporins and carbapenems (eg, penicillins, monobactams), or 
hypersensitivity to linezolid (Note: For β-lactams, a history of a mild rash 
followed by uneventful re-exposure is not a contraindication to enrollment)  
3. Subjects with a Gram-negative infection caused by a carbapenem-resistant 
pathogen, if known at the time of randomization (Note: Subjects who have a 
carbapenem-resistant pathogen identified after randomization should be evaluated 
clinically before discontinuation of study treatment.) 
4. Subjects with coinfection caused by invasive aspergillosis, mucormycosis or other 
highly lethal mold 
5. Subjects who have central nervous system infection (eg, meningitis, brain abscess, 
shunt infection) 
6. Subjects with cystic fibrosis  


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7. Subjects in refractory septic shock, defined as persistent hypotension despite 
adequate fluid resuscitation or despite vasopressive therapy at the time of 
randomization 
8. Subjects with neutropenia (ie, polymorphonuclear neutrophils < 500 cells/µL) 
9. Female subjects who have a positive pregnancy test at Screening, who are 
lactating, or who refuse to use 1 of the previously specified methods of 
contraception 
10. Subjects with an Acute Physiology and Chronic Health Evaluation II (APACHE) 
II score of > 35 
11. Subjects who have received potentially effective antibiotic therapy for a 
continuous duration of more than 24 hours during the previous 72 hours prior to 
randomization (Note: Subjects failing empiric therapy as defined in inclusion 
criterion 9 may be eligible for inclusion.) 
12. Subjects with any condition or circumstance that, in the opinion of the 
investigator, would compromise the safety of the subject or the quality of the 
study data 
13. Subjects receiving peritoneal dialysis (hemofiltration and hemodialysis are 
permitted) 
14. Subjects requiring continued treatment with methotrexate, procainamide, 
probenecid, monoamine oxidase inhibitors, or valproic acid (see Section 5.2) 
15. Subjects who have received another investigational drug or device within 30 days 
prior to study entry 
16. Subjects who have previously been randomized in this study or have previously 
received S-649266 
17. Subjects with 1 or more of the following laboratory abnormalities in baseline 
specimens: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase, or total bilirubin level > 3 times the upper limit of normal 
(ULN), platelet count < 40,000/μL 
18. Subjects with bronchiectasis with symptoms of persistent or recurrent bronchial 
infection related to irreversibly damaged and dilated bronchi; namely, subjects 
with clinical bronchiectasis  
19. Subjects with lung abscesses 
Test Drug, Dose, and Mode of Administration:  
S-649266 (cefiderocol), 2 g, is to be administered intravenously q8h as a 3-hour infusion 
in subjects with normal renal function. Dose adjustment for renal function or dialysis is 
required, and the dosages established by clinical testing are presented in the protocol. The 
solution volume for infusion must be at least 100 mL.  
Control Treatment, Dose, and Mode of Administration:  
The control population will be treated with meropenem. The dosing regimen will be 2 g 
as a 3-hour infusion q8h. Dosage adjustment for renal function is required. The solution 
volume for infusion must be at least 100 mL.  


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Concomitant Linezolid Treatment, Dose, and Mode of Administration:  
Linezolid 600 mg will be administered intravenously every 12 hours (q12h) over 
30 minutes to 2 hours concomitantly to provide coverage for Gram-positive bacteria in 
the S-649266 arm, to provide coverage for MRSA in both study arms, and to maintain the 
study blind. Linezolid can be discontinued after 5 days if a subject’s lower respiratory 
tract specimens do not provide evidence of Gram-positive infection when appropriate 
lower respiratory tract specimens have been obtained, and the subject is not at high risk 
for MRSA infection (eg, no prior known MRSA colonization in the lower airway, no 
prior MRSA pneumonia in the past 6 months, or low prevalence (< 10% to 20%) of 
MRSA in the healthcare facility, etc). If a subject’s lower respiratory tract specimens 
demonstrate Gram-positive infection, if respiratory specimens have not been obtained, or 
if a subject is at high risk for MRSA infection, then linezolid should be administered for 
the entire treatment period of 7 to 14 days along with S-649266 or meropenem. 
Duration of Treatment: 
The treatment duration for S-649266 or meropenem is anticipated to be 7 to 14 days, 
which is consistent with published treatment guidelines for HABP/VABP/HCABP 
infections. Based on the investigator’s clinical assessment of the subject and a clear 
reason being documented in the electronic case report form, treatment may be extended 
up to 21 days. All study treatments are to be administered in the hospital. 
Prohibited Concomitant Therapy: 
• Systemic antibiotics, other than linezolid, meropenem, and S-649266, are not 
permitted from randomization until TOC 
• Aerosolized antibiotics are not permitted from randomization until after TOC 
• Probenecid, methotrexate, procainamide, monoamine oxidase inhibitors, and 
valproic acid are not permitted from Screening until EOT 
Efficacy Assessment: 
In addition to the 14-day all-cause mortality (primary efficacy endpoint), both clinical 
and microbiological outcomes will be assessed by the investigator at EA, EOT, TOC, and 
FU. If case study treatment duration is extended beyond 14 days, an additional clinical 
and microbiological outcome will be assessed on Day 14.  
Pharmacokinetic Assessments: 
All subjects will have blood drawn for sparse sampling of plasma concentrations of 
S-649266 for pharmacokinetic assessment. Pharmacokinetic blood sampling will 
preferably be performed on Day 3 or 4. The following is the schedule for the sampling 
time points:  
(1) Just prior to the start of the 3-hour infusion  
(2) 1 hour after the start of infusion  
(3) Before the end of infusion 
(4) 1 hour after the end of infusion  
The actual sampling date and time will be recorded. 
The pharmacokinetic sampling will be repeated when/if the drug dosage was changed due 


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to changes in renal function determined at EA; this should occur 24 to 72 hours after the 
change in dosing regimen.  
In the case of premature EOT, a single blood sampling should be performed, if possible, 
as soon as possible at EOT (within 24 hours), which is defined as receiving < 7 days of 
intravenous treatment with either S-649266 or meropenem. 
Safety Assessments: 
Subject safety will be assessed from the time of having signed informed consent to the 
end of the study by identifying adverse events (AEs) with the addition of physical and 
laboratory evaluations, which include multiple electrocardiograms obtained early in the 
treatment with study drug. 
In case treatment duration is extended beyond 14 days, additional safety assessments will 
be conducted on Day 14. Safety surveillance will extend up to 28 days after the last dose 
of the drug treatment.  
Statistical Methods: 
For the primary efficacy endpoint, the adjusted estimates of the difference in the all-cause 
mortality at Day 14 between S-649266 and meropenem will be presented along with 95% 
confidence intervals (CIs) based on a stratified analysis using Cochran-Mantel-Haenszel 
(CMH) weights. The CI will be 2-sided. The CMH weights will be calculated with the 
stratification factor: APACHE II score (≤ 15 and ≥ 16).  
Sample Size: 
The study design and the primary objective are based on a 12.5% noninferiority margin to 
exclude the possibility that S-649266 is more than 12.5% inferior to meropenem for the 
endpoint of all-cause mortality at Day 14.  
A sample size of 244 evaluable subjects (122 evaluable subjects in the S-649266 group 
and 122 evaluable subjects in the meropenem group) is required to have 90% power with 
a 1-sided significance level of 0.025 assuming a 10% all-cause mortality rate at Day 14 in 
both groups with a 12.5% noninferiority margin. It is further estimated that 
approximately 20% of randomized subjects will be nonevaluable, and therefore excluded 
from the primary population, because they have not received any doses of a study drug 
treatment, or they had a bacterial pneumonia caused by anaerobic and/or Gram-positive 
aerobic bacteria only. Therefore, it is expected that it will be necessary to randomize up 
to 300 subjects. The nonevaluable rate will be assessed based on a blinded estimate 
performed after approximately 150 subjects are enrolled and the randomized population 
size may be adjusted to meet study requirements. Additionally, the sponsor will conduct a 
blinded evaluation of all-cause mortality after approximately 150 subjects are enrolled 
and may perform a blinded re-estimation of sample size if deemed necessary. 
Stratification at Randomization:  
Randomization will be performed by the stratified randomization method using the 
infection diagnosis (HABP/VABP/HCABP) and APACHE II score (≤ 15 and ≥ 16) as 
allocation factors. 


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Safety and Efficacy Evaluation: 
When approximately 50 and 150 subjects have completed treatment and the FU visit, an 
evaluation of safety and efficacy data will be performed by the Data Safety Monitoring 
Board (DSMB) according to the DSMB charter. After the review, the DSMB will 
communicate their recommendation(s) to the sponsor.  
Number of Study Sites/Countries: 
It is estimated that approximately 135 study sites from around the world will participate 
in this clinical study. 
Study Duration:  
Study duration for individual subjects: approximately 5 to 7 weeks 
Planned duration of the study: approximately 26 months (24 months for enrollment and 
5 to 7 weeks to complete the study) 
Date of Original (Version 1): 02 Aug 2016 
Date of Latest Amendment: 22 Feb 2019 
 
 


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TABLE OF CONTENTS 
SYNOPSIS .......................................................................................................................... 3 
TABLE OF CONTENTS .................................................................................................. 11 
LIST OF IN-TEXT TABLES ........................................................................................... 16 
LIST OF IN-TEXT FIGURES .......................................................................................... 16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 17 
GLOSSARY ..................................................................................................................... 20 
1. 
INTRODUCTION .................................................................................................... 21 
1.1 
Background and Rationale .............................................................................. 21 
1.2 
Biological Features of S-649266 for Injection ................................................ 22 
1.3 
Nonclinical Experience ................................................................................... 24 
1.3.1 
Pharmacokinetics/Pharmacodynamics .................................................. 26 
1.3.1.1 
Animal Models of Efficacy ......................................................... 26 
1.4 
Clinical Experience ......................................................................................... 28 
1.4.1 
Phase 1 .................................................................................................. 28 
1.4.2 
Phase 2 and Phase 3 .............................................................................. 29 
1.4.2.1 
Phase 2 Complicated Urinary Tract Infections ........................... 29 
1.4.2.2 
Phase 3 ........................................................................................ 29 
2. 
STUDY OBJECTIVES ............................................................................................. 30 
2.1 
Primary Objective ........................................................................................... 30 
2.2 
Secondary Objectives ...................................................................................... 30 
2.2.1 
Key Secondary Objectives .................................................................... 30 
2.2.2 
Other Secondary Objectives ................................................................. 30 
3. 
INVESTIGATIONAL PLAN ................................................................................... 31 
3.1 
Overall Study Design and Plan ....................................................................... 31 
3.2 
Rationale for Study Design and Control Group .............................................. 32 
3.2.1 
Rationale for Subject Population .......................................................... 32 
3.2.2 
S-649266 Dose Regimen ...................................................................... 32 
3.2.3 
Meropenem Dose Regimens ................................................................. 34 
3.2.4 
Linezolid Dose Regimens ..................................................................... 35 
3.2.5 
Duration of Study Treatment ................................................................ 35 
3.3 
Study Duration ................................................................................................ 36 
3.3.1 
Study Duration in Individual Subjects .................................................. 36 
3.3.2 
Planned Study Duration for the Study .................................................. 36 
4. 
STUDY POPULATION SELECTION .................................................................... 36 
4.1 
Study Population ............................................................................................. 36 
4.2 
Inclusion Criteria ............................................................................................ 37 


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4.3 
Exclusion Criteria ........................................................................................... 39 
4.4 
Screen Failures ................................................................................................ 40 
5. 
STUDY TREATMENTS .......................................................................................... 40 
5.1 
Description of Treatments ............................................................................... 40 
5.1.1 
Test Drug .............................................................................................. 40 
5.1.2 
Control Treatment ................................................................................. 40 
5.1.3 
Linezolid Treatment .............................................................................. 40 
5.2 
Treatments to Be Administered ...................................................................... 41 
5.2.1 
S-649266 Group .................................................................................... 41 
5.2.2 
Meropenem Group ................................................................................ 41 
5.2.3 
Linezolid ............................................................................................... 42 
5.3 
Selection and Timing of Dose for Each Subject ............................................. 42 
5.3.1 
S-649266 Dosing .................................................................................. 42 
5.3.2 
Meropenem Dosing ............................................................................... 42 
5.3.3 
Linezolid Dosing ................................................................................... 43 
5.4 
Randomization to Treatment Groups .............................................................. 45 
5.5 
Blinding ........................................................................................................... 46 
5.6 
Packaging and Labeling .................................................................................. 47 
5.7 
Storage and Accountability ............................................................................. 47 
5.7.1 
S-649266 Treatment Arm ..................................................................... 47 
5.7.2 
Meropenem Treatment Arm ................................................................. 47 
5.7.3 
Linezolid Treatment .............................................................................. 47 
5.8 
Investigational Product Retention at Study Site ............................................. 47 
5.9 
Treatment Compliance .................................................................................... 48 
5.9.1 
Changes in Treatment Regimen ............................................................ 48 
6. 
RESTRICTIONS ...................................................................................................... 48 
6.1 
Prior Therapy .................................................................................................. 48 
6.2 
Concomitant Therapy during the Study .......................................................... 48 
6.2.1 
Antibiotic Therapies .............................................................................. 48 
6.2.2 
Nonantibiotic Therapies and Procedures .............................................. 49 
6.2.3 
Prohibited Therapy ................................................................................ 49 
6.2.4 
Rescue Therapy ..................................................................................... 50 
7. 
STUDY PROCEDURES AND METHODS OF ASSESSMENTS ......................... 50 
7.1 
Informed Consent ............................................................................................ 50 
7.2 
Baseline Subject Characteristics and Medical History ................................... 51 
7.2.1 
Hospitalization ...................................................................................... 51 
7.3 
Enrollment in the Study and Dispensing Study Drug Treatments .................. 51 
7.4 
Efficacy Assessments ...................................................................................... 51 


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7.4.1 
Specific Evaluations .............................................................................. 51 
7.4.1.1 
Survival ....................................................................................... 52 
7.4.1.2 
Sequential Organ Failure Assessment ........................................ 52 
7.4.1.3 
Oxygenation Status ..................................................................... 52 
7.4.1.4 
Clinical Assessment of Signs and/or Symptoms ........................ 52 
7.4.1.5 
Vital Signs ................................................................................... 53 
7.4.1.6 
Clinical Pulmonary Infection Score ............................................ 53 
7.4.1.7 
Chest Radiographs ...................................................................... 53 
7.4.2 
Efficacy Criteria for Clinical Outcomes for Early Assessment, End 
of Treatment, and Test of Cure ............................................................. 53 
7.4.3 
Clinical Outcomes for Follow-up ......................................................... 54 
7.4.4 
Microbiological Outcomes for Early Assessment, End of Treatment, 
and Test of Cure .................................................................................... 54 
7.4.5 
Microbiological Outcomes for Follow-up ............................................ 55 
7.5 
Pharmacokinetic Assessments ........................................................................ 55 
7.6 
Safety Assessments ......................................................................................... 56 
7.6.1 
Physical Examinations .......................................................................... 56 
7.6.1.1 
Glasgow Coma Scale .................................................................. 56 
7.6.1.2 
APACHE II Score ....................................................................... 56 
7.6.2 
Vital Sign Measurements ...................................................................... 56 
7.6.3 
Electrocardiography .............................................................................. 56 
7.6.4 
Clinical Laboratory Tests ...................................................................... 57 
7.6.4.1 
Laboratory Parameters ................................................................ 57 
7.6.4.2 
Microbiologic Cultures ............................................................... 57 
7.6.4.3 
Routine Laboratory Tests ............................................................ 59 
7.6.4.4 
Creatinine Clearance ................................................................... 59 
7.6.5 
Adverse Event Assessments ................................................................. 60 
7.6.5.1 
Performing Adverse Event Assessments .................................... 60 
7.6.5.2 
Timing ......................................................................................... 61 
7.6.5.3 
Severity ....................................................................................... 61 
7.6.5.4 
Relationship ................................................................................ 62 
7.6.5.5 
Expectedness ............................................................................... 62 
7.6.6 
Clinical Laboratory Adverse Events ..................................................... 62 
7.6.6.1 
Liver Abnormalities .................................................................... 63 
7.6.7 
Serious Adverse Events ........................................................................ 63 
7.6.7.1 
Definition .................................................................................... 63 
7.6.7.2 
Reporting Serious Adverse Events ............................................. 64 


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7.6.7.3 
Special Situations - Abuse, Misuse, Overdose, and 
Medication Error ......................................................................... 65 
7.6.7.4 
Pregnancy .................................................................................... 65 
7.6.7.5 
Treatment-emergent Adverse Events .......................................... 66 
7.7 
Subject Withdrawal or Discontinuation from the Study Treatment ............... 66 
7.8 
Other Study Procedures .................................................................................. 67 
7.9 
Appropriateness of Measurements .................................................................. 67 
7.10 
Acceptable Time Windows ............................................................................. 67 
8. 
STUDY ACTIVITIES .............................................................................................. 68 
8.1 
Screening (Day –2 to Randomization) ............................................................ 69 
8.2 
Treatment Period (Days 1 to 14) ..................................................................... 69 
8.2.1 
Randomization and Treatment Initiation (Day 1) ................................. 69 
8.2.2 
All Treatment Days ............................................................................... 69 
8.2.3 
Treatment Day 3 or Day 4 .................................................................... 70 
8.2.4 
Early Assessment (Occurs Once at the Investigator’s Discretion 
During Day 3 or 4) ................................................................................ 70 
8.2.5 
Treatment Day 14 (If Not End of Treatment) ....................................... 70 
8.2.6 
End of Treatment (Last Day of Study Treatment) ................................ 71 
8.3 
Study Day 14 (14 Days After Initiation of Treatment) ................................... 71 
8.4 
Test of Cure (End of Treatment + 7 Days) ..................................................... 71 
8.5 
Follow-up (End of Treatment + 14 Days) ....................................................... 72 
8.6 
Study Day 28 (28 Days After Initiation of Treatment) ................................... 73 
8.7 
End of Study (End of Treatment + 28 Days) .................................................. 73 
9. 
PLANNED STATISTICAL METHODS ................................................................. 73 
9.1 
General Considerations ................................................................................... 73 
9.2 
Determination of Sample Size ........................................................................ 74 
9.3 
Analysis Populations ....................................................................................... 74 
9.4 
Handling of Missing Data ............................................................................... 75 
9.5 
Subject Disposition ......................................................................................... 75 
9.6 
Demographic and Baseline Characteristics .................................................... 75 
9.7 
Prior Therapies ................................................................................................ 75 
9.8 
Concomitant Therapies ................................................................................... 76 
9.9 
Efficacy Analyses ........................................................................................... 76 
9.9.1 
Primary Efficacy Endpoint ................................................................... 76 
9.9.2 
Key Secondary Endpoints ..................................................................... 76 
9.9.3 
Other Secondary Efficacy Endpoints .................................................... 77 
9.10 
Safety Analyses ............................................................................................... 77 
9.10.1 
Adverse Events ..................................................................................... 77 


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9.10.2 
Vital Signs ............................................................................................. 78 
9.10.3 
Clinical Laboratory Analysis ................................................................ 78 
9.11 
Pharmacokinetics ............................................................................................ 78 
9.12 
Pharmacokinetic/Pharmacodynamic Analyses ............................................... 78 
9.13 
Pharmacoeconomics Associated with Treatment ........................................... 78 
9.14 
Data Safety Monitoring Board Safety and Efficacy Evaluation ..................... 79 
9.15 
Interim Analysis .............................................................................................. 79 
10. ADMINISTRATIVE CONSIDERATIONS ............................................................. 79 
10.1 
Investigators and Study Administrative Structure .......................................... 79 
10.2 
Institutional Review Board or Institutional Ethics Committee Approval ....... 80 
10.3 
Ethical Conduct of the Study .......................................................................... 81 
10.4 
Subject Information and Consent .................................................................... 81 
10.5 
Subject Confidentiality ................................................................................... 81 
10.6 
Study Monitoring ............................................................................................ 82 
10.7 
Case Report Forms and Source Documents .................................................... 82 
10.7.1 
Case Report Forms ................................................................................ 82 
10.7.2 
Source Documents ................................................................................ 82 
10.7.3 
External Data ........................................................................................ 83 
10.8 
Committees ..................................................................................................... 83 
10.8.1 
Independent Data Safety Monitoring Board ......................................... 83 
10.9 
Termination or Suspension of the Study ......................................................... 83 
10.9.1 
Termination or Suspension of the Entire Study .................................... 83 
10.9.2 
Termination or Suspension of the Study by Medical Institution .......... 84 
10.10 Protocol Deviations and Modifications .......................................................... 84 
10.11 Data Management ........................................................................................... 85 
10.12 Retention of Data ............................................................................................ 85 
10.13 Quality Control and Assurance ....................................................................... 85 
10.14 Publication and Disclosure Policy .................................................................. 85 
10.15 Financial Disclosure ........................................................................................ 86 
11. REFERENCE LIST .................................................................................................. 87 
Appendix 1 
Time and Events Schedule .................................................................... 90 
Appendix 2 
Glasgow Coma Scale ............................................................................ 93 
Appendix 3 
APACHE II Score ................................................................................. 94 
Appendix 4 
Sequential Organ Failure Assessment Score ........................................ 96 
Appendix 5 
Clinical Pulmonary Infection Score Parameters ................................... 97 
Appendix 6 
Management and Discontinuation Criteria for Abnormal Liver 
Function Tests ...................................................................................... 98 
Appendix 7 
Empiric Therapy Case: Eligibility Flow Chart ................................... 100 


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Appendix 8 
Sponsor Signature ............................................................................... 101 
Appendix 9 
Investigator’s Signature ...................................................................... 102 
 
LIST OF IN-TEXT TABLES 
Table 3-1 
Probability of Target Attainment for Subjects with 
Augmented Renal Clearance ....................................................... 34 
Table 5-1 
S-649266 Dosing Adjustments for Various Degrees of Renal 
Function and Augmented Renal Clearance ................................. 44 
Table 5-2 
Meropenem Dosing Adjustments for Various Degrees of 
Renal Function ............................................................................ 45 
Table 7-1 
Routine Laboratory Tests ............................................................ 59 
Table 7-2 
Acceptable Time Windows ......................................................... 68 
 
LIST OF IN-TEXT FIGURES 
Figure 1-1 
Depiction of Cefiderocol Cell Entry and Mechanism of Action 23 
Figure 1-2 
Efficacy of S-649266 (Human 3- and 1-hr Infusion of 2 g IV 
q8h) Compared with Meropenem (Human 1 g IV q8h) 
Against K. pneumoniae VA-384 in a Respiratory Tract 
Infection Model in Cannulated Rats ........................................... 27 
Figure 3-1 
Study Schematic .......................................................................... 32 
Figure 3-2 
Probability of Target Attainment for 50% or 75% fT>MIC .......... 33 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
%fT>MIC 
percentage of the dosing interval for which the free-drug 
concentration in plasma exceeds the minimum inhibitory 
concentration  
ΔΔQTcF 
baseline and placebo corrected QTc interval(s) calculated using 
Fridericia's correction 
ABG 
arterial blood gas 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
ARC 
augmented renal clearance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BAL 
bronchoalveolar lavage 
BLA 
β-lactamase 
C0 
concentration at the end of infusion 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CPIS 
Clinical Pulmonary Infection Score 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CT 
computed tomography 
cUTI 
complicated urinary tract infection 
DDI 
drug-drug interaction 
DMPK 
drug metabolism and pharmacokinetics 
DSMB 
Data Safety Monitoring Board 
EA 
Early Assessment 
ECG 
electrocardiogram/electrocardiography 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate  
ELF 
epithelial lining fluid 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
ETA 
endotracheal aspiration 
FDA 
Food and Drug Administration 


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FiO2 
fraction of inspired oxygen 
FU 
Follow-up evaluation at end of treatment + 14 days 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
HABP 
hospital-acquired bacterial pneumonia 
HCABP 
healthcare-associated bacterial pneumonia 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IEC 
Institutional Ethics Committee 
IgM 
immunoglobulin M 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous  
KPC 
Klebsiella pneumoniae carbapenemase 
LS 
least squares  
MATE 
multidrug and toxin extrusion transporter 
MATE2-K 
multidrug and toxin extrusion protein 2 
MDR 
multidrug resistant 
MDRD 
modification of diet in renal disease 
ME-PP 
microbiological-evaluable per-protocol 
MIC 
minimum inhibitory concentration 
mITT 
modified intent-to-treat 
MRSA 
methicillin-resistant Staphylococcus aureus 
NOAEL  
no-observed-adverse-effect-level 
OAT1 
organic anion transporter 1 
OAT3 
organic anion transporter 3 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
OCT1 
organic cation transporter 1 
OCT2 
organic cation transporter 2 
P-gp 
P-glycoprotein  
PaO2 
partial pressure of oxygen 
PD  
pharmacodynamic 
PK 
pharmacokinetic 
PT-INR 
prothrombin time-international normalized ratio 
PSB 
protected specimen brush  


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q6h 
every 6 hours 
q8h 
every 8 hours 
q12h 
every 12 hours 
QTc 
corrected QT interval 
QTcF 
Fridericia’s correction formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
serum creatinine concentration 
SOFA 
Sequential Organ Failure Assessment  
SmPC or SPC 
Summary of Product Characteristics  
TBL 
total bilirubin level 
TEAE 
treatment-emergent adverse event 
TOC 
Test of Cure 
TQT 
thorough QT 
TQTc 
corrected thorough QT/QTc  
uCr 
urinary creatinine concentration 
ULN 
upper limit of normal 
VABP 
ventilator-associated bacterial pneumonia 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary  
XDR 
extensively drug-resistant 
 


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GLOSSARY 
Augmented renal 
clearance (ARC) 
Augmented renal clearance describes a hyperdynamic 
cardiovascular state as a consequence of systemic 
inflammatory response associated with increased perfusion of 
the kidneys resulting in increases in the glomerular filtration 
rate and enhanced renal elimination of circulating solutes, 
including antibiotics. This phenomenon is known as renal 
hyperfiltration, or ARC. In this protocol, ARC is defined as 
estimated glomerular filtration rate (≥ 90 mL/min/1.73 m2) 
and a creatinine clearance (CrCl > 120 mL/min). 
Carbapenem 
resistance 
Carbapenem resistance is defined by the in vitro susceptibility 
phenotype (minimum inhibitory concentration [MIC], E-test, 
disc diffusion) and subject to the approved breakpoints for 
carbapenems in the respective countries. For this study, 
intermediate breakpoints to imipenem/cilastatin, doripenem, 
or meropenem are classified as carbapenem-susceptible.  
Comparator  
drug 
Comparator drug refers to meropenem, which is an antibiotic 
approved by regulatory agencies for the treatment of bacterial 
infections. 
Concomitant 
antibiotic 
A concomitant antibiotic is an antibiotic added to the primary 
Gram-negative antibiotic treatment regimen to treat 
Gram-positive bacterial infections. Only linezolid will be 
allowed and used in both treatment arms. 
Effective antibiotic 
The term “effective antibiotic” refers to an antibiotic to which 
the specific pathogen is susceptible based on in vitro 
susceptibility test methods performed by the local 
microbiology laboratory. 
Nosocomial infection A nosocomial infection is an infection that is contracted from 
the environment or staff of a healthcare facility. It can be 
spread in the hospital environment, nursing home 
environment, rehabilitation facility, clinic, or other clinical 
settings.  
Study drug 
Study drug refers to S-649266  
Study treatment 
Study treatment refers to either S-649266 or meropenem 
therapy and includes the use of linezolid in both treatment 
groups.  
 


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1. INTRODUCTION 
1.1 
Background and Rationale 
The ability to treat bacterial infections due to multidrug resistant (MDR) and extensively 
drug-resistant (XDR) Gram-negative bacteria, including Enterobacteriaceae and the 
nonfermenters Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and 
Acinetobacter baumannii, is a critical and growing unmet medical need. In particular, the 
emergence of resistance to carbapenems in Gram-negative bacteria, including 
Enterobacteriaceae, Pseudomonas, and Acinetobacter species, over the last decade has 
become a major concern worldwide, because of its rapid spread and the lack of 
development of new antimicrobial drugs effective in this area [1].  
Since the description of imipenemase-1, a metallo-β-lactamase (BLA), in P. aeruginosa, 
oxacillinase-23, a serine carbapenemase, in A. baumannii, and Klebsiella pneumoniae 
carbapenemase-1 (KPC-1), a serine carbapenemase, in K. pneumoniae, 
carbapenemase-encoding genes have spread worldwide and are now distributed 
throughout different species of Gram-negative MDR bacteria. They are now responsible 
for a large and increasing number of nosocomial infections. These carbapenemases 
inhibit almost all β-lactam antibiotics, including carbapenems, and are reported mainly in 
Enterobacteriaceae, A. baumannii, and P. aeruginosa [1]. 
Although most reports of β-lactam resistance focus on hydrolyzing enzymes, 2 other 
mechanisms of resistance are important when considering the overall phenotype of 
Gram-negative resistance among the β-lactam classes and other classes of antibiotics. 
These include porin channel mutants (entrance channels for antibiotics and important 
bacterial nutrients) and efflux pumps (exit channels with active excretion mechanisms for 
removal of antibiotics from the bacterial cells). They are particularly prevalent among 
XDR P. aeruginosa [2, 3]. Not infrequently, more than 1 β-lactam resistance mechanisms 
exist in the same bacterial strain. 
In 2011, Nordmann et al observed that carbapenemases had been reported increasingly in 
Enterobacteriaceae during the previous 10 years and that their spread across the world 
was of great concern. They concluded that society was now at the edge of 2 concomitant 
epidemics of carbapenemase-producers worldwide; the first to be caused mainly by 
carbapenemase-producing Escherichia coli as a source of community-acquired infections, 
and the second, likely to be caused mainly by nosocomial carbapenemase-producing 
K. pneumoniae of all types [4].  
The outcome of a carbapenem-resistant infection can often be fatal. Falagas et al 
calculated that 26% to 44% of deaths in 7 studies were attributable to carbapenem 
resistance. A pooled analysis of 9 studies showed that the death rate was higher among 
those subjects infected with carbapenem-resistant Enterobacteriaceae than those infected 
with carbapenem-susceptible Enterobacteriaceae (relative risk 2.05, 95% confidence 
interval [CI] 1.56 to 2.69) [5]. 


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S-649266 has an approved international nonproprietary name: cefiderocol. For purposes 
of this protocol, S-649266 will be used to refer to the study drug.  
S-649266 is being developed to address the unmet medical need to treat 
carbapenem-resistant infections caused by Gram-negative bacteria, including 
Enterobacteriaceae, Pseudomonas, Stenotrophomonas, and Acinetobacter species 
independent of the underlying mechanism of carbapenem resistance. Although S-649266 
was designed to have bacterial-killing ability for carbapenem-resistant species of 
Gram-negative bacteria, it also has improved bacterial-killing ability for common 
community-acquired Gram-negative infections, as demonstrated by reduced minimum 
inhibitory concentration (MIC) values (for additional information refer to the current 
Investigator’s Brochure).  
1.2 
Biological Features of S-649266 for Injection 
S-649266 is an injectable siderophore cephalosporin discovered and being developed by 
Shionogi & Co., Ltd., Osaka, Japan. The antibacterial activity of S-649266 is based on 
the inhibition of Gram-negative bacterial cell wall synthesis.  
The chemical structure of S-649266 is similar to cefepime, which is a fourth-generation 
cephalosporin with an extended spectrum of activity against Gram-positive and 
Gram-negative bacteria with greater activity against both types of organisms than 
third-generation agents. The major difference in the chemical structure of S-649266 
compared with cefepime is the presence of a catechol group on the side chain at 
position 3. S-649266 also has a pyrrolidinium group in the side chain at position 3 and 
a carboxypropanoxyimino group in the side chain at position 7 of the cephem nucleus. As 
a consequence of its structure, S-649266 has the following features in addition to the 
basic mechanism of action to inhibit cell wall synthesis: 
1. A unique mode of action, which enhances entry into the periplasmic space of 
Gram-negative aerobic bacteria through the outer cell membrane. S-649266 forms 
complexes with trivalent iron and is transported via the active iron transport 
system common to Gram-negative bacteria. In this way, it also overcomes other 
mechanisms of resistance such as porin channel loss and efflux pumps. 
2. Enhanced stability against BLA enzymes, including carbapenemases of the serine 
or metallo-BLA classes. 
3. Enhanced activity against aerobic Gram-negative bacteria, especially 
Enterobacteriaceae, particularly K. pneumoniae and E. coli, and the nonfermenters 
P. aeruginosa, S. maltophilia, and A. baumannii. 
4. No activity against Gram-positive bacteria and anaerobic bacteria.  
The host’s innate immune response to bacterial infection is to remove or severely limit 
the available free iron, an essential cation for bacterial growth [6]. In response, bacteria 
upregulate the production of extracellular molecules called siderophores that scavenge for 
available free iron [7]. S-649266 is a siderophore compound that binds free iron, and this 
antibiotic-iron complex is transported through the outer membrane of Gram-negative 


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bacteria into the periplasmic space using the bacteria’s active siderophore transport 
system [2, 6-11]. A graphic depiction of this process is presented in Figure 1-1. This 
process achieves bactericidal concentrations at relatively low blood concentrations of 
S-649266. Once inside the periplasmic space of the Gram-negative bacteria, S-649266 is 
resistant to the usual mechanisms of degradation of β-lactam or carbapenem antibiotics 
by bacterial BLAs. The primary bactericidal activity is due to inhibition of bacterial cell 
wall synthesis. 
Figure 1-1 
Depiction of Cefiderocol Cell Entry and Mechanism of 
Action  
 
Source: Shionogi Inc. 
The greatest current unmet medical need is in the treatment of bacterial infections caused 
by MDR aerobic Gram-negative bacilli, broadly including the Enterobacteriaceae and the 
nonfermenters P. aeruginosa, S. maltophilia, and A. baumannii. Multidrug resistant 
bacteria, defined as > 3 class antibiotic resistance, include most Enterobacteriaceae 
producing AmpC, extended-spectrum BLAs, and serine BLAs. While they may be 
resistant to penicillins, cephalosporins, fluoroquinolones, and aminoglycosides, they 
have, for the most part, remained susceptible to carbapenems [2, 10, 11]. More recently, 
these same Enterobacteriaceae, particularly K. pneumoniae and E. coli, have acquired 
serine KPCs, oxacillinases, and metallo-BLAs (eg, Verona integron-encoded 


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metallo-BLA, imipenemase, and New Delhi metallo-BLA-1) capable of hydrolyzing 
carbapenems [12-14]. Most of these bacteria remain susceptible only to polymyxins 
(polymyxin B or colistin), and thus should be considered XDR, not just MDR. The 
nonfermenters P. aeruginosa, S. maltophilia, and A. baumannii have also acquired 
carbapenemases and are also considered XDR bacteria [15]. Rarely, these XDR 
pathogens may also be resistant to polymyxins, and, therefore, can be considered pandrug 
resistant organisms, defined as resistant to all classes [15, 16]. 
The principal objective for S-649266 clinical development is to demonstrate efficacy for 
the treatment of serious, life-threatening infections caused by Gram-negative bacteria, 
including Enterobacteriaceae and nonfermenters, such as P. aeruginosa, S. maltophilia, 
and A. baumannii. One of the most serious of these infections is pneumonia. 
Gram-negative pneumonia is almost always nosocomial, meaning it is associated with 
prior or current hospitalization or other contact with healthcare services [17]. Variably 
defined as hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial 
pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP), when the 
infection is caused by Gram-negative bacteria, the outcomes are especially dire, with 
mortality rates approaching 60% [17-21]. Increasing antibiotic resistance among 
Gram-negative organisms, particularly that to aminoglycosides, fluoroquinolones, and 
cephalosporins, has limited therapeutic options to carbapenems and polymyxins [17-25]. 
Clinical trials in HABP/VABP/HCABP are particularly challenging due to the severity of 
illness, preexisting comorbidities, and controversies over study endpoints [26]. Recent 
clinical trials have failed to meet predefined endpoints for noninferiority (tigecycline, 
doripenem). Despite these setbacks, the need for new antibiotic treatments for 
Gram-negative infections has resulted in renewed interest in HABP/VABP as an 
important area for clinical investigation. Both the Food and Drug Administration (FDA) 
and the European Medicines Agency (EMA) have updated their clinical trial guidelines 
for these indications [27, 28]. 
1.3 
Nonclinical Experience 
In vitro, S-649266 showed potent antibacterial activity against carbapenem-resistant 
Enterobacteriaceae, including metallo-BLA producing isolates, MDR A. baumannii, and 
MDR P. aeruginosa. S-649266 also showed more robust antibacterial activity than other 
β-lactam antibiotics in systemic, lung, urinary tract, and subcutaneous animal models of 
infection due to MDR P. aeruginosa, carbapenem-resistant A. baumannii, or enteric 
bacteria, such as extended-spectrum BLA-producing E. coli and K. pneumoniae.  
The safety and drug metabolism and pharmacokinetics (DMPK) profiles of S-649266 
have been evaluated in toxicity studies (general toxicity, reproductive and developmental 
toxicity, genotoxicity, and antigenicity), safety pharmacology studies, and DMPK 
studies. No severe toxic changes were observed in the rat and monkey 2-week and 
1-month intravenous toxicity studies, the monkey 3-month intravenous toxicity study, the 
safety pharmacology studies, and the antigenicity study.  
In the rat 3-month intravenous toxicity study (doses levels: 0, 300, 1000, and 
1500 mg/kg/day), convulsions and subsequent deaths were noted at 1000 and 


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1500 mg/kg/day. In order to assess more in depth the dose-response relationship of 
convulsions between 300 and 1000 mg/kg/day, a supplemental 3-month intravenous 
toxicity study was conducted in rats with intermediate dose levels at 500 and 
750 mg/kg/day. The study showed neither convulsion nor death at either dose level. 
Overall, the no-observed-adverse-effect-level (NOAEL) was judged to be 750 mg/kg/day 
in rat 3-month toxicity studies. The concentration at the end of infusion (C0) value at 
750 mg/kg (1500 or 1610 µg/mL, values of the last day of dosing in the supplemental 
3-month toxicity study) was approximately 17-fold of the maximum plasma 
concentration (Cmax) value in humans (89.7 µg/mL from the thorough QT [TQT] study 
[R2116] at the intended clinical dosing regimen (2 g, infused over 3 hours, 3 times daily). 
In the monkey cardiovascular safety pharmacology study and 2-week, 1-month, and 
3-month intravenous toxicity studies, an increase in the corrected QT interval (QTc) was 
observed at the highest doses of 600 or 1000 mg/kg; no QTc interval prolongation was 
observed at the next lower dose of 300 mg/kg in any of these studies, which was 
considered to be the study’s NOAEL, and provides approximately a 9- to 10-fold margin 
relative to the Cmax of S-649266 in the currently proposed study (eg, C0 of 770 to 
876 μg/mL, values on the last day of dosing in the repeat-dose toxicity studies vs the Cmax 
of 89.7 µg/mL at the intended clinical dose of 2 g, infused over 3 hours, from the TQT 
study [R2116]). No dose-dependent increases in the QTc interval were observed in these 
studies. The TQT study, which was subsequently performed, was negative (ie, without 
any clinically significant increase in the QTc interval of regulatory concern [refer to 
Section 1.4.]) 
In a fertility and early embryonic development study in rats treated intravenously with up 
to 1000 mg/kg/day of S-649266, no adverse findings were observed.  
In studies for effects on embryo-fetal development in rats (dose levels: 0, 100, 300, and 
1000 mg/kg/day, intravenous injection) and mice (dose levels: 0 , 500, 1000, and 
2000 mg/kg/day [0, 250, 500, or 1000 mg/kg/injection, twice a day]; 6 hours apart 
subcutaneous injection), there were no deaths in dams and no treatment-related changes 
in fetal viability, including external, visceral, or skeletal morphology of fetuses. As 
described above, there was no evidence of embryo-fetal lethality or teratogenicity in mice 
or rats.  
In a pre- and postnatal development study in rats treated intravenously with up to 
1000 mg/kg/day of S-649266, no effects on parturition and nursing on dams, and pre- and 
postnatal development of offspring were observed and the NOAEL was judged to be 
1000 mg/kg/day for pre- and postnatal development in offspring. 
Positive reactions were observed in the in vitro chromosomal aberration tests and mouse 
lymphoma cell line (L5178Y tk+/− 3.7.2C) assay at high drug concentrations, but 
genotoxicity risk of S-649266 in humans was judged to be low, because the results of the 
bacterial reverse mutation test and the hypoxanthine-guanine phosphoribosyltransferase 
gene mutation assay were negative. In addition, the results of the in vivo rat micronucleus 
test and the rat comet assay were negative.  


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In the rat micronucleus test, death and acute symptoms, including convulsions, occurred 
only at the highest single dose (2000 mg/kg). Because death and these acute symptoms 
did not occur at 1000 mg/kg twice a day (total 2000 mg/kg), they were judged to be 
caused by high plasma concentration immediately after administration rather than total 
drug exposure represented by area under the concentration-time curve (AUC). 
Based on the DMPK studies in rats and monkeys, S-649266 is rapidly and widely 
distributed in the whole body and is mainly excreted in urine as unchanged drug. In 
addition, S-649266 did not inhibit major cytochrome P450 drug metabolizing enzymes. 
S-649266 is not an inhibitor of P-glycoprotein (P-gp).  
As S-649266 is not a substrate for human P-gp, organic anion transporter 1 (OAT1), 
organic anion transporter 3 (OAT3), organic cation transporter 2 (OCT2), multidrug and 
toxin extrusion 1 (MATE1), or multidrug and toxin extrusion protein 2 (MATE2-K), 
the risk for drug-drug interactions (DDIs) with S-649266 mediated by these transporters 
is low. Since S-649266 is not an inhibitor for human P-gp or bile salt export pump, the 
risk of a DDI with S-649266 as a perturbator of these transporters is low. S-649266, in a 
concentration-dependent manner, reduced the uptake and transcellular transport activity 
of each typical substrate via breast cancer resistance protein, organic anion transporting 
polypeptide 1B1, organic anion transporting polypeptide 1B3 (OATP1B3), organic cation 
transporter 1 (OCT1), MATE1, MATE2-K, OAT1, OAT3, and OCT2. The half maximal 
inhibitory concentration values for OAT1, OAT3, OCT1, OCT2, OATP1B3, and 
MATE2-K were calculated to be 141, 292, 1550, 2170, 2570, and 1230 µmol/L. The free 
concentration of Cmax value at the intended clinical dose (2 g, 3 times daily) was 
calculated to be 57.4 μmol/L (43.2 μg/mL) by multiplying the Cmax (119 μmol/L 
[89.7 μg/mL]) and the in vitro free fraction ratio of S-649266 in human at 100 µg/mL 
(48.2%). S-649266 was suggested to have DDI potential on OAT1, OAT3, OCT1, OCT2, 
OATP1B3, and MATE2-K from the evaluation conducted in accordance with FDA draft 
guidance [29] and EMA guideline [30] of drug interaction, and therefore, a clinical DDI 
study was performed (R2115). Topline data from that DDI study showed no significant 
effects on the pharmacokinetics of furosemide (an OAT1 and OAT3 substrate) or 
metformin (an OCT1, OCT2, and MATE2-K substrate). Coadministration of S-649266 
and rosuvastatin (an OATP1B3 substrate) increased the AUC for rosuvastatin by 21%, 
but because it is unlikely that oral medications such as rosuvastatin, other statins, or 
medications that are OATP1B3 substrates will occur during a treatment course requiring 
intravenous antibiotics, the potential for a clinically meaningful outcome in the clinically 
setting is considered to be low.  
1.3.1 
Pharmacokinetics/Pharmacodynamics 
1.3.1.1 
Animal Models of Efficacy 
As with all β-lactams that target penicillin-binding proteins, the controlling 
pharmacodynamic (PD) parameter for S-649266 is the percentage of the dosing interval 
for which the free-drug concentration in plasma exceeds the minimum inhibitory 
concentration (% fT > MIC), and while the plasma pharmacokinetic measurements can 


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determine the drug exposure over time, corrected for protein binding, the MIC remains 
the key variable in determining %fT>MIC. 
Shionogi has conducted a series of studies in animal models of infection, including 
urinary tract (murine), thigh (murine), and lung (murine and rat). In addition to the dose 
fractionation used in the murine models, the rat lung model was designed to reproduce 
human drug exposure, including infusion times of 1 and 3 hours (Figure 1-2).  
Figure 1-2 
Efficacy of S-649266 (Human 3- and 1-hr Infusion of 2 g 
IV q8h) Compared with Meropenem (Human 1 g IV q8h) 
Against K. pneumoniae VA-384 in a Respiratory Tract 
Infection Model in Cannulated Rats 
 
 
cfu = colony-forming units; IV = intravenous; MIC = minimum inhibitory concentration; 
NTC = nontreatment control; q8h = every 8 hours  
The results of the curative effect of the drug on carbapenem-resistant rat lung infections 
were better with a 3-hour infusion than a 1-hour infusion (for additional information refer 
to the current Investigator's Brochure).  
The pharmacokinetics/pharmacodynamics (PK/PD) parameter required for efficacy was 
determined in a murine thigh model of infection caused by 16 strains of Gram-negative 
bacteria with widely divergent MICs. The % fT>MIC values of S-649266 required for a 
static effect and 1-log10 reduction were approximately 60% to 70% and 70% to 80%, 
respectively. The % fT>MIC values required for efficacy were similar among bacterial 
species (for additional information refer to the current version of Investigator's Brochure). 
0
1
2
3
4
5
6
7
8
9
10
Log10 cfu/lungs
Limit of detection
GSK2696266
1 h i f
i
1 hr NTC
96 hr NTC
Meropenem
8
GSK2696266
3 h i f
i
96hr NTC 
1hr NTC 
Meropenem 
q8h 
S-649266 
1hr infusion 
q8h 
S-649266 
3hr infusion 
q8h 
Inoculum 7.1 log10 cfu/rat 
S-649266 MIC = 16 g/mL 


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In summary, the nonclinical data support the clinical development of S-649266 as a 
potential human therapeutic agent against serious bacterial infections. The target PK/PD 
parameter is 70% to 80% fT>MIC. 
1.4 
Clinical Experience 
1.4.1 
Phase 1 
The safety and tolerability of S-649266 has been assessed in a total of 212 healthy adult 
subjects who participated in 6 clinical pharmacology studies (a single-and multiple-
ascending dose study [Study 1203R2111], an intrapulmonary pharmacokinetic study 
[Study 1214R2112], a renal impairment study [Study 1222R2113], a mass balance study 
[Study 1516R2114], a thorough QT/QTc study [Study 1603R2116], and a 3-part drug 
interaction study [Study 1521R2115]). In these studies, healthy adult subjects or subjects 
with impaired renal function received single doses of S-649266 ranging from 100 to 
4000 mg (4 g) or multiple doses of up to 2000 mg (2 g) for up to 10 days, infused 
intravenously over 1 or 3 hours. In general, S-649266 was safe and well tolerated in the 
clinical pharmacology studies. There were no treatment-related or dose-dependent trends 
in vital sign measurements, electrocardiogram/electrocardiography (ECG) parameters, or 
clinical laboratory test results. There were no deaths or serious adverse events (SAEs) 
reported in any study. Adverse events (AEs) occurred relatively infrequently, were 
mostly mild in severity, and almost all resolved spontaneously without intervention. 
There were no dose-dependent trends in the frequency or type of AEs reported. 
S-649266 is primarily excreted unchanged (approximately 90%) in the urine 
(Study R2114), has a plasma half-life of 2.75 hours, and is associated with linear 
pharmacokinetics in the therapeutic dose range with little accumulation after multiple-
dose administration. After administration of single 100- to 2000-mg (2 g) doses, infused 
over 1 hour (single ascending dose study [R2111]) and single 2- to 4-g doses, infused 
over 3 hours (thorough QT/QTc [TQTc] study [R2116]), the Cmax and AUC of S-649266 
increased in proportion to the dose. After administration of multiple 2-g doses of 
S-649266 q8h infused over 1 hour (once daily doses on Days 1 and 10 and q8h doses 
from Days 2 to 9), only a slight accumulation (1.05- to 1.16-fold) for the Cmax and AUC 
of S-649266 was observed, and plasma concentrations of S-649266 reached steady state 
within 1 day of repeated administration [Study R2111]. After administration of a single 
1000-mg (1-g) dose of [14C]-S-649266, S-649266 was the major component in plasma, 
accounting for 92.27% of the plasma AUC for total radioactivity. A degradation product, 
pyrrolidine chlorobenzamide, accounted for 4.70% of the plasma AUC for plasma total 
radioactivity, with all other metabolites each accounting for < 2% of the plasma AUC for 
plasma total radioactivity [Study R2114]. The majority (98.6%) of total radioactivity was 
excreted unchanged in urine, with negligible amounts (2.8%) excreted in feces (Study 
R2114). 
A Phase 1 study to assess the repolarization effects of S-649266 on the human heart was 
conducted as a TQTc study (Study R2116) in accordance with the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) E14 Guidance and subsequent Questions & Answers. The first part of the study 


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consisted of a sequential-group safety and tolerability study in which the safety of the 
supratherapeutic dose of S-649266 was confirmed. The second part of the study consisted 
of a thorough QTc study in which single 2-g (therapeutic) and 4-g (supratherapeutic) 
doses of S-649266 administered as 3-hour infusions were assessed along with placebo (to 
S-649266) and moxifloxacin (active control) in a double-blinded, crossover design in a 
total of 48 subjects.  
The point estimates of the least squares (LS) means of baseline and placebo-corrected 
QTc intervals (ΔΔQTcF) calculated using Fridericia's correction for the 2- and the 4-g 
doses of S-649266 were < 5 msec and the upper bounds of the 1-sided 95% CI were 
< 10 msec at all postinitiation of the infusion time points. For the moxifloxacin treatment, 
a prolongation of the QTcF interval was observed for all time points from 1 to 10 hours 
postdose, confirming that a positive effect on the QTcF interval could be detected in the 
study (the lower bound of 1-sided 95% CI of LS means in the ΔΔQTcF > 5 msec). The 
results indicate that single 2- and 4-g doses of S-649266 did not prolong the ΔΔQTcF 
interval to a level of regulatory concern and met the criteria stipulated in the ICH E14 
guideline associated with a negative TQT study.  
1.4.2 
Phase 2 and Phase 3 
1.4.2.1 
Phase 2 Complicated Urinary Tract Infections 
A Phase 2 study of the safety and efficacy of S-649266 administered at a 2-g dose over a 
1-hour infusion to 300 subjects with complicated urinary tract infections (cUTIs) has 
been completed (Study R2121). The results support the safety profile of S-649266 in a 
subject population using the same dose (2 g, q8h) proposed for this study.  
1.4.2.2 
Phase 3 
A Phase 3 study of the safety and efficacy of S-649266 administered at a 2-g dose over a 
3-hour infusion at 8-hour intervals in subjects with infections caused by 
carbapenem-resistant Gram-negative pathogens is ongoing (Study R2131). This 
randomized study (NCT02714595) is enrolling subjects with pneumonia, blood stream 
infections, or cUTIs determined to be resistant to carbapenems to compare S-649266 with 
best available therapy as selected by the investigator. 
Refer to the current Investigator’s Brochure for additional details of completed studies. 


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2. STUDY OBJECTIVES 
Hypothesis:  
• All-cause mortality at Day 14 in subjects who receive S-649266 will not be 
inferior to subjects who receive meropenem if the upper bound of a 2-sided 95% 
CI for the difference in all-cause mortality at Day 14 between the 2 treatment 
groups (S-649266 and meropenem) is smaller than a noninferiority margin of 
12.5%.  
2.1 
Primary Objective 
• To compare all-cause mortality at Day 14 of subjects who receive S-649266 with 
that of subjects who receive the comparator, meropenem, in adults with hospital-
acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia 
(VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by 
Gram-negative pathogens 
2.2 
Secondary Objectives 
2.2.1 
Key Secondary Objectives 
• To compare the clinical outcome of treatment with S-649266 with that of 
meropenem in subjects at Test of Cure (TOC)1  
• To compare the microbiologic outcome of treatment with S-649266 with that of 
meropenem at TOC 
• To compare Day 14 all-cause mortality of S-649266 with that of meropenem for 
superiority of S-649266 
2.2.2 
Other Secondary Objectives 
Efficacy: 
• To compare the clinical outcome of treatment with S-649266 with that of 
meropenem in subjects at Early Assessment (EA)2, End of Treatment (EOT)3, and 
Follow-up (FU) 
• To compare the microbiologic outcome of treatment with S-649266 with that of 
meropenem at EA, EOT, and FU 
• To compare the all-cause mortality at Day 28 of subjects treated with S-649266 
with that of subjects treated with meropenem   
• To compare the all-cause mortality during treatment and the follow-up period 
(until End of Study [EOS])4 of S-649266 with that of meropenem  
 
1  TOC is defined as End of Treatment (EOT) + 7 days (± 2 days). 
2  EA is defined as start of treatment + 3days to 4 days.  
3  EOT is defined as the last day of study treatment. 
4  EOS is defined as the last day of the study 


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• To compare the resource utilization required for the 2 study treatments for the 
study-qualifying infection. This end point will not be included in the CSR, but it 
will be analyzed based upon a separate analytical plan after the conclusion of the 
study. 
Safety: 
• To assess the safety of S-649266 
3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 3, multicenter (multinational), double-blind, parallel-group, randomized, 
active-controlled study in approximately 300 subjects with documented nosocomial 
pneumonia caused by Gram-negative bacteria. Subjects meeting eligibility criteria and 
assessed by the investigator as requiring 7 to 14 days of intravenous treatment in the 
hospital will be randomized (1:1) to either S-649266, 2 g, administered intravenously 
over 3 hours, q8h or meropenem, 2 g, administered intravenously over 3 hours, q8h. 
Linezolid will be administered for at least 5 days to subjects in both arms to provide 
coverage for methicillin-resistant Staphylococcus aureus (MRSA), to maintain the study 
blind and, in the S-649266 arm, to provide coverage for Gram-positive bacteria. 
Sequential oral antibiotic (step-down) therapy is not permitted by this protocol. 
A subject’s clinical status will be reviewed daily and will be formally evaluated at 
specified intervals for clinical assessment and safety during hospitalization and 
periodically during follow-up for approximately 28 days from EOT (ie, End of Study 
[EOS]). The end of the trial for this study is defined as the last visit of the last subject and 
is 28 days (± 3 days) after the EOT for that subject.  
The study design is shown in Figure 3-1. The study time and events table is shown in 
Appendix 1.  
 
 
 


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Figure 3-1 
Study Schematic 
D −2 to D 1 
 
D 3 to D 4 
EOTa 
EOT  
+ 7  
(±2) 
EOT  
+ 14 
 (±3) 
EOT  
+ 28 
 (±3) 
Screening\Baseline 
Randomization 
Treatment Period 
Test of Cure (TOC) 
Follow-up (FU) 
End of Study (EOS) 
D 1 
Early Clinical/Micro 
Assessment (EA) 
Pharmacokinetic blood 
sampling 
Up to 
D 14a 
S-649266 daily 2-g intravenous 
dosing at 8-hour intervalsb as a 
3-hour infusion 
 
Meropenem daily 2-g intravenous 
dosing at 8-hour intervalsb as a  
3-hour infusion 
 
D = day; EOT = End of Treatment  
a 
The treatment duration can be extended up to 21 days based on the investigator’s clinical assessment of 
the subject. A clear reason should be documented. 
b 
Dosing adjustments for renal impairment (see Table 5-1 and Table 5-2) 
3.2 
Rationale for Study Design and Control Group 
3.2.1 
Rationale for Subject Population 
This study is designed to show that S-649266 is noninferior to the carbapenem, 
meropenem, which has a similar spectrum of Gram-negative activity and a similar dosing 
interval, in the treatment of subjects with HABP/VABP/HCABP caused by 
Gram-negative aerobic pathogens. The target pathogens do not include Gram-positive or 
anaerobic bacteria. Concomitant treatment with linezolid will be administered to subjects 
in both arms to provide coverage for MRSA and to maintain the study blind and, in the 
S-649266 arm, to provide coverage for Gram-positive bacteria. 
3.2.2 
S-649266 Dose Regimen 
The dose and dosage regimen for this study were developed from extensive PK/PD 
analyses of treatment of infections in appropriate animal models and pharmacokinetic 
modeling based on human pharmacokinetics. The controlling PD parameter for S-649266 
is % fT>MIC. Although the plasma pharmacokinetic measurements corrected for protein 
binding determines the drug exposure over time, the MIC remains the key variable in 
determining % fT>MIC. The dosage for this study was chosen to provide concentrations of 
plasma free drug sufficient to maintain the % fT>MIC that had been established in the 
animal infection models to be bactericidal for Gram-negative bacteria, including 
carbapenem-resistant Enterobacteriaceae and carbapenem-resistant strains of 
P. aeruginosa and A. baumannii (see Section 1.3.1.1).  


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Monte Carlo simulations using a population pharmacokinetic model, which was 
developed with data from the ascending dose Phase 1 study (Study R2111), were 
performed to assess the dose regimens that would attain the PD target of 50% or 75% 
fT>MIC as free plasma concentrations over a dosing interval for at least 90% of the 
population. The probability of target attainment for the percentage of dosing interval over 
MIC with administration of 2 g q8h with 1- or 3-hour infusions is shown in Figure 3-2. 
Figure 3-2 
Probability of Target Attainment for 50% or 75% fT>MIC 
 
hr = hour; MIC = minimum inhibitory concentration; PTA = probability of target attainment; T = the length 
of the dosing interval in hours; % fT>MIC = percentage of the dosing interval for which the free-drug 
concentration in plasma exceeds the minimum inhibitory concentration 
The results indicated that with administration of 2 g q8h with 1- or 3-hour infusions, 
more than 90% of subjects with normal renal function would achieve 50% fT>MIC at a 
MIC of 8 μg/mL and 75% fT>MIC at a MIC of 4 μg/mL. A 2-g q8h dosage regimen with a 
3-hour infusion could be considered a potential treatment for > 90% of the target 
Gram-negative pathogens (each MIC90: ≤ 4 μg/mL, for additional information refer to the 
current Investigator’s Brochure). 
A 2-g q8h 1-hour infusion dose was the maximum dose regimen administered for 10 
days. The 2-g dose of S-649266 was well tolerated in Study R2111, and no significant 
AEs occurred. The 2-g q8h 1-hour infusion of S-649266 was administered to subjects in 
the recently completed cUTI study.  
MIC (g/mL)
0.25
0.5
1
2
4
8
16
Probability of Target Attainment (%) 
0
20
40
60
80
100
120
PTA for 50% fT>MIC, 2 g with 1-hr infusion 
PTA for 75% fT>MIC, 2 g with 1-hr infusion 
PTA for 50% fT>MIC, 2 g with 3-hr infusion 
PTA for 75% fT>MIC, 2 g with 3-hr infusion 


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The proposed S-649266 dosage regimen for the treatment of HABP/VABP/HCABP with 
Gram-negative pathogens is 2 g q8h over a 3-hour infusion. Dosage adjustments for 
either impaired renal function or augmented renal clearance (ARC) are required in this 
study to allow for enrollment of subjects with significant comorbidities while maintaining 
the target drug exposure (Table 5-1). 
A 2-g every 6 hours (q6h) dosage regimen with a 3-hour infusion is proposed for subjects 
with ARC, in which > 90% probability of target attainment would be expected against 
pathogens requiring an MIC of 4 µg/mL, as shown in Table 3-1. 
Table 3-1 
Probability of Target Attainment for Subjects with 
Augmented Renal Clearance 
Dose Regimen 
CrCl: 120 to 150 mL/min 
CrCl: 150 to 200 mL/min 
2 g, q8h, 3-hour infusion 
82.0% 
72.7% 
2 g, q6h, 3-hour infusion 
96.4% 
94.1% 
CrCl = creatinine clearance (calculated by Cockcroft-Gault equation); q6h = every 6 hours; q8h = every 
8 hours 
Interindividual variability of 40% was assumed. 
3.2.3 
Meropenem Dose Regimens 
Because of the life-threatening nature of the protocol specified infections, a 
placebo-controlled study is not appropriate. Meropenem was chosen as the comparator 
given that it is listed by the American Thoracic Society/Infectious Disease Society 
guidelines of 2004 as an option for initial combination empiric therapy at a dosage of 1 g 
intravenously q8h in subjects with late-onset disease or risk factors for MDR 
pathogens [17].  
The dosage of meropenem administered and the duration of treatment should take into 
account the type and severity of infection to be treated, and the clinical response to 
treatment. A dosage of up to 2 g given 3 times daily in adults and adolescents may be 
particularly appropriate when treating some types of infections, such as infections due to 
less susceptible bacterial species (eg, Enterobacteriaceae, P. aeruginosa, S. maltophilia, 
and Acinetobacter spp.) or very severe infections [18].  
The efficacy of an antibiotic agent is dependent on its pharmacokinetic and 
pharmacodynamic properties [19,20]. The β-lactams are characterized by time-dependent 
bactericidal activity, which means that % fT>MIC must be maintained for efficacy. For 
these agents, increasing the concentration does not necessarily increase the rate or extent 
of killing; best results are achieved by optimizing the duration of exposure to effective 
concentrations. Several investigations of carbapenem (eg, meropenem, ertapenem, and 
imipenem) bactericidal activity in animal models of infection have suggested that the PD 
target for maximal bactericidal activity is a % fT>MIC of free drug of ~ 40% [21-24]. 
Monte Carlo simulation of the effects of other dosages of meropenem administered as a 
3-hour infusion, compared with the standard 30-minute infusion, showed that prolonged 


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infusion increased the probability of conservative bactericidal target attainment 
(50% fT>MIC) for Acinetobacter species and P. aeruginosa. For those pathogens, the 
highest target-attainment rates were obtained with a 3-hour infusion of 2 g of meropenem 
q8h. 
The dosage of meropenem will be 2 g q8h infused intravenously over 3 hours to ensure 
the highest probability of bactericidal target attainment (40% fT>MIC), which is important 
especially in less susceptible bacterial species. This approach is most appropriate 
especially when using meropenem as monotherapy in subjects with 
HABP/VABP/HCABP and risk factors for MDR pathogens or caused by less susceptible 
species, eg, Enterobacteriaceae, P. aeruginosa, S. maltophilia, and Acinetobacter spp. 
Dosage adjustment for renal impairment will be done per label (see Table 5-2). 
3.2.4 
Linezolid Dose Regimens 
Linezolid will be administered for at least 5 days to subjects in both arms to provide 
coverage for MRSA and to maintain the study blind and, in the S-649266 arm, to provide 
coverage for Gram-positive bacteria. The dosage is 600 mg intravenously every 12 hours 
(q12h). No dosage adjustment is required for impaired renal function as per the approved 
label. Linezolid can be discontinued after 5 days if the subject’s lower respiratory tract 
specimens do not provide evidence of Gram-positive infection when appropriate lower 
respiratory tract specimens have been obtained, and the subject is not at high risk for 
MRSA infection (eg, no prior known MRSA colonization in the lower airway, no prior 
MRSA pneumonia in the past 6 months, low prevalence [< 10% to 20%] of MRSA in the 
healthcare facility, etc). If a subject’s respiratory specimens demonstrate Gram-positive 
infection, if respiratory specimens have not been obtained, or if a subject is at high risk 
for MRSA infection, then linezolid should be administered for the entire treatment period 
of 7 to 14 days along with S-649266 or meropenem. 
Linezolid should be administered by intravenously infusion over a period of 30 minutes 
to 2 hours, q12h. If linezolid is to be given concomitantly with another drug, each drug 
should be given separately in accordance with the recommended dosage and route of 
administration for each product. 
3.2.5 
Duration of Study Treatment 
The treatment duration for S-649266 or meropenem is anticipated to be 7 days to 14 days, 
which is consistent with published treatment guidelines for serious infections [17, 25-28]. 
Treatment with linezolid will be the same as that for S-649266 or meropenem when a 
Gram-positive infection has been demonstrated in subject’s lower respiratory tract 
specimens. Linezolid can be discontinued after 5 days when appropriate lower respiratory 
tract specimens have been obtained that do not provide evidence of Gram-positive 
infection and if the subject is not at high risk for MRSA infection. Based on the 
investigator’s clinical assessment of the subject, treatment may be extended up to 
21 days. The reason for the extension should be clearly documented in the electronic case 
report form (eCRF). All study treatments will be performed in the hospital. 


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3.3 
Study Duration 
3.3.1 
Study Duration in Individual Subjects 
The approximate timing for the subject-related activities during the study is up to 2 days 
for screening, 7 days to 14 days for treatment, and 28 days for post-treatment testing and 
safety follow-up. This gives a total study participation time from treatment initiation to 
EOS of approximately 5 weeks to 7 weeks for each subject. 
3.3.2 
Planned Study Duration for the Study 
It is anticipated that it will take approximately 24 months to complete enrollment and an 
additional 5 to 7 weeks for the last subject to complete the study. 
4. STUDY POPULATION SELECTION 
4.1 
Study Population 
Male or female subjects 18 years of age or older who have a documented nosocomial 
pneumonia (HABP/VABP/HCABP) caused by an aerobic Gram-negative pathogen only, 
or in combination with an aerobic Gram-positive or anaerobic pathogen, and who require 
hospitalization for the parenteral (intravenous) treatment of the infection may be enrolled 
in the study. The sponsor will monitor the blinded mortality rate when 50 subjects have 
completed the study, and if the mortality rate is deemed too low (≤ 8%) compared with 
the assumption of 10%, the lower limit of the acceptable Acute Physiology and Chronic 
Health Evaluation II (APACHE II) score will be set to ≥ 8 (see Exclusion Criterion 10). 
HABP/VABP/HCABP Definitions  
HABP is defined as an acute bacterial pneumonia in a subject hospitalized for more than 
48 hours or developing within 7 days after discharge from a hospital. Subjects may 
experience acute respiratory failure and require mechanical ventilation for HABP 
(ventilated-HABP). 
VABP is defined as an acute bacterial pneumonia in a subject receiving mechanical 
ventilation via an endotracheal (or nasotracheal) tube for a minimum of 48 hours.  
HCABP is defined as an acute bacterial pneumonia in a subject who meets any of the 
following criteria: 
• hospitalized in an acute care hospital for 2 or more days within 90 days of the 
HCABP  
• residing in a nursing home or long-term care facility  
• received intravenous antibiotic therapy or chemotherapy 
• received wound care within the past 30 days of the current infection  
• attended a hospital clinic or hemodialysis clinic 


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4.2 
Inclusion Criteria 
Subjects who fulfill the following criteria at Screening will be included in the study: 
1. Subjects 18 years or older at the time of signing informed consent  
2. Subjects who have provided written informed consent or their informed consent 
has been provided by a legally authorized representative (Note: Country-specific 
rules and local ethics committee approval for legally authorized representative 
informed consent will determine whether or not and how a subject unable to 
comprehend or sign the informed consent is allowed to be enrolled in the study) 
3. Subjects who meet the clinical diagnosis criteria for HABP/VABP/HCABP (see 
above) 
4. All subjects must fulfill at least 1 of the following clinical criteria at Screening:  
a. New onset or worsening of pulmonary symptoms or signs, such as cough, 
dyspnea, tachypnea (eg, respiratory rate > 25 breaths/minute), expectorated 
sputum production, or requirement for mechanical ventilation 
b. Hypoxemia (eg, a partial pressure of oxygen [PaO2] < 60 mm Hg while the 
subject is breathing room air, as determined by arterial blood gas [ABG], or 
worsening of the ratio of the PaO2 to the fraction of inspired oxygen 
[PaO2/FiO2]) 
c. Need for acute changes in the ventilator support system to enhance 
oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2) 
or needed changes in the amount of positive end-expiratory pressure 
d. New onset of or increase in (quantity or characteristics) suctioned respiratory 
secretions, demonstrating evidence of inflammation and absence of 
contamination 
5. All subjects must have at least 1 of the following signs: 
a. Documented fever (ie, core body temperature [tympanic, rectal, esophageal] 
≥ 38°C [100.4°F], oral temperature ≥ 37.5°C, or axillary temperature ≥ 37°C) 
b. Hypothermia (ie, core body temperature [tympanic, rectal, esophageal] ≤ 35°C 
[95.0°F], oral temperature ≤ 35.5°C and axillary temperature ≤ 36°C)  
c. Leukocytosis with a total peripheral white blood cell (WBC) count 
≥ 10,000 cells/mm3 
d. Leukopenia with total peripheral WBC count ≤ 4500 cells/mm3 
e. Greater than 15% immature neutrophils (bands) noted on peripheral blood 
smear  
6. All subjects must have a chest radiograph during screening or have a previous 
chest radiograph within 48 hours prior to randomization showing the presence of 
new or progressive infiltrate(s) suggestive of bacterial pneumonia. A computed 
tomography (CT) scan in the same time window showing the same findings could 
also be acceptable.  
7. All subjects must have a suspected Gram-negative infection involving the lower 
respiratory tract by 1 or more of the following: 


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a. Gram stain of lower respiratory secretions showing Gram-negative bacteria, 
either alone or mixed with Gram-positive bacteria at or within 72 hours prior 
to randomization 
b. Microbiologic culture of respiratory tract secretions within 72 hours prior to 
randomization identifying Gram-negative aerobic bacteria 
c. Other diagnostic tests, including molecular tests, which provide evidence of 
Gram-negative bacterial infection of the lower respiratory tract 
d. Pneumonia highly suspected to be due to Gram-negative bacteria based on 
prior antibiotic use or local epidemiologic evidence of Gram-negative 
infection outbreak  
8. Subject is male (no contraception required) or female and meets 1 of the 
following criteria: 
a. Surgically sterile (has had a hysterectomy and/or bilateral oophorectomy, or a 
bilateral salpingectomy or tubal ligation for the purpose of contraception for at 
least 6 weeks with appropriate documentation of such surgery) 
b. Postmenopausal (defined as older than 45 years of age with cessation of 
regular menstrual periods for at least 6 months and a follicle-stimulating 
hormone level of > 40 mIU/mL, or amenorrhea for at least 12 months) 
c. Of childbearing potential and using combined (estrogen and progestogen) or 
progestogen-only hormonal contraception associated with inhibition of 
ovulation (including oral, intravaginal, injectable, implantable, and 
transdermal contraceptives), or an intrauterine device, or intrauterine 
hormone-releasing system for the entire duration of the study 
d. Of childbearing potential and practicing abstinence as a preferred and usual 
life style and agrees to continue practicing abstinence from screening for the 
entire duration of the study 
e. Of childbearing potential and whose sole heterosexual partner has been 
successfully vasectomized and agrees to not have other heterosexual partners 
for the entire duration of the study 
9. Subjects who failed empiric therapy will be allowed in this study. However, 
confirmation of both clinical and microbiological failure is necessary (see flow 
chart in Appendix 7): 
a. Clinical failure: An investigator needs to confirm clinical failure of empiric 
treatment by clinically available information such as vital signs, physical 
examinations, laboratory data, and/or imaging 
b. Microbiological failure: Respiratory specimens from a subject need to meet 
either i OR ii: 
i. 
The lower respiratory tract specimen taken at the time of or before empiric 
therapy shows that the pathogen cultured is Gram-negative aerobic 
bacteria and the pathogens are resistant or intermediate to all the empiric 
antibiotics used 


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ii. 
The pathogen from a specimen obtained after at least 2 calendar days of 
the empiric antibiotic regimen demonstrates that it is a Gram-negative 
aerobe, or shown in Gram stain as Gram-negative bacteria 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Subjects who have known or suspected community-acquired bacterial pneumonia, 
atypical pneumonia, viral pneumonia, or chemical pneumonia (including 
aspiration of gastric contents, inhalation injury) 
2. Subjects who have a history of any hypersensitivity to cephalosporins or to 
carbapenems, or severe hypersensitivity to any other type of β-lactams other than 
cephalosporins and carbapenems (eg, penicillins, monobactams), or 
hypersensitivity to linezolid (Note: For β-lactams, a history of a mild rash 
followed by uneventful re-exposure is not a contraindication to enrollment)  
3. Subjects with a Gram-negative infection caused by a carbapenem-resistant 
pathogen, if known at the time of randomization (Note: Subjects who have a 
carbapenem-resistant pathogen identified after randomization should be evaluated 
clinically before discontinuation of study treatment.) 
4. Subjects with coinfection caused by invasive aspergillosis, mucormycosis or other 
highly lethal mold 
5. Subjects who have central nervous system infection (eg, meningitis, brain abscess, 
shunt infection) 
6. Subjects with cystic fibrosis  
7. Subjects in refractory septic shock, defined as persistent hypotension despite 
adequate fluid resuscitation or despite vasopressive therapy at the time of 
randomization 
8. Subjects with neutropenia (ie, polymorphonuclear neutrophils < 500 cells/µL) 
9. Female subjects who have a positive pregnancy test at Screening, who are 
lactating, or who refuse to use 1 of the previously specified methods of 
contraception 
10. Subjects with an APACHE II score of > 35 
Note: Sponsor may limit to subjects with an APACHE II score < 8 (see 
Section 4.1). This restriction will be communicated to investigators via a 
sponsor’s notification letter. 
11. Subjects who have received potentially effective antibiotic therapy for a 
continuous duration of more than 24 hours during the previous 72 hours prior to 
randomization (Note: Subjects failing empiric therapy as defined in inclusion 
criterion 9 may be eligible for inclusion.) 
12. Subjects with any condition or circumstance that, in the opinion of the 
investigator, would compromise the safety of the subject or the quality of the 
study data 


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13. Subjects receiving peritoneal dialysis (hemofiltration and hemodialysis are 
permitted) 
14. Subjects requiring continued treatment with methotrexate, procainamide, 
probenecid, monoamine oxidase inhibitors, or valproic acid (see Section 5.2) 
15. Subjects who have received another investigational drug or device within 30 days 
prior to study entry 
16. Subjects who have previously been randomized in this study or have previously 
received S-649266 
17. Subjects with 1 or more of the following laboratory abnormalities in baseline 
specimens: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (ALP), or total bilirubin level (TBL) > 3 times the upper 
limit of normal (ULN), platelet count < 40,000/μL 
18. Subjects with bronchiectasis with symptoms of persistent or recurrent bronchial 
infection related to irreversibly damaged and dilated bronchi; namely, subjects 
with clinical bronchiectasis  
19. Subjects with lung abscesses 
4.4 
Screen Failures  
Screen failures are defined as subjects who consent to participate in the study but are not 
subsequently randomized/administered the study drug. Minimal information collected 
will include informed consent date, baseline subject characteristics, all eligibility criteria 
violated, reason(s) for screen failure, and AEs that lead to screen failure, including any 
SAEs. Rescreening is allowed for the following situations: 
1. If a screen failed subject has a relapse or new HCABP/HABP/VABP 
2. If a screen failed subject’s respiratory specimen grows Gram-negative aerobic 
causative pathogen(s) that are not covered by empiric therapy in addition to lack 
of clinical improvement with that therapy 
5. STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Test Drug 
S-649266 (1 g/vial): as a powder for solution for intravenous administration, 
manufactured by Shionogi & Co., Ltd., Japan  
5.1.2 
Control Treatment  
Meropenem (500/1000 mg/vial): as a powder for solution for injection or infusion, as 
commercially available 
5.1.3 
Linezolid Treatment 
Linezolid for intravenous injection is supplied as a ready-to-use sterile isotonic solution 
for infusion with a concentration of 2 mg/mL of linezolid, as commercially available. 


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5.2 
Treatments to Be Administered 
Each subject who is qualified for entry in the study will be randomized into 1 of 
2 treatment groups according to the method of treatment assignment specified in 
Section 5.4.  
S-649266 will be administered intravenously over 3 hours, q8h. Meropenem will also be 
administered intravenously over 3 hours, q8h. Linezolid will be administered 
intravenously over 30 minutes to 2 hours, q12h.  
The study treatment duration is anticipated to be 7 to 14 days, which is consistent with 
published treatment guidelines for HABP/VABP/HCABP and serious infections 
[17,25-29]. Linezolid will be administered for at least 5 days, but will be extended if a 
Gram-positive pathogen or MRSA is present in addition to the Gram-negative pathogen. 
It is recommended that dosing not exceed 14 calendar days or the equivalent of 14 full 
days of dosing. However, treatment may be extended up to 21 days based on the 
investigator's clinical assessment of the subject and a clear reason being documented in 
the eCRF. All study treatments will be administered in the hospital in a manner that 
preserves the blinded nature of the study. 
If a subject needs to be treated for longer than 21 days, the subject should be discontinued 
from the study treatment, an EOT visit should be performed after last dose (same 
calendar day or within 24 hours), and antibiotic treatment should be instituted per local 
clinical practice. These subjects are still considered to be in the study and should be 
followed through to the completion of all study activities (ie, TOC, FU, and EOS).  
The latest recommendations in the drug labelling should be followed in regard to 
precautions, contraindications, warnings, and DDIs with other medication that is or might 
be added as concomitant medication so that it does not interact adversely with the study 
antibiotics. The latest drug labelling can be found at the local regulatory agency’s 
website.  
5.2.1 
S-649266 Group 
The preparation of the dosing solutions for S-649266 is described in the pharmacy 
manual. The solution volume for infusion must be at least 100 mL. Dilution volumes 
> 100 mL may be used, if deemed necessary by the investigator, to reduce any emerging 
symptoms related to nausea or infusion site issues (eg, pain, swelling).  
5.2.2 
Meropenem Group 
The control population will be treated with meropenem, supplied by the sponsor. The 
solution volume for infusion must be at least 100 mL. The preparation of the dosing 
solutions for meropenem is described in the pharmacy manual. To be comparable with 
the S-649266 dosing solution, the meropenem dosage will be prepared in normal saline 
and will be the same volume as the S-649266 dose.  


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5.2.3 
Linezolid 
All subjects will be treated with linezolid for the duration of treatment if Gram-positive 
pathogens are identified in the subject’s respiratory specimens. If no Gram-positive 
pathogens are identified, and the subject is not at high risk for a MRSA infection, 
linezolid can be discontinued after 5 days. Linezolid will be supplied by the sponsor.  
5.3 
Selection and Timing of Dose for Each Subject 
Both study treatments, S-649266 and meropenem, are renally excreted and require dosage 
adjustment based on renal function estimated from serum creatinine concentration. 
Dosage adjustment based on reduced renal function will be made by the investigator or a 
qualified designee in a blinded manner, and then the dosage of randomized antibiotic will 
be prepared by an unblinded pharmacist or qualified designee. Dosage adjustments for 
S-649266 for subjects with various degrees of renal function and ARC are found in Table 
5-1. Dosage adjustments for meropenem for subjects with various degrees of renal 
function are found in Table 5-2.  
5.3.1 
S-649266 Dosing 
The proposed S-649266 dosage regimen for the treatment of serious or life-threatening 
infections is 2 g q8h infused over 3 hours.  
The initial dosage for each subject will be adjusted based on estimated glomerular 
filtration rate (eGFR) calculated by modification of diet in renal disease (MDRD) 
equation [32,33] and creatinine clearance (CrCl) by Cockcroft-Gault equation [34] as per 
Table 5-1.  
Renal function for all subjects will be assessed at EA to determine if there are changes in 
renal function for which the dosage of the study drug needs to be adjusted. The main 
purpose for this is to ensure that drug levels remain in a safe and therapeutic range. If 
renal function is changed at EA from Screening, dosage adjustment will be required as 
per Table 5-1.  
For subjects with eGFR ≥ 90 mL/min/1.73 m2 and CrCl ≥ 120 mL/min by 
Cockcroft-Gault equation at Screening or at EA, a CrCl measured by urinary excretion 
with urine collection of 2 to 8 hours duration will be determined (see Section 7.6.4.4) in 
order to determine if an additional dosing adjustment is required.  
During treatment period other than at EA, dosage adjustment will be required on review 
of renal function conducted per local clinical practice.  
5.3.2 
Meropenem Dosing 
The dosage for meropenem of 2 g q8h with infusion over 3 hours was selected to provide 
an appropriate target MIC for Gram-negative bacteria that are associated with nosocomial 
pneumonia. In order to maintain the blinding during the treatment of a subject, it will be 
necessary to use the same dosing procedure for both of the study drugs, S-649266 and the 
comparator drug, meropenem; therefore, the volume of solution will be the same, and the 


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length of the infusion will be the same. The solutions will be made in saline for injection 
for either drug.  
Renal function for all subjects will be assessed at EA to determine if there are changes in 
renal function for which the dosage of the study drug needs to be adjusted. The main 
purpose for this is to ensure that drug levels remain in a safe and therapeutic range. If 
renal function is changed at EA from Screening, dosage adjustment will be required as 
per Table 5-2.  
During treatment period other than at EA, dosage adjustment will be required on review 
of renal function conducted per local clinical practice.  
5.3.3 
Linezolid Dosing 
Linezolid will be administered by infusion over 30 minutes to 2 hours q12h to both 
treatment groups. If no evidence of Gram-positive infection is identified, and the subject 
is not at high risk for MRSA infection, linezolid can be discontinued after 5 days in both 
treatment groups. The linezolid dose does not have to be administered at the same time as 
the Gram-negative antibiotic. If needed, the infusions of the antibiotics could be 
overlapped or separated to accommodate the difference in the timing of the infusions. 
Linezolid does not require dosage adjustment in subjects with reduced renal function 
according to label prescribing information. 


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Table 5-1 
S-649266 Dosing Adjustments for Various Degrees of 
Renal Function and Augmented Renal Clearance 
Creatinine Clearance 
Dosage 
Augmented renal function  
(MDRD-eGFR ≥ 90 mL/min/1.73 m2 and  
CrCl ≥ 120 mL/min)a 
2 g, q6h, 3-hour infusion 
Normal renal function  
(MDRD-eGFR ≥ 90 mL/min/1.73 m2 and  
CrCl < 120 mL/min) 
2 g, q8h, 3-hour infusion 
Mild renal impairment 
(MDRD-eGFR 60 to < 90 mL/min/1.73 m2) 
2 g, q8h, 3-hour infusion 
Moderate renal impairment 
(MDRD-eGFR 30 to < 60 mL/min/1.73 m2) 
1.5 g, q8h, 3-hour infusion 
Severe renal impairment 
(MDRD-eGFR 15 to < 30 mL/min/1.73 m2) 
1 g, q8h, 3-hour infusion 
ESRD (MDRD-eGFR < 15 mL/min/1.73 m2)  
0.75 g, q12h, 3-hour infusion 
Subject with intermittent HD 
0.75 g, q12h, 3-hour infusionb 
CVVH 
1 g, q12h, 3-hour infusionc 
CVVHD or CVVHDF 
1.5 g, q12h, 3-hour infusionc 
CrCl = creatinine clearance; CVVH = continuous venovenous hemofiltration; CVVHD = continuous 
venovenous hemodialysis; CVVHDF = continuous venovenous hemodiafiltration; EA = Early 
Assessment, eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; 
HD = hemodialysis; MDRD-eGFR = estimated glomerular filtration rate calculated with the 
modification of diet in renal disease (MDRD) equation; q6h = every 6 hours; q8h = every 8 hours; 
q12h = every 12 hours 
a 
Creatinine clearance will be calculated by Cockcroft-Gault equation at Screening and at EA. A urine 
measured CrCl will be calculated by using timed urine collections of 2 hours to 8 hours at Screening 
and EA in order to determine if an additional dosing adjustment is required.  
b 
S-649266 is hemodialyzable, thus a supplemental dose of 0.75 g will be administered after the 
completion of intermittent HD as a 3-hour infusion on dialysis days. If the supplemental dose 
overlaps with the next regular dose, the investigator can consider skipping either a next regular q12h 
dose or the supplemental dose to avoid excessive exposure and complexity of clinical operation.  
c 
The dose will be determined based on MDRD-eGFR on nondialysis days. 
 
The dosage of meropenem should be adjusted per label on review of renal function tests, 
whether part of required study assessments or conducted per local clinical practice (see 
Table 5-2) [18, 35]. Neither the US package insert nor the UK Medicines and Healthcare 
products Regulatory Agency Summary of Product Characteristics (SPC or SmPC) makes 
any recommendations for ARC. Dosing recommendations are made for hemodialysis and 
hemofiltration [18].  


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Table 5-2 
Meropenem Dosing Adjustments for Various Degrees of 
Renal Function  
Creatinine Clearance (mL/min)a 
Dosage 
CrCl > 50 
2 g, q8h, 3-hour infusion 
CrCl 26-50 
2 g, q12h, 3-hour infusion 
CrCl 10-25 
1 g, q12h, 3-hour infusion 
CrCl < 10 
1 g, q24h, 3-hour infusion 
CrCl = creatinine clearance; q8h = every 8 hours; q12h = every 12 hours; q24h = every 24 hours 
a 
Creatinine clearance calculated by Cockcroft-Gault equation at Screening, early assessment, and at 
other times as needed. Meropenem is cleared by hemodialysis and hemofiltration. The required dose 
should be administered after completion of the hemodialysis cycle. There are no established dosage 
recommendations for subjects receiving peritoneal dialysis. There are no established dosage 
recommendations for subjects with augmented renal clearance. 
Source: Meropenem Medicines and Healthcare products Regulatory Agency Summary of Product 
Characteristics dosing information [18] 
The administration schedule of study treatment after initial administration may be 
adjusted gradually, within reason, and based on the clinical judgment of the investigator 
to fit the routine treatment schedules of the investigator’s hospital, as long as the dosing 
intervals and infusion durations indicated by the protocol are maintained following 
adjustment. 
5.4 
Randomization to Treatment Groups 
The treatments will be randomized to subject identification numbers by the Interactive 
Response Technology (IRT) provider in a 1:1 fashion to S-649266 or meropenem. The 
IRT will be used to assign subjects to identification numbers for which treatment has 
already been randomly assigned. Randomization will be performed by the stratified 
randomization method using their infection diagnosis (HABP, VABP, and HCABP) and 
APACHE II score (≤ 15 and ≥ 16) as allocation factors. The number of ventilated 
subjects in the study is anticipated to be approximately 50%. This would include subjects 
with VABP, as well as subjects with HABP and HCABP who are ventilated.  
When the centralized IRT has accepted and randomized the subject to either treatment 
group, the dispensing pharmacist will prepare for administration of the allocated 
treatment according to the pharmacy manual.  
The process for subject number assignment and treatment assignment are described in the 
IRT procedure documents. 
The person or organization responsible for randomization will prepare and complete the 
randomization procedures/processes.  


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5.5 
Blinding 
This is a randomized, double-blind study. The investigator, site personnel, sponsor, and 
sponsor’s designees involved in blinded monitoring, data management, or other aspects 
of the study will be blinded to treatment assignment. The site pharmacist or qualified 
designee who will prepare the intravenous infusion solution will be unblinded so that 
he/she may obtain the assigned drug and prepare the intravenous dosing solutions. The 
drug supply itself will not be blinded. 
Since this is a blinded study, S-649266 will be prepared and administered within the same 
timeframe after preparation as meropenem. The infusion bag containing a reconstituted 
study or comparator drug will be identified with the study number and subject’s 
identification number, but will not identify the specific drug product. For comparability 
of the study drug and the comparator drug meropenem, the dosing solutions will be 
normal saline and dosed within the time limits established for meropenem. Linezolid will 
not require blinding, and it will be labeled with the study number, subject’s identification 
number, and drug name.  
Unblinding by request of an investigator should occur only in the event of an SAE 
assessed by the investigator to possibly be drug-related and for which it is necessary to 
know the study treatment to determine an appropriate course of therapy for the subject. 
Subjects who are unblinded due to a treatment-related SAE should be withdrawn from 
study treatment. If the investigator must identify the treatment assignment to an 
individual subject, an investigator or qualified designee should request the medication 
information from the IRT. They should not attempt to get this information from the site 
unblinded pharmacist or qualified designee. The documentation received from the IRT 
indicating the code break must be retained with the subject's source documents in a 
secure manner so as not to unblind the treatment assignment to other site or sponsor 
personnel. The investigator is also advised not to reveal the study treatment assignment to 
other site or sponsor personnel.  
Prior to unblinding, and if the situation allows it, the investigator should try to contact the 
site monitor or the sponsor’s medical monitor in order to get additional information about 
the investigational product. If this is impractical, the investigator must notify the site 
monitor or the sponsor’s medical monitor as soon as possible, without revealing the 
treatment assignment of the unblinded subject. The investigator must document the 
subject’s number, the date, and the time for breaking the blind and must clearly explain 
the reasons for breaking the code. For subjects withdrawing consent, EOT procedures 
should be completed.  
Plasma concentrations of S-649266 will be reported to the sponsor by the analytical 
laboratory only after the database is locked in order to maintain the blind.  


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5.6 
Packaging and Labeling 
Study treatments, S-649266 and meropenem, will be supplied to the study sites in 
containers that identify the contents (ie, not blinded). The individual vials of both study 
treatments will be labeled with the name of active ingredient, protocol number, lot 
number, dosage form, strength, dosing instructions, medication identification number, 
storage conditions, caution statements, name, and address of the manufacturer or sponsor 
as appropriate for a given country labeling requirements. 
5.7 
Storage and Accountability 
5.7.1 
S-649266 Treatment Arm 
S-649266 vials will be stored in a tight, light-resistant container at 2°C to 8°C (36°F to 
46°F), and must be protected from light.  
The investigator/site pharmacist will ensure that all study drugs are stored and dispensed 
in accordance with local health regulations concerning the storage and administration of 
investigational drugs. All drug supplies must be kept in a secure locked, 
temperature-controlled area with access limited to those authorized by the investigator. 
The unblinded pharmacist or designee will maintain accurate records of the following 
information: receipt and condition of all study drugs, date of the receipt, when and how 
much study drug is dispensed and administered to each subject in the study, date and time 
of reconstitution, and any reasons for departure from the protocol-dispensing regimen.  
The drug accountability records and the spent dosage vials will be available for 
verification by the unblinded sponsor monitor, unblinded contract research organization 
(CRO), or designee at each monitoring visit as specified in the unblinded monitoring 
plan. If the local procedures at a site require immediate disposal of spent vials, an 
alternative process for drug accountability will be made with the site and the process will 
be documented in the study files. At the completion of the study, a final reconciliation of 
all study drugs will be performed. Study drugs must not be used for any purpose other 
than the present study. 
5.7.2 
Meropenem Treatment Arm 
Meropenem will be stored as specified by the label. 
5.7.3 
Linezolid Treatment  
Linezolid will be stored as specified by the label.  
5.8 
Investigational Product Retention at Study Site 
All unused study drug supplies will be held in the medical institution; although, those 
supplies will not be required to be stored under the storage conditions defined above. At 
the completion of the study, all of the unused drug supplies must be returned to the 
sponsor (or designee) as per the sponsor’s written instructions or destroyed as per the 


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CRO’s or local standard operating procedures upon agreement and written approval of 
the sponsor. 
5.9 
Treatment Compliance 
Start times and end times of the administration of intravenous treatments and the 
approximate extent of completion of all infusions will be recorded in the eCRF. Any 
interruption or adjustment of the rate of an infusion will be noted in the eCRF. The reason 
for interruption or adjustment also will be noted in the eCRF. 
5.9.1 
Changes in Treatment Regimen 
Subjects, who have their treatment regimen altered for reasons such as, but not limited to, 
lack of therapeutic response, possible drug-related toxicity, or de-escalation, will be 
identified, and the reason for the change in treatment regimen will be recorded in the 
eCRF.  
Alteration of treatment dosage or dosing regimen for any reason will be reported in the 
eCRF.  
6. RESTRICTIONS 
6.1 
Prior Therapy 
Prior therapies are defined as therapies that were taken prior to randomization of the 
subject into the study.  
Systemic antibiotic treatment or prophylaxis for Gram-negative pathogens, including 
aerosolized antibiotics, must be stopped before administration of study drug treatments.  
Any prior systemic antibiotic therapy and the reason for its use within 2 weeks prior to 
randomization of the study will be recorded in the eCRF, and the information will 
include: 
• Name of used drug  
• Dose, dosing frequency, and route of administration (if a drug is administered) 
• Duration of treatment  
• Reason for use  
6.2 
Concomitant Therapy during the Study 
6.2.1 
Antibiotic Therapies 
Concomitant antibiotic therapies are defined as therapies administered after 
randomization in the study. No concomitant systemic antibiotics except for linezolid are 
permitted from randomization until after TOC. Topical antibiotics, excluding aerosolized 
antibiotics, are permitted. 


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The investigator, subinvestigator, or designee will record the following information for 
all therapies (prescription drugs, over-the-counter drugs, and herbal preparations) used 
during the study (from randomization to completion of EOS) in the eCRF:  
• Name of used drug  
• Dose, dosing frequency, and route of administration (if a drug is administered) 
• Duration of treatment  
• Reason for use 
6.2.2 
Nonantibiotic Therapies and Procedures 
Concomitant nonantibiotic therapies are defined as therapies including concomitant 
medication to support blood pressure or renal output, antiviral agents, or antifungal 
therapy that are administered after randomization in the study.  
Concomitant procedures are defined as procedures including surgical procedures, 
mechanical blood pressure device, and intravenous or urinary catheters, which are 
performed after randomization in the study. 
The investigator, subinvestigator, or designee will record all Prior Therapy (including all 
types of antibiotics, prescription drugs, over-the–counter drugs and procedures) used 
from 2 weeks prior to randomization in the eCRF.   
The investigator, subinvestigator, or designee will record the following information for 
all therapies (prescription drugs, over-the-counter drugs, herbal preparations, and 
procedures without any medication) used during the study (from Screening to completion 
of EOS) in the eCRF.  
• Name of used drug or used procedures 
• Dose, dosing frequency, and route of administration (if a drug is administered) 
• Duration of treatment  
• Reason for use 
It is not required to record the following concomitant medications: intravenous fluids, 
nutrition, mineral supplements (potassium, sodium, etc), nonantibiotic herbal 
supplements, ointments, or ocular drops.  
6.2.3 
Prohibited Therapy 
• Systemic antibiotics for Gram-negative infections, other than meropenem and 
S-649266, are not permitted from randomization until TOC. Systemic antibiotics 
for Gram-positive infections other than linezolid are not permitted from 
randomization until TOC. 
• Aerosolized antibiotics are not permitted from randomization until after TOC. 


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• Monoamine oxidase inhibitors and valproic acid are not permitted from Screening 
until EOT. 
Metronidazole or clindamycin to cover anaerobes is permitted. Oral vancomycin or 
metronidazole for C. difficile infection is permitted. 
6.2.4 
Rescue Therapy 
Alternative systemic antibacterial treatment should be administered when a subject has 
been deemed a treatment failure. Subjects determined as treatment failure and needing 
rescue therapy should be considered as EOT, and EOT procedures should be completed. 
All antibiotics drugs will continue to be recorded in the eCRF until the completion of the 
EOS assessment.  
7. STUDY PROCEDURES AND METHODS OF ASSESSMENTS 
In the case that a subject is screened and randomized on the same day, the information 
requirements for Screening (Day −2 to Day 1) and for Randomization (Day 1) are to be 
completed, but only 1 set of screening tests/results for the complete physical examination, 
vital signs, and laboratory tests are needed. 
7.1 
Informed Consent 
The investigator or subinvestigator will fully explain the nature of the study to a subject 
or, if the subject is unable to give consent him/herself, to the subject’s legally authorized 
representative using the Institutional Review Board (IRB)/Institutional Ethics Committee 
(IEC)-approved informed consent document. When the subject or his/her legally 
authorized representative agrees that he/she can participate in the study, the subject or 
his/her legally authorized representative must voluntarily sign a consent form prior to the 
initiation of any study procedures. A copy of the signed and dated informed consent 
document will be given to the subject. The signed and dated original consent form will be 
retained by the investigator. The date the informed consent was signed will be recorded in 
the eCRF. 
Informed consent will be obtained for all subjects. A subject cannot be entered in the 
study until he/she or his/her guardian or holder of an appropriate medical power of 
attorney has signed and dated the consent form. The subject who can only be enrolled 
with the consent of his/her legally authorized representative should be informed about the 
study when the subject is able to sign a consent during the study and, if capable, the 
subject should sign and personally date the written informed consent. (Note: 
Country-specific rules and local ethics committee approval for legally authorized 
representative informed consent will determine whether or not a subject unable to 
comprehend or sign the informed consent is allowed to be enrolled in the study). 
The investigator or subinvestigator is responsible for ensuring that the subject 
understands the risks and benefits of participating in the study, including answering any 
questions the subject may have throughout the study and sharing any new information in 


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a timely manner that may be relevant to the subject’s willingness to continue his/her 
participation in the study. 
7.2 
Baseline Subject Characteristics and Medical History 
The following baseline subject characteristics will be obtained upon entering into the 
study and entered in the eCRF: age, sex, ethnicity, race, onset of infection, severity of 
infection, prior/concomitant therapies, and medical history with time of onset. Medical 
history will include previous significant medical conditions (eg, cancer, stroke, and 
myocardial infarction), any concurrent medical conditions, surgical history, history of 
diagnosis, and history of treatment of current infection or other infections requiring 
antibiotic therapy. All subjects must receive a clinical diagnosis of nosocomial 
pneumonia (HABP/VABP/HCABP) presumably caused by a Gram-negative pathogen at 
the time of randomization.  
7.2.1 
Hospitalization 
Additional information to be entered into the eCRF to assist in the pharmacoeconomic 
evaluation is the date of any hospitalization from 90 days prior to enrollment through the 
study, admission source (home, clinic, skilled nursing facility, acute care treatment 
facility, etc), admission type (elective, urgent, emergent, other), date of discharge, 
discharge status (expired, home, hospice, transferred, etc), main location of care, 
initial/end date of intensive care unit (ICU) admission or isolation, initial/end date of 
treatment with ventilator, and status at EOS. 
7.3 
Enrollment in the Study and Dispensing Study Drug Treatments 
After a subject is determined to be eligible according to the inclusion/exclusion criteria, 
the investigator, designee or study site pharmacist will contact the IRT for an 
identification number and specify the: 
• Clinical diagnosis (HABP, VABP, or HCABP) 
• Calculated APACHE II score 
If the registration is accepted, the subject will be randomized to either treatment group. 
The number of ventilated subjects in the study is anticipated to be approximately 50%. 
This would include subjects with VABP, as well as subjects with HABP and HCABP 
who are ventilated.  
7.4 
Efficacy Assessments 
7.4.1 
Specific Evaluations 
Several of the assessments used in this study are considered to be both efficacy 
assessments and safety assessments (eg, survival and vital signs). These evaluations will 
be collected in the eCRF. The specific evaluations will then be incorporated into the 
appropriate analysis according to the Statistical Analysis Plan (SAP) for the respective 
evaluation.  


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7.4.1.1 
Survival 
The investigator or qualified designee will enter survival status (survival or death) in the 
eCRF, including the date and cause of death if the subject dies during this study up to the 
EOS. Survival will be assessed on a continuous basis and will be evaluated as an 
endpoint on Days 14 and 28 after the initiation of study treatment.  
In case there is no other requirement for a study visit on Day 14, such as EOT, or if 
dosing will go beyond Day 14, the survival of the subject will be confirmed by 
designated study staff and recorded in the eCRF. If the Day 28 survival determination 
does not coincide with a planned study visit, such as the FU visit, the survival of the 
subject will be confirmed by designated study staff and recorded in the eCRF. If the 
subject is no longer in the hospital at the time of the Day 14 or 28 survival determination, 
a phone call to the subject or caregiver to confirm survival will be sufficient, and the 
result will be recorded in the eCRF.  
7.4.1.2 
Sequential Organ Failure Assessment 
The Sequential Organ Failure Assessment (SOFA) score is a scoring system to determine 
the extent of a subject's organ function or rate of failure. The score is based on 6 different 
scores, 1 each for the respiratory, cardiovascular, hepatic, coagulation, renal, and 
neurological systems (see Appendix 4). The investigator or qualified designee will collect 
and enter the SOFA scores in the eCRF at the specified evaluation points based on 
Appendix 1. In nonventilated subjects, a respiration score of 0 may be assigned. 
7.4.1.3 
Oxygenation Status 
The subject’s oxygenation status, including PaO2, partial pressure of carbon dioxide, 
FiO2, and O2 saturation, will be determined by ABG measurements (ABG measurement 
is preferable but not mandatory), and peripheral capillary oxygen saturation will be 
measured by pulse oximetry as relevant at the specified evaluation points and entered in 
the eCRF. The oxygen inhalation devices, ie, a ventilation device, and the flow rate also 
will be identified and entered in the eCRF. If a subject is on a ventilation device, the start 
date and time of initiation of ventilation will be recorded in the eCRF. If the subject is 
taken off ventilation, the date and time of the end of ventilation will be recorded in the 
eCRF. If the subject was on ventilation during the time of the PK blood sampling, the 
FiO2 should be recorded.  
7.4.1.4 
Clinical Assessment of Signs and/or Symptoms 
Signs and symptoms specific to HABP/VABP/HCABP, such as expectorated sputum 
production, worsening of tracheal secretions, cough, dyspnea (including retractions), 
chest pain, wheezing, rales, rhonchi, egophony, dullness to percussion, and bronchial 
breath sounds will be assessed at baseline as absent, mild, moderate, severe, or unknown. 
Signs and symptoms present at baseline will similarly be assessed at the specified 
subsequent evaluation points. Any new sign or symptom of the underlying infection, 
which may occur in any specific subject during the course of the study, will also be 
assessed. The results will be entered in the eCRF. 


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7.4.1.5 
Vital Signs 
Blood pressure (systolic/diastolic), body temperature, pulse rate, and respiratory rate will 
be measured at Screening and at specified times. 
The vital signs will be recorded once a day during Screening and at least 3 times a day, at 
approximately evenly spaced intervals, across a calendar day, starting on Day 1 of the 
infusions and continuing while the subject is hospitalized and receiving treatment.  
For subjects treated in ICU, vital signs obtained through continuous monitoring methods, 
including intra-arterial catheters, may be used to record blood pressure, temperature, and 
heart rate. 
The investigator or subinvestigator will consider whether changes from baseline are 
clinically significant (see also Section 7.6.5). Results of blood pressure, temperature, 
pulse rate, and respiratory rate will be entered in the eCRF. 
7.4.1.6 
Clinical Pulmonary Infection Score 
Clinical Pulmonary Infection Score (CPIS) is a surrogate for diagnosis and treatment 
response. Points (0, 1, or 2) will be assigned for observed findings for 5 variables: body 
temperature, WBC count, tracheal secretion, PaO2/FiO2, and chest radiograph. The 
investigator or qualified designee will collect and enter the points in the eCRF at the 
specified evaluation points based on Appendix 5. In nonventilated subjects in whom 
blood gasses are not drawn, a PaO2/FiO2 score of 0 may be assigned.  
7.4.1.7 
Chest Radiographs 
A chest radiograph (posterior/anterior or portable [when the subject’s condition does not 
permit transport to the radiology department]) will be performed at the specified 
evaluation points: Screening, EOT, TOC, at Day 14 if dosing is to be extended to 
21 days, and when clinically indicated. If appropriate, additional radiography (eg, CT 
scan) could be performed to better delineate lung pathology according to local practice. 
The results will be entered in the eCRF, preferably by a certified radiologist. 
7.4.2 
Efficacy Criteria for Clinical Outcomes for Early Assessment, End 
of Treatment, and Test of Cure 
The clinical outcomes will be assessed by the investigator according to the following 
criteria at EA, EOT, and TOC. In case treatment duration is extended beyond 14 days, an 
additional clinical outcome will be assessed on Day 14. The clinical outcomes will be 
entered in the eCRF. 
• Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms of pneumonia, including a reduction in SOFA and CPIS scores, and 
improvement or lack of progression of chest radiographic abnormalities such that 
no additional antibacterial therapy is required for the treatment of the current 
infection at the EA and EOT visits, and no antibacterial therapy is required for the 
treatment of the current infection at TOC.  


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• Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms of pneumonia; reappearance of signs and/or 
symptoms of pneumonia; development of new signs and/or symptoms of 
pneumonia requiring antibiotic therapy other than, or in addition to, study 
treatment therapy; progression of chest radiographic abnormalities; or death due 
to pneumonia.  
• Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 
7.4.3 
Clinical Outcomes for Follow-up 
The clinical outcomes will be assessed by the investigator according to the following 
criteria. The clinical outcomes will be entered in the eCRF. 
• Sustained Clinical Cure: Continued resolution or substantial improvement of 
baseline signs and symptoms of pneumonia, such that no antibacterial therapy has 
been required for the treatment of pneumonia in a subject assessed as cured at 
TOC.  
• Relapse: Recurrence of signs and/or symptoms of pneumonia, appearance of new 
signs and/or symptoms of pneumonia, or new chest radiographic evidence of 
pneumonia in a subject assessed as cured at TOC. 
• Indeterminate: Lost to follow-up such that a determination of clinical sustained 
cure/relapse cannot be made or subject received additional antibacterial therapy 
for the treatment of the current infection. 
7.4.4 
Microbiological Outcomes for Early Assessment, End of 
Treatment, and Test of Cure 
The microbiological outcomes by baseline pathogen will be determined by the sponsor 
according to the following criteria at EA, EOT, and TOC. In case treatment duration is 
extended beyond 14 days, an additional microbiological outcome will be assessed on 
Day 14. An overall per-subject microbiological outcome will also be determined based on 
the individual microbiological outcomes for each baseline pathogen. Emergent (ie, 
nonbaseline) pathogens will be considered separately and will not affect the per-subject 
microbiological outcome. 
• Eradication: Absence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. If it is not possible to obtain a sample for 
appropriate clinical culture, and the subject has a successful clinical outcome, the 
response will be presumed as eradication. 
• Persistence: Continued presence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. Persistence at EOT or TOC will be carried forward. 
• Indeterminate: No culture obtained from an appropriate clinical specimen or 
additional antibacterial therapy for the treatment of the current infection.  


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7.4.5 
Microbiological Outcomes for Follow-up 
Microbiological outcomes by baseline pathogen will be determined by the sponsor 
according to the following criteria at FU.  
• Sustained Eradication: Absence of the baseline Gram-negative pathogen from 
an appropriate clinical specimen after TOC. If it is not possible to obtain a sample 
for appropriate clinical culture, and the subject has a successful clinical response 
after TOC, the response will be presumed eradication. 
• Recurrence: Recurrence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen taken after TOC and the test of cure culture was 
negative.  
• Indeterminate: No culture obtained from an appropriate clinical specimen or 
subject received additional antibacterial therapy for the treatment of the current 
infection. 
7.5 
Pharmacokinetic Assessments 
All subjects will have blood drawn for sparse pharmacokinetic sampling of plasma 
concentrations of S-649266. Pharmacokinetic blood sampling will preferably be 
performed on Day 3 or 4. Every effort should be made to collect all 4 blood samples after 
administration of the same dose of study drug or at least the same day of administration, 
in order to reduce variability. The following is the schedule for the sampling time points 
(see Table 7-2 for acceptable time windows): 
(1) Just prior to the start of the 3-hour infusion  
(2) 1 hour after the start of infusion  
(3) Before the end of infusion  
(4) 1 hour after the end of infusion 
The actual sampling date and time will be recorded. If the subject is on a ventilation 
device, the FiO2 should be recorded. 
The pharmacokinetic blood sampling will be repeated in the event that the drug dosage 
was changed due to changes in renal function determined at EA; this should occur 24 to 
72 hours after the change in dosing regimen. 
If possible, a single blood sampling should be performed as soon as possible (within 
24 hours) in the case of premature EOT, which is defined as receiving < 7 days of 
intravenous treatment with either S-649266 or meropenem. 
Plasma samples will be shipped to a designated bioanalytical laboratory for drug 
concentration analysis. Detailed procedures for sample collection, handling, labeling, 
storage, and shipping will be specified in the laboratory manual. Shipping labels, 
instructions for shipping, and courier service will be provided by the sponsor or CRO. 


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Only blood samples from S-649266 subjects will be assayed. To maintain the blind, 
results of the assays will not be reported to the sponsor until after the database is locked.  
A substudy may be developed to determine drug concentrations in epithelial lining fluid 
(ELF) in subjects with VABP receiving S-649266. The plasma sampling for drug 
concentrations will be the same as that for the pharmacokinetic portion of the study. 
Ventilator-associated bacterial pneumonia subjects participating in the ELF study will 
only provide blood samples during the ELF pharmacokinetic study. Any substudy 
designed to determine the concentrations of S-649266 in ELF would require a separate 
written informed consent by the subject or representative. 
7.6 
Safety Assessments 
7.6.1 
Physical Examinations 
A complete physical examination will be performed at Screening. A limited physical 
examination relevant to the subject’s current condition will be performed at the specified 
evaluation time points (see Section 8 and/or Appendix 1). Body weight in kilograms and 
height in centimeters will be obtained at Screening. The physical examination should be 
performed according to the normal practice of the clinical study site by the investigator or 
subinvestigator. Clinically significant findings on physical examination will be recorded 
as AEs. Weight and height will be entered in the eCRF. 
7.6.1.1 
Glasgow Coma Scale 
The Glasgow Coma Scale (GCS) will be estimated based on eye (4), verbal (5), and 
motor (6) criteria. The investigator or qualified designee will calculate the GCS according 
to Appendix 2, record it in the source document, and use it to complete the APACHE II 
and SOFA scores in the eCRF at the specified evaluation points. In ventilated and sedated 
subjects, the GCS cannot be properly assessed, and a normal score of 15 could be used to 
complete the APACHE II and SOFA scores. If a reliable presedation score is available, it 
can be used. 
7.6.1.2 
APACHE II Score 
The component values, observations, and calculation of the APACHE II score will be 
collected and used as a method to establish the severity of disease for a given subject. The 
APACHE II score will be collected and entered in the eCRF at Screening by the 
investigator or qualified designee based on Appendix 3. If a core temperature 
measurement is not available (ie, tympanic, rectal, esophageal), oral and axillary 
temperatures could be adjusted by adding 0.5°C and 1°C, respectively.  
7.6.2 
Vital Sign Measurements 
Vital sign measurements are described in Section 7.4.1.5.  
7.6.3 
Electrocardiography 
A standard 12-lead ECG will be performed during Screening. The ECG will be 
performed at a paper speed of 25 mm/second after the subject has been in a supine or 


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semirecumbent position for several minutes. Electrocardiograms obtained by the site 
within the 48 hours prior to signing the ICF could be acceptable as screening data for this 
study. If that ECG is not a standard 12-lead ECG, a 12-lead ECG will have to be 
completed during Screening.  
The following ECG parameters will be recorded: heart rate, PR interval, RR interval, 
QRS duration, QT interval, and diagnostic statements. The QTc data will be calculated 
using Fridericia's correction by the electronic data capture system once the basic ECG 
data are entered therein.  
The investigator or subinvestigator will assess whether the ECG is normal or abnormal, if 
abnormal, was it associated with any AE or Medical History. The results of this ECG 
evaluation and its interpretation will be entered in the eCRF.  
Additional ECGs conducted per local clinical practice should also be assessed for any 
clinically significant abnormalities, which should then be reported as AEs and assessed as 
to whether they meet the criteria for being serious (see Section 7.6.5). 
7.6.4 
Clinical Laboratory Tests 
7.6.4.1 
Laboratory Parameters 
Blood and urine samples will be collected for clinical laboratory tests at specified times 
as specified in Appendix 1. Safety laboratory tests obtained within 24 hours prior to 
randomization as a standard of care are allowed to be used for screening tests.  
The samples other than some specialized tests, as outlined in Table 7-1, will be measured 
at a local laboratory, and the results will be entered in the eCRF. If required for 
specialized testing, detailed procedures for sample collection, handling, labeling, storage, 
and shipping will be provided in the separate study laboratory manual. Shipping labels, 
instructions for shipping, and courier service will be provided from the sponsor or CRO. 
The investigator or subinvestigator will assess whether any abnormal changes from 
baseline are clinically significant (see also Section 7.6.5.5). 
7.6.4.2 
Microbiologic Cultures 
Appropriate clinical specimens are to be obtained from all subjects within 48 hours prior 
to the start of infusion of the first dose of study treatment. Lower respiratory tract 
specimens (eg, sputum, endotracheal aspiration [ETA], endobronchial culture specimens 
collected by bronchoalveolar lavage [BAL], or protected specimen brush [PSB], lung 
biopsy tissue, pleural effusions, etc) and blood for microbiologic cultures are to be sent to 
the local laboratory for identification of all pathogens causing the infection. Lower 
respiratory tract specimens should be grown semiquantitatively or quantitatively with 
appropriate method-specific dilutions. Two blood samples from separate venipunctures 
are to be obtained from all subjects and sent to the local laboratory. After initiation of 
study treatment, appropriate clinical specimens, including blood samples, are to be 
obtained at the specified evaluation points. Subsequent blood cultures are to be completed 
only if the immediate previous culture is positive. Culture results obtained prior to 


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informed consent, but directly related to the current infection, should be recorded and 
may form the basis for subject inclusion in the study. 
For patients who failed empiric treatment (as defined in inclusion criterion 9), clinical 
specimens obtained within 72 hours of randomization in this study could be used as 
screening/baseline cultures. A culture should be done again before first dose of study 
drug is administered, and the pathogen isolated sent to central laboratory. 
Local culture results should be recorded in the eCRF and identified isolates sent to the 
central laboratory. 
All baseline respiratory specimens should also have a Gram stain of infected material (not 
from a swab) performed. The low-power microscopic view of the Gram stain can be used 
to ascertain the quality of the respiratory specimen, which helps to ensure that the 
respiratory specimen sent for culture does not represent oropharyngeal contamination (ie, 
fewer than 10 squamous epithelial cells and > 25 neutrophils is an example of an 
adequate expectorated sputum specimen) and should only be performed for ETA and 
expectorated sputum (microscopic check is not required for BAL, mini-BAL, or PSB). 
The high power microscopic view of the Gram stain can be used to characterize the 
general type of bacteria causing the pneumonia (eg, a Gram-positive or a Gram-negative 
bacterial pathogen). A report of both inflammatory cells and bacteria is necessary. A 
Gram stain result showing the presence of Gram-negative bacteria is a primary indication 
of the infection that will be most appropriate for this study.  
Inappropriate clinical specimens should not be used for confirmatory culture 
identification of causative pathogens.  
All isolated pathogens will be frozen and stored for later shipping to the central 
laboratory. Detailed procedures for sample collection, handling, labeling, storage, and 
shipping will be provided in the separate study laboratory manual. Shipping labels, 
instructions for shipping, and courier service will be provided from the sponsor or CRO. 
Carbapenem resistance is defined by the in vitro susceptibility phenotype (MIC, E-test, 
disc diffusion) and subject to the approved breakpoints for carbapenems in the respective 
countries. For this study, intermediate breakpoints to imipenem/cilastatin, doripenem, or 
meropenem are classified as carbapenem-susceptible. Imipenem/cilastatin, doripenem, or 
meropenem have been chosen for the carbapenem-resistant criteria for this study because 
of their coverage against Gram-negative species. Carbapenem resistance for isolated 
pathogens will be recorded in the eCRF. 
Bacteria in the airway may persist as a colonizer following treatment of pneumonia, 
without causing signs or symptoms of infection. When the bacteria considered to be a 
causative pathogen at Screening (baseline) are identified later to be a colonizer, the 
isolate of the colonizer, regardless of whether it is Gram-negative or Gram-positive, 
should be sent to the central laboratory. The rationale for performing identification and 
antimicrobial susceptibility by the central laboratory is to provide information of 


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antibiotic susceptibility over time, which is important in understanding the pathogenicity 
of the bacteria and development of resistance to study drugs.  
7.6.4.3 
Routine Laboratory Tests 
Clinical laboratory tests are shown in Table 7-1.  
Table 7-1 
Routine Laboratory Tests 
Category 
Evaluation Items 
Hematology Tests 
Hematocrit, hemoglobin, platelet count, RBC, WBC with differential and 
morphology indices, INR, and PTT 
Blood Chemistry Tests ALP, ALT, AST, GGT, LDH, CPK, CRP, and amylase, BUN, creatinine, TBL, 
sodium, potassium, bicarbonate, chloride, calcium, magnesium, glucose, total 
protein, albumin, uric acid, and total cholesterol 
Urinalysisa 
Glucose, blood, protein, ketones, bilirubin, urobilinogen, leukocyte esterase, and 
microscopicb (WBC, RBC, crystals, and casts) 
Specialized Tests 
Iron, TIBC, transferrin iron saturation, and hepcidin at Screening, and TOC 
Others 
Serum or urine pregnancy test at Screening  
CrCl and eGFR: from serum at screening and at EA (see Section 7.6.4.4) 
CrCl determined from a timed urine collection at Screening and EAc (see Section 
7.6.4.4) 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CPK = creatine phosphokinase; CrCl = creatinine clearance; CRP = C-reactive 
protein; EA = Early Assessment; eGFR = estimated glomerular filtration rate; GGT = gamma glutamyl 
transferase; INR = international normalized ratio; LDH = lactate dehydrogenase; MDRD-eGFR = estimated 
glomerular filtration rate calculated with the modification of diet in renal disease (MDRD) equation; 
PTT = partial thromboplastin time; RBC = red blood cell; TBL = total bilirubin level; TIBC = total iron-
binding capacity; TOC = Test of Cure; WBC = white blood cell  
a 
Urinalysis for anuric patients is not mandatory 
b 
If sediment is present.  
c 
For subject with MDRD-eGFR ≥ 90 mL/min/1.73 m2 and CrCl ≥ 120 mL/min by Cockcroft-Gault 
equation at Screening or at EA. 
False positive urinalysis tests for protein or ketones (by dipstick) were found in the 
previous Phase 1 study (Study R2111). In the case that a positive dipstick test is found, 
the result will be confirmed by a secondary laboratory method. 
7.6.4.3.1 
Pregnancy Tests 
A serum or urine pregnancy test for females who are not postmenopausal or surgically 
sterile will be performed at Screening. 
7.6.4.4 
Creatinine Clearance 
Renal function should be monitored per local clinical practice and dosage adjustments 
made accordingly and captured in the eCRF. 


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7.6.4.4.1 
Creatinine Clearance from Serum Creatinine  
In addition, a CrCl (the Cockcroft-Gault equation) and eGFR (the MDRD equation) will 
be calculated from the serum creatinine for all subjects at Screening and at EA. If renal 
function has changed at EA from Screening, dosage adjustment will be required as per 
Table 5-1. Examples of the MDRD equation and the Cockcroft-Gault equation are as 
follows [32-34]: 
MDRD equation 
– Japanese 
 eGFR (mL/min/1.73 m2) = 194 × (age in years)-0.287 × sCr-1.094 × (0.739 if 
female) 
– Non-Japanese 
 eGFR (mL/min/1.73 m2) = 175 × (age in years)-0.203 × sCr-1.154 × (0.742 if 
female) × (1.212 if African descent) 
Cockcroft-Gault equation 
– CrCl (mL/min) = weight × (140 − age in years)/(72 × sCr) × (0.85 if female) 
where sCr is the serum creatinine concentration (mg/dL) 
7.6.4.4.2 
Urine Measured Creatinine Clearance 
For subjects with eGFR calculated with the MDRD equation (MDRD-eGFR) 
≥ 90 mL/min/1.73 m2 and CrCl ≥ 120 mL/min by the Cockcroft-Gault equation at 
baseline, urine samples will be collected for a time interval as short as 2 hours or up to 
8 hours at Screening or at EA. The total volume of urine, hours, and urinary creatinine 
concentration will be measured and recorded in the eCRF. 
The CrCl calculated using timed urine collections, which is given by the following 
equation, will be performed for the subjects suspected to have ARC (ie, MDRD-eGFR 
≥ 90 mL/min/1.73 m2 and CrCl ≥ 120 mL/min by Cockcroft-Gault equation ) to confirm 
the presence of ARC. 
CrCl (mL/min) = uCr × volume/sCr/(time × 60)  
where uCr is urinary creatinine concentration (mg/dL), volume is urine volume (mL), sCr 
is serum creatinine concentration (mg/dL), and time is collection time (hours). 
7.6.5 
Adverse Event Assessments 
7.6.5.1 
Performing Adverse Event Assessments 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product (including investigational drug) during the course of a clinical 
investigation. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporarily associated with the use of 
an investigational product, whether or not considered related to the investigational 
product. Where symptoms or signs form part of a diagnosis, the diagnosis should be 
reported as AE instead of the individual symptoms and signs. 


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Adverse events will be found by the subject’s spontaneous complaint, subject comment 
cards, or as a result of nonleading questions, physical examinations, vital signs, or 
laboratory tests. Adverse events include any occurrences that are new in onset or 
aggravated in severity or frequency from the baseline condition, or abnormal results of 
diagnostic procedures, including laboratory test abnormalities. Medical histories not 
related to the infection that are reported at baseline and worsen will be considered AEs.  
Lack of efficacy, aggravation, or relapse of HABP/VABP/HCABP infection or related 
symptoms and signs will not be considered AEs in the study and, therefore, also not 
SAEs (unless fatal). This statement applies until TOC. Any aggravation or relapse of 
HABP/VABP/HCABP after TOC should be considered an AE.  
New onset infection involving a site other than lung such as blood stream infection is 
considered an AE. 
Hospitalizations for preplanned or elective procedures to treat a preexisting condition that 
did not worsen after study start will not be considered AEs or SAEs. The exception is 
when the subject experiences another event or has an outcome that is fatal, 
life-threatening, leads to prolonged hospitalization, or is considered to be clinically 
significant during/following the procedure. 
The investigator or subinvestigator is responsible for assessing AEs. Adverse events 
should be fully investigated and recorded in detail, including the onset date, date of 
outcome assessment (if outcome is other than not recovered, recovering, or unknown), 
severity, seriousness (with a category of seriousness), relationship with the study 
treatment, action taken to manage the AE, and outcome of the AE in the eCRF. 
7.6.5.2 
Timing 
Adverse events will be collected from the time of having signed informed consent 
through approximately 28 days after the last dose of the study treatment (ie, EOS) for 
randomized subjects. If a subject withdraws early from the study, the investigator or 
subinvestigator will make an effort to collect AEs until EOS. Major nonfatal events (eg, 
acute respiratory distress syndrome, respiratory failure, septic shock, empyema, 
bacteremia, endocarditis, and meningitis) if present, should also be evaluated on Days 14 
and 28 at the same time as the evaluation of survival. Major nonfatal events will be 
reported and followed through EOS. 
All SAEs, regardless of causality will be followed until resolution, stabilization, the 
condition becomes chronic, or the subject is lost to follow-up.  
7.6.5.3 
Severity 
The severity of an event will be graded by the investigator or subinvestigator according to 
the following definitions: 
• Mild: A finding or symptom is minor and does not interfere with usual daily 
activities. 


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• Moderate: The event causes discomfort and interferes with usual daily activity or 
affects clinical status. 
• Severe: The event causes an interruption of the subject’s usual daily activities or 
has a clinically significant effect. 
The highest severity during the period in which the AE occurred will be recorded in the 
eCRF and the SAE or other expedited form as required. 
7.6.5.4 
Relationship 
The relationship of an event to the study treatment will be determined by the investigator 
or subinvestigator according to the following criteria: 
• Related: An AE that can be reasonably explained as having been caused by the 
study drug. For example, the occurrence of the AE can be explained by any of the 
following: a pharmacological effect of the study drug (eg, a similar event had 
been reported previously); an increase or decrease of the dose affects the 
occurrence or seriousness of the AE; or all other causative factors (eg, medical 
history, concomitant medication, etc) can be ruled out after careful analysis of 
sufficient information. 
• Not Related: An AE that cannot be reasonably explained as having been caused 
by the study treatment. 
7.6.5.5 
Expectedness 
A treatment-related AE is considered expected if it is listed in Expected Adverse 
Reactions in Section “Undesirable Effects” of “SUMMARY OF DATA AND 
GUIDANCE FOR INVESTIGATORS” in the current Investigator’s Brochure for 
S-649266. The expected adverse reactions of meropenem will be those found in the EMA 
SmPC. The expected adverse reactions of linezolid will be those found in the EMA 
SmPC. Expectedness will be assessed by the sponsor. 
7.6.6 
Clinical Laboratory Adverse Events 
For any abnormal laboratory test results (hematology, blood chemistry, or urinalysis) or 
other safety assessments (eg, physical examinations, vital signs) that are worsening from 
baseline or occur thereafter in the course of the study, the investigator or subinvestigator 
will consider whether these results are clinically significant. Abnormal laboratory test 
results are defined as values outside the reference range. Any test results that are 
considered to be clinically significant at the discretion of the investigator or 
subinvestigator are to be recorded as AEs. If an abnormal laboratory finding is associated 
with disease or organ toxicity, the investigator should report only the disease or organ 
toxicity as AEs. These AEs should also be assessed as to whether they meet the definition 
of seriousness and reported accordingly. 
The investigator or subinvestigator will consider test results to be clinically significant in 
the following circumstances: 


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• Test result leads to any of the outcomes included in the definition of an SAE 
• Test result leads to discontinuation from the study 
• Test result leads to a concomitant medication treatment or other therapy 
• Test result requires additional diagnostic testing or other medical intervention 
• Test result meets the management criteria for liver function abnormalities 
identified in the Appendix 6 
7.6.6.1 
Liver Abnormalities 
Management and Discontinuation Criteria for Abnormal Liver Function tests have been 
designed to ensure subject safety and evaluate liver event etiology. The investigator or 
subinvestigator must review study subject laboratory results as they become available to 
identify if any values meet the criteria in Appendix 6. When any test result meets the 
management criteria for liver function abnormalities, the results of further assessments 
and required follow-up should be recorded in the Liver Event Form. 
7.6.7 
Serious Adverse Events 
7.6.7.1 
Definition 
An SAE is defined by regulation as any AE occurring at any dose that results in any of 
the following outcomes: 
• Death 
• Life-threatening condition 
• Hospitalization or prolongation of existing hospitalization for treatment 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Other medically important condition 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical intervention to 
prevent 1 of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 
at-home, blood dyscrasias or convulsions that do not result in subject hospitalization, or 
the development of drug dependency or drug abuse. Test results that meet the criteria of 
Hy’s law are considered SAEs (Appendix 6). The investigator or subinvestigator will 
determine the seriousness of AEs. 
An elective procedure not reflecting a worsening of a known underlying medical 
condition is not considered an AE, and therefore will not be considered an SAE despite 
requiring hospitalization. However, complications of a procedure will be considered an 
AE and may be considered an SAE if hospitalization is prolonged (or any other SAE 
criteria are met). A hospitalization or prolongation of a hospitalization for reasons other 
than an AE would not be considered an SAE. 


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7.6.7.2 
Reporting Serious Adverse Events 
All SAEs must be reported to CRO or the sponsor in detail within 24 hours from the point 
in time when the investigator first becomes aware of the SAE. All SAEs must be reported 
regardless of causal relationship to the study treatment. An SAE should be reported using 
the appropriate page in the eCRF. If technical difficulties are encountered or the eCRF 
page for SAE reporting is unavailable, a paper SAE Form should be used instead. A 
sample of the SAE Form and further instructions can be found in the site regulatory 
binder. Follow-up information on the SAE may be requested by the sponsor. 
When reporting SAEs, the investigator should record the diagnosis whenever possible. If 
no diagnosis is available at the time of reporting, individual signs and symptoms can be 
reported. 
In the event of any SAE reported or observed during the study, whether or not 
attributable to the study treatment, site personnel must report within 24 hours. 
SAEs can be reported by electronic data capture system eCRF or by phone or fax, if 
eCRF is not available. 
: 
 
 
OR  
 
United States: 
 
 
Canada: 
 
Belgium: 
 
 
France: 
 
Ukraine: 
 
 
Germany: 
 
Russia: 
 
 
Spain: 
 
Georgia: 
 
 
 
Hungary: 
 
Czech Republic: 
 
 
Serbia: 
 
Israel: 1
 
 
Estonia: 8
 
Japan: 
 
 
Philippines: 1
 
Latvia: 
 
 
Brazil: 
 
Taiwan: 
 
 
United Kingdom: 
 
 
If the sponsor requires a follow-up assessment, the investigator should provide new 
information as it becomes available and then report to the CRO or the sponsor. Discharge 
summaries, consultant reports, autopsy reports, or other relevant documents must be 


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evaluated by the investigator, and all relevant information must be reported. Copies of 
these reports may also be requested by the sponsor. 
Appropriate remedial measures should be taken by the investigator using his/her best 
medical judgment to treat the SAE. These measures and the subject’s response to these 
measures should be recorded. Clinical, laboratory, and diagnostic measures should be 
employed by the investigator as needed to adequately determine the etiology of the event.  
Any SAEs occurring after the AE assessment period specified in this section that are 
considered by the investigator to be related to drug treatment must be reported to the 
CRO or the sponsor. 
The investigator will be responsible for reporting all SAEs to the IRB or IEC and the 
CRO or the sponsor. The sponsor or CRO will be responsible for reporting SAEs to the 
regulatory authorities as required by the applicable regulatory requirements. 
7.6.7.3 
Special Situations - Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication errors (as defined below) in subjects treated with 
S-649266 or meropenem must be reported by the investigator to the CRO or the sponsor 
via fax using a Special Situations Report Form within 24 hours of becoming aware (refer 
to Section 7.6.7.2 for reporting destination). Special Situations information for Linezolid 
is not required to be reported. Adverse Events or SAEs associated with the administration 
of any medication will be reported by the investigator.  
• Abuse: Persistent or sporadic, intentional, excessive use of an investigational 
product, which is accompanied by harmful physical or psychological effects. 
• Misuse: Intentional and inappropriate use of an investigational product other than 
as directed or indicated at any dose. 
• Overdose: Intentional or unintentional intake of a dose of investigational product 
higher than the assigned dose in the protocol or labeling. 
• Medication Error: Any unintended error in the prescribing, dispensing, or 
administration of an investigational product. Cases of subjects missing doses of 
investigational product are not considered reportable as medication error.  
7.6.7.4 
Pregnancy 
Women of childbearing potential will be screened for pregnancy at the time of study 
enrollment. A positive test is reason for exclusion. Female subjects will be instructed to 
avoid conception until 28 days following treatment or according to country specific 
requirements, whichever is longer.  
If a female subject becomes pregnant during the study, investigator or subinvestigator 
will immediately discontinue study drug treatment and appropriate antibiotic therapy 
should be provided. All pregnancies that occur after the first dose of the study treatment 
through the EOS must be reported by the investigator to the CRO or sponsor within 
24 hours of becoming aware of the pregnancy using the Pregnancy Form (refer to 


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Section 7.6.7.2 for reporting destination). Pregnancy complications and elective 
terminations for medical reasons must be reported as AEs or SAEs as appropriate. 
Spontaneous abortion must be reported as an SAE. The outcome of the pregnancy (ie, 
birth, miscarriage, abortion) should be followed by the study site and must be reported 
using the Pregnancy Form.  
7.6.7.5 
Treatment-emergent Adverse Events 
Adverse events reported after the initial dose of study drug or comparator will be 
considered treatment-emergent adverse events (TEAEs). 
7.7 
Subject Withdrawal or Discontinuation from the Study 
Treatment 
The investigator will make every reasonable attempt to complete the study for each 
enrolled subject.  
Withdrawal 
A subject may withdraw consent to participate in the study for any reason at any time. 
The investigator will advise the sponsor about the withdrawal of any subject from the 
study by using the eCRF. Date of completion/ discontinuation of the study treatment, 
period of discontinuation, and reason for discontinuation will be entered in the CRF. For 
subjects who withdraw consent at any time after the start of treatment, all EOS study visit 
assessments should be completed, if possible. 
Discontinuation  
The investigator or subinvestigator may discontinue a subject from the study treatment 
for any of the following reasons. Please note that unless the subject withdraws consent to 
participate in the study, all randomized subjects should be followed for the entire duration 
of the study even if study drug treatment was discontinued prematurely due to AE or 
treatment failure: 
• A serious or intolerable AE occurs and the investigator considers that the subject 
should be withdrawn because of the AE 
• The target disease worsens because of poor response to the study treatment and 
the investigator considers that the subject should be withdrawn 
• The subject is lost to follow-up 
• The investigator determines that the subject should be removed from the study 
because of other reasons 
For subjects who are discontinued by the investigator or subinvestigator at any time after 
the start of treatment, they will be still considered to be in the study, and they should still 
be followed through to the completion of all study activities (ie, EOT, TOC, FU, and 
EOS, if possible). All subjects discontinued due to AEs will be followed until resolution 
of any AEs, until the unresolved AEs are judged by the investigator to have stabilized or 
the subject is lost to FU. 


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All withdrawn or discontinued subjects will remain in the study for safety and clinical 
outcome purposes. Subjects withdrawn or discontinued from study treatment should 
receive additional standard of care antibiotic therapy if, in the judgment of the 
investigator, such treatment is clinically indicated (see Section 6.2.4). 
7.8 
Other Study Procedures 
Not applicable 
7.9 
Appropriateness of Measurements 
The primary measure of efficacy selected in the study, all-cause mortality, has been 
discussed with regulatory agencies. The individual efficacy measurements for clinical or 
microbiological outcome selected for the study are commonly used in clinical trials of 
subjects with pneumonia. Therefore, these measurements are considered appropriate. 
The safety evaluations selected for the study are typical of those for this subject 
population and type of investigation and utilize widely accepted measures that are 
appropriate. 
7.10 Acceptable Time Windows 
Measurements for efficacy or safety endpoints will be performed according to the 
schedule of assessments shown in Appendix 1. The following time window, shown in 
Table 7-2, is acceptable.  
 
 
 


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Table 7-2 
Acceptable Time Windows 
Study Activity 
Acceptable Time Window 
Screening  
--- 
−48 hours 
Randomization 
Day 1  
--- 
Day 3 
pharmacokinetic 
blood sampling 
At approximately the same time 
as the EA evaluation  
Day 3 or Day 4 
 
Just prior to the next infusion 
–1 to 0 hours 
1 hour after the start of infusion 
± 15 minutes 
At the end of infusion 
–30 minutes to just before the 
end of infusion 
1 hour after the end of infusion (4 
hours after the start of infusion) 
± 0.5 hours 
EA 
Day 3  
+ 1 day 
EOT 
Last day of study treatment, 
clinical evaluations 
As soon as possible after last 
dose (same calendar day or 
within 24 hours)  
Unexpected EOT 
(an EOT with < 7 
days of treatment) 
Last day of study treatment 
clinical evaluations, and  
a blood sample should be 
obtained if possible 
Same calendar day or within 
24 hours  
TOC 
EOT + 7 
± 2 days 
FU 
EOT + 14  
± 3 days 
EOS 
EOT + 28 
± 3 days 
EA = Early Assessment; EOS = End of Study; EOT = End of Treatment; FU = Follow-up; TOC = Test of 
Cure 
8. STUDY ACTIVITIES 
The overall schedule of events for the study is presented in Appendix 1. The general 
philosophy about obtaining measurements, samples, or evaluations for this study is that 
any particular item that is obtained because of the standard of care for the ICU would not 
have to be repeated and the information can go directly into the eCRF. In the event that 
Screening and Randomization take place on the same day, only 1 set of laboratory 
evaluations, including microbiological cultures and clinical laboratory tests, needs to be 
drawn/recorded before initiation of treatment. Laboratory results, ECGs, and 
microbiological cultures obtained prior to informed consent for this study may be added 
to the screening eCRF as needed to complete the subject evaluation.  


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8.1 
Screening (Day –2 to Randomization)  
• Informed consent 
• Inclusion and exclusion criteria assessments 
• Baseline subject characteristics (demographics) 
• Medical history, including previous significant medical conditions 
• Pregnancy test 
• Physical examination, including height and body weight 
• Vital signs, including blood pressure, body temperature, pulse rate, and 
respiratory rate 
• Clinical laboratory tests, including hematology, blood chemistry, urinalysis, 
specialized tests, and others; see Table 7-1 
• 12-lead ECG 
• GCS  
• Calculate APACHE II score 
• Calculate SOFA score 
• Provide parameters for CPIS score 
• Clinical assessment of signs and/or symptoms 
• Oxygenation status 
• Chest radiograph 
• Lower respiratory tract specimens and blood for microbiological culture 
• AE assessment (begins with the signing of the informed consent form) 
• Prior and concomitant therapies 
• CrCl by Cockcroft-Gault equation and eGFR by MDRD equation (see 
Section 7.6.4.4) 
• Screen subject via IRT 
• Hospitalization 
8.2 
Treatment Period (Days 1 to 14) 
8.2.1 
Randomization and Treatment Initiation (Day 1) 
• Randomize subject via IRT 
• Initiate treatment based on eGFR by MDRD equation and CrCl by Cockcroft-
Gault equation 
8.2.2 
All Treatment Days 
• Continue randomized treatment  
• Vital signs, including blood pressure, body temperature, pulse rate, and 
respiratory rate 
• Oxygenation status 


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• Concomitant therapy 
• AE assessment 
• Hospitalization 
• Dosage adjustment considered necessary on review of renal function conducted 
per local clinical practice; however, the second or later dose adjustment needs to 
be done at least 24 hours after the previous dose adjustment 
• Survival 
8.2.3 
Treatment Day 3 or Day 4 
• Activities for all treatment days (see Section 8.2.2) 
• Clinical assessment of signs and/or symptoms 
• Plasma drug concentration for all subjects (see Section 7.5)  
8.2.4 
Early Assessment (Occurs Once at the Investigator’s Discretion 
During Day 3 or 4) 
• Activities for all treatment days (see Section 8.2.2) 
• Limited physical examination relevant to the subject’s current condition 
• Clinical laboratory tests, including hematology, blood chemistry, urinalysis; see 
Table 7-1 
• CrCl by Cockcroft-Gault equation and eGFR by MDRD equation 
• CrCl from urinary creatinine with a 2- to 8-hour urine collection, if needed 
• GCS 
• Calculate SOFA score 
• Provide parameters for CPIS score 
• Clinical assessment of signs and/or symptoms 
• Chest radiograph, if clinically indicated 
• Lower respiratory tract specimens and, if necessary, blood for microbiological 
culture 
• Assess clinical outcome 
• Assess microbiological outcome 
• Survival 
8.2.5 
Treatment Day 14 (If Not End of Treatment) 
In case treatment duration is extended beyond 14 days, an additional assessment will be 
conducted on Day 14.  
• Activities for all treatment days (see Section 8.2.2) 
• Limited physical examination relevant to the subject’s current condition 
• Clinical laboratory tests, including hematology, blood chemistry, and urinalysis;  


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see Table 7-1 
• GCS  
• Calculate SOFA score 
• Provide parameters for CPIS score 
• Clinical assessment of signs and/or symptoms 
• Chest radiograph, if clinically indicated  
• Lower respiratory tract specimens and, if necessary, blood for microbiological 
culture 
• Assess clinical outcome 
• Assess microbiological outcome 
• Survival 
• Record extension of treatment up to 21 days via IRT and reason for extension via 
eCRF as per Section 5.2 
8.2.6 
End of Treatment (Last Day of Study Treatment) 
• Activities for all treatment days (see Section 8.2.2) 
• If premature EOT, defined as < 7 days of treatment, a single blood draw for 
pharmacokinetics (within 24 hours of last dose) should be performed 
• Limited physical examination relevant to the subject’s current condition 
• Clinical laboratory tests, including hematology, blood chemistry, and urinalysis;  
see Table 7-1 
• GCS 
• Calculate SOFA score 
• Provide parameters for CPIS score 
• Clinical assessment of signs and/or symptoms 
• Chest radiograph  
• Lower respiratory tract specimens and, if necessary, blood for microbiological 
culture 
• Assess clinical outcome 
• Assess microbiological outcome 
• Record subject as EOT via IRT 
8.3 
Study Day 14 (14 Days After Initiation of Treatment) 
• Survival  
• Major nonfatal events, if present, should be evaluated 
8.4 
Test of Cure (End of Treatment + 7 Days) 
• Limited physical examination relevant to the subject’s current condition 


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• Vital signs, including blood pressure, body temperature, pulse rate, and 
respiratory rate 
• Clinical laboratory tests, including hematology, blood chemistry, urinalysis, and 
specialized tests; see Table 7-1 
• Clinical assessment of signs and/or symptoms 
• Oxygenation status 
• Chest radiograph 
• Lower respiratory tract specimens and, if necessary, blood for microbiological 
culture 
• GCS 
• Calculate SOFA score 
• Provide parameters for CPIS score subjects 
• AE assessment 
• Concomitant therapy 
• Assess clinical outcome 
• Assess microbiological outcome 
• Hospitalization 
• Survival  
8.5 
Follow-up (End of Treatment + 14 Days) 
• Limited physical examination relevant to the subject’s current condition 
• Vital signs, including blood pressure, body temperature, pulse rate, and 
respiratory rate 
• Clinical laboratory tests, including hematology, blood chemistry, and urinalysis;  
see Table 7-1 
• Clinical assessment of signs and/or symptoms 
• Oxygenation status 
• Chest radiograph, if clinically indicated 
• Lower respiratory tract specimens and, if necessary, blood for microbiological 
culture 
• GCS 
• Calculate SOFA score 
• Provide parameters for CPIS score 
• AE assessment 
• Concomitant therapy 
• Assess clinical outcome 
• Assess microbiological outcome 
• Hospitalization 


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• Survival 
8.6 
Study Day 28 (28 Days After Initiation of Treatment) 
• Survival 
• Major nonfatal events, if present, should be evaluated 
8.7 
End of Study (End of Treatment + 28 Days) 
• Limited physical examination relevant to the subject’s current condition 
• Vital signs, including blood pressure, body temperature, pulse rate, and 
respiratory rate 
• Clinical laboratory tests, including hematology, blood chemistry, and urinalysis;  
see Table 7-1, if required to follow abnormal safety test results 
• AE assessment 
• Concomitant therapy 
• Hospitalization 
• Survival 
The EOS assessment may be performed by phone to document current subject status, in 
which case, the physical examination, vital signs, and laboratory tests will not be 
performed.  
9. PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The statistical analyses and pharmacokinetic analyses will be performed by the sponsor 
or designee. The detailed statistical analyses methods will be specified in a SAP. 
Deviations from analyses outlined in the protocol will be detailed and justified in the 
SAP. The SAP will be finalized before the scheduled database lock. The separate detailed 
population pharmacokinetic analysis and PK/PD analysis plans also will be prepared.  
Unless otherwise noted, continuous variables will be summarized by using the number of 
nonmissing observations, arithmetic mean, standard deviation, median, minimum, and 
maximum values as descriptive statistics; categorical variables will be summarized by 
using the frequency count and the percentage of subjects in each category as descriptive 
statistics.  
All subject study data, including data not appearing in tables, will be presented in data 
listings by subject. In general, all tables and associated graphics will be presented by 
treatment group. Individual subject data, pharmacokinetic data, and any derived data will 
be presented by treatment and subject. All analyses and tabulations will be performed by 
using SAS® Version 9.2 or higher, Phoenix® WinNonlin® Version 6.2.1 or higher, and 
NONMEM® Version 7.3 or higher. 
All statistical testing is performed with a significance level of 2-sided 0.05 unless 


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otherwise noted.  
The following individual evaluations have been planned at these prespecified milestones 
during the course of the study: 
• When approximately 50 and 150 subjects have completed treatment and FU, an 
evaluation of safety and efficacy data will be performed by the Data Safety 
Monitoring Board (DSMB). 
• The nonevaluable rate will be assessed based on a blinded estimate performed 
after approximately 150 subjects are enrolled and the randomized population size 
may be adjusted to meet study requirements. 
• A blinded evaluation of all-cause mortality will be done after approximately 
150 subjects are enrolled and blinded re-estimation of sample size may be 
performed if deemed necessary. 
• If the mortality rate is deemed too low (≤ 8%) compared with the assumption of 
10% based on a blinded mortality rate when 50 subjects have completed the 
study, the lower limit of the acceptable APACHE II score will be set to ≥ 8. 
9.2 
Determination of Sample Size 
The study design and the primary objective are based on the hypothesis that S-649266 is 
noninferior to meropenem for the treatment of nosocomial pneumonia; this will be 
established based on a 12.5% noninferiority margin to exclude the possibility that 
S-649266 is more than 12.5% inferior to meropenem for the endpoint of all-cause 
mortality at Day 14. The 12.5% noninferiority margin was discussed with and agreed to 
by the US FDA. 
A sample size of 244 evaluable subjects (122 evaluable subjects in the S-649266 group 
and 122 evaluable subjects in the meropenem group) is required to have 90% power with 
a 1-sided significance level of 0.025 assuming a 10% all-cause mortality rate at Day 14 in 
both groups with a 12.5% noninferiority margin. It is further estimated that 
approximately 20% of randomized subjects will be nonevaluable, and therefore excluded 
from the primary population, because they have not received any doses of study drug 
treatment or they had a bacterial pneumonia caused by anaerobic and/or Gram-positive 
aerobic bacteria only. Therefore, it is expected that it will be necessary to randomize up 
to 300 subjects. The nonevaluable rate will be assessed based on a blinded estimate 
performed after approximately 150 subjects are enrolled and the randomized population 
size may be adjusted to meet study requirements. Additionally, the sponsor will conduct a 
blinded evaluation of all-cause mortality after approximately 150 subjects are enrolled 
and may perform a blinded re-estimation of sample size if deemed necessary.  
9.3 
Analysis Populations 
The following analysis populations will be examined in this study:  
• Intent-to-treat (ITT) population: all randomized subjects who received at least 
1 dose of a study drug treatment  


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• Modified ITT (mITT) population: all subjects in the ITT population who meet 
either of the following: 
- Those who have evidence of a Gram-negative infection of the lower 
respiratory tract based on either a culture, Gram-stain, or other diagnostic test 
- Those who have evidence of a lower respiratory tract infection but culture or 
other diagnostic tests do not provide a microbiologic diagnosis 
Note: Subjects with bacterial pneumonia caused by Gram-positive aerobic or 
anaerobic (Gram-positive or Gram-negative) bacteria only will be excluded from 
the mITT population. 
• Micro-evaluable Per-protocol (ME-PP) population: all subjects in the mITT 
population who do not have major protocol violations and have a culture 
confirmed diagnosis of a Gram-negative bacterium  
• Safety population: all randomized subjects who receive at least 1 dose of the study 
treatment (ITT population); this population will be analyzed according to the 
treatment that the subjects actually received, rather than the treatment to which the 
subjects were randomized 
• The pharmacokinetic concentration population: all subjects who undergo plasma 
sampling and have at least 1 evaluable pharmacokinetic assay result for S-649266; 
this population will be used for the concentration listing, plotting of the 
concentration-time data, population pharmacokinetic analyses, PK/PD analyses, 
and the concentration summary 
9.4 
Handling of Missing Data 
Missing data will not be replaced.  
9.5 
Subject Disposition 
Among the randomized subjects in the Safety population, the ITT population, the mITT 
population, and the ME-PP population, the number and percentage of subjects who 
complete the study and those subjects who prematurely discontinue before completing at 
least 7 days of treatment from the study will be summarized. In addition, reasons leading 
to study discontinuation will be summarized for each treatment group. The number and 
percentage of subjects randomized to each study treatment in each analysis population 
also will be presented.  
9.6 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized with descriptive statistics 
for the ITT population and the mITT population. 
9.7 
Prior Therapies 
Prior therapies for drugs will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Subjects who received prior therapy will be listed and 
summarized for the Safety population and the mITT population.  


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9.8 
Concomitant Therapies 
Concomitant therapies for drugs will be coded using the WHO-DD. Subjects who 
received concomitant therapy will be listed and summarized for the Safety population and 
the mITT population. 
9.9 
Efficacy Analyses 
The mITT population will be the primary population for efficacy. The ITT population 
and the ME-PP population will be used for sensitivity analyses.  
9.9.1 
Primary Efficacy Endpoint 
All-cause mortality at Day 14 for S-649266 or the active comparator, meropenem, in 
adult subjects with either HABP, VABP, or HCABP.  
The adjusted estimates of the difference in the all-cause mortality at Day 14 between 
S-649266 and meropenem will be presented along with 95% CIs based on a stratified 
analysis using Cochran-Mantel-Haenszel (CMH) weights. The CI will be 2-sided. The 
CMH weights will be calculated with stratification factor APACHE II score (≤ 15 and ≥ 
16). Noninferiority can be concluded if the upper bound of a 2-sided 95% CI for the 
difference in mortality at Day 14 between the 2 treatment groups (S-649266 and 
meropenem) is smaller than a noninferiority margin of 12.5%. 
9.9.2 
Key Secondary Endpoints 
The key secondary endpoints will be compared between treatment groups. 
• The clinical outcome of treatment with S-649266 or meropenem per subject at 
TOC  
• The microbiologic outcome of treatment with S-649266 or meropenem per 
subject at TOC 
• Day 14 all-cause mortality rates of S-649266 with meropenem for superiority of 
S-649266 
In the analysis of key secondary endpoints, a fixed-sequence testing approach will be 
applied for multiplicity adjustment with the primary efficacy analysis in order of (1) the 
microbiologic outcome at TOC, (2) the clinical outcome at TOC, and (3) Day 14 
all-cause mortality rates of S-649266 with meropenem for superiority of S-649266 
A per-subject microbiological outcome is determined based on individual microbiological 
outcomes for each baseline Gram-negative pathogen. For the subject to have a favorable 
microbiological outcome (ie, eradication), the outcome for each baseline Gram-negative 
pathogen has to be favorable (ie, all baseline pathogens are eradicated at the specified 
time point). If the microbiological outcome for any Gram-negative pathogen is 
unfavorable, the subject is considered to have an unfavorable overall (per-subject) 
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Superiority of S-649266 over meropenem can be concluded if the 2-sided 95% CI for the 
difference in mortality at Day 14 between the 2 treatment groups (S-649266 and 
meropenem) lies completely below zero. 
9.9.3 
Other Secondary Efficacy Endpoints 
The other secondary endpoints will be compared between treatment groups.  
• The clinical outcome of treatment with S-649266 or meropenem per subject at 
EA, EOT, and FU  
• The microbiologic outcome of treatment with S-649266 or meropenem per 
subject at EA, EOT, and FU 
• The all-cause mortality at Day 28  
• The all-cause mortality during treatment and the follow-up period (until EOS)  
• The resource utilization required for the treatment of the study-qualifying 
infection. This end point will not be included in the CSR, but it will be analyzed 
based upon a separate analytical plan after the conclusion of the study. 
9.10 Safety Analyses 
Safety assessments consist of AEs, clinical laboratory tests (hematology, blood 
chemistry, and urinalysis), specialized chemistry tests, and vital signs. Safety analyses 
will be performed for the Safety population. 
9.10.1 
Adverse Events 
Adverse events will be classified by System Organ Class and Preferred Term using the 
Medical Dictionary for Regulatory Activities (MedDRA). Of AEs reported in the eCRF, 
TEAEs will be used for the safety analyses. The definition of TEAE is described in 
Section 7.6.7.5.  
The number and the percentage of subjects who experienced TEAEs will be summarized 
by treatment group. TEAEs will be tabulated in a similar fashion. The number of AEs, 
which are counted by cases reported, will also be presented in the same AE category in 
the overall summary.  
For the summary of TEAEs by System Organ Class and Preferred Term, the number of 
subjects who experienced AEs will be presented for each treatment group with the 
percentage of subjects. The summary by severity and the summary by relationship to 
study treatment will be presented by System Organ Class and Preferred Term.  
All AEs including AEs that have occurred before or after the first dose of the study 
treatment will be listed. 


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9.10.2 
Vital Signs 
Summary statistics for vital signs will be presented for EOT, TOC, and for the change 
from baseline to each time point. Baseline will be the last value obtained before 
randomization.  
9.10.3 
Clinical Laboratory Analysis 
Summary statistics for laboratory test data will be presented for each scheduled time 
point and for the change from baseline to each time point. Baseline will be the last value 
obtained before randomization. 
9.11 Pharmacokinetics 
Individual plasma concentrations of S-649266 will be listed and summarized by nominal 
sampling time window, and if possible, dosing group based on renal function. The time 
course of individual and mean plasma concentrations will be presented by appropriate 
graphics. Population pharmacokinetic analyses will be performed and reported separately 
by Clinical Pharmacology & Pharmacokinetics of Shionogi & Co., Ltd. 
9.12 Pharmacokinetic/Pharmacodynamic Analyses 
The PK/PD analyses will be performed and reported separately by the Clinical 
Pharmacology & Pharmacokinetics of Shionogi & Co., Ltd. For each subject randomized 
to S-649266 with an identified Gram-negative pathogen, the % fT>MIC will be calculated 
and the relationship between % fT>MIC, and clinical and microbiologic outcome will be 
described. 
9.13 Pharmacoeconomics Associated with Treatment 
The pharmacoeconomics of treatment collected during the study will focus primarily on 
the resource utilization required for the treatment of the study-qualifying infection. 
Facility utilization will be assessed by determination of the time in 24-hour days 
associated with the treatment of the infection:  
• Length of hospital stay attributable to the infection 
• Days in ICU 
• Hours on assisted mechanical ventilation including ventilation method and 
parameters 
• Days in isolation for infection control (ICU or ward) 
• Discharge status, eg, to home, hospice, or other healthcare facility (nursing home 
or long-term acute hospital) 
Analyses of the above data will not be included in the CSR, but it will be analyzed based 
upon a separate analytical plan after the conclusion of the study. 


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9.14 Data Safety Monitoring Board Safety and Efficacy Evaluation 
When approximately 50 and 150 randomized and treated subjects have completed 
treatment and FU, an evaluation of safety and efficacy data will be performed by the 
DSMB according to the DSMB charter. A safety review, including AEs and clinical 
laboratory tests (hematology, blood chemistry, urinalysis, vital signs, and physical 
examinations), will be summarized by treatment group. An efficacy review, including 
clinical evaluations, central laboratory findings, and central microbiological laboratory 
findings, will be summarized by treatment group. The description of the DSMB is 
described in Section 10.8.1. After the review, the DSMB will communicate their 
recommendations to the sponsor. The recommendations may include, but are not limited 
to, continuing, stopping, or modifying the study; they will also provide the reason for 
each recommendation. 
9.15 Interim Analysis 
The results of interim analyses performed by the DSMB are blinded to sponsor’s 
personnel and not shared with the sponsor. An alpha spend of 0.0001 based on 
Haybittle-Peto will be used to control alpha for each interim analysis. 
10.  ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
Sponsor for North America 
and South America: 
Shionogi Inc. 
300 Campus Drive, Florham Park, NJ 07932 USA 
Sponsor for Europe/Middle 
East: 
Shionogi B.V. 
Kingsfordweg 151,  
1043 GR Amsterdam, Netherlands   
Sponsor for Asia-Pacific: 
Shionogi & Co., Ltd. 
(Head Office) 1-8 Doshomachi, 3 Chrome, Chuo-ku, 
Osaka 541-0045, Japan 
(Development Office) 12F, Hankyu Terminal Bldg., 
1-4, Shibata 1-chome, Kita-ku, Osaka 530-0012, 
Japan 
Sponsor Contact: 
 
Shionogi Inc. 
300 Campus Drive 
Florham Park, NJ 07932, USA 
 
 
  
Shionogi B.V. 
Kingsfordweg 151,  
1043 GR Amsterdam, Netherlands   
 
E-mail: 
 


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Clinical Research Department, Shionogi & Co., Ltd. 
1-1-4, Shibata, Kita-ku, Osaka 530-0012, Japan 
Tel: 
 
 
 
 
 
 
 
Medical Monitor in Shionogi: 
 
 Clinical Development  
Shionogi Inc. 
300 Campus Drive 
Florham Park, NJ 07932, USA 
 
Medical Monitor in CRO:  
  
 
 
 
 
 
 
 
Investigator and Study Center: 
Multicenter 
Study Monitoring: 
 
 
 
Bioanalytical Laboratory: 
  
  
 
  
  
 
Microbiological Laboratory: 
 
 
 
  
 
 
10.2 Institutional Review Board or Institutional Ethics Committee 
Approval 
Relevant IRBs/IECs will safeguard the rights, safety, and well-being of the subjects by 
reviewing the following study documents: the protocol, informed consent form, written 
information on subject recruitment procedures (if applicable), other written information 


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given to the subjects, Investigator’s Brochure, safety updates, annual progress reports (if 
applicable), and any significant revisions to these documents. The investigator or the 
sponsor will provide these study documents to the IRB/IEC. The IRB/IEC will be 
appropriately constituted in accordance with ICH good clinical practice (GCP), and local 
requirements, as applicable. The study will be undertaken only after the IRB/IEC has 
given full approval and the sponsor has received a document being approved.  
Amendments to the protocol will be subject to the same requirements as the initial 
review. The investigator will submit all periodic reports and updates as required by the 
IRB/IEC. The investigator will inform the IRB/IEC of any reportable AEs. 
10.3 Ethical Conduct of the Study 
The study will be conducted in accordance with all appropriate regulatory requirements 
and under the protocol approved by an IRB/IEC. The study will be conducted in 
accordance with current ICH GCP, all appropriate subject privacy requirements, and the 
ethical principles that are outlined in the Declaration of Helsinki.  
10.4 Subject Information and Consent 
The sponsor will provide the investigators with a proposed informed consent form that 
complies with the ICH GCP guidelines and regulatory requirements. The sponsor must 
agree to any changes to the proposed consent form suggested by the investigator prior to 
submission to the IRB/IEC, and the IRB/IEC approved version must be provided to the 
site monitor after IRB/IEC approval. 
The investigator will generate an informed consent form for the study. The consent form 
will include all the elements required by the ICH GCP and any additional elements 
required by local regulations and will be reviewed and approved by the appropriate 
IRB/IEC before use. The investigator or subinvestigator will explain the nature, purpose, 
methods, reasonable anticipated benefits, and potential hazards of the study to the subject 
or, if incapacitated, to his/her legally qualified representative in simple terms by using the 
consent form before the subject is entered into the study. The method of obtaining and 
documenting informed consent will comply with ICH GCP and all applicable regulatory 
requirements. 
10.5 Subject Confidentiality 
Procedures for protecting subject privacy must adhere to applicable data privacy laws and 
regulations. In order to maintain subject privacy, all eCRFs, study drug accountability 
records, study reports, and communications will identify the subject by the subject 
number. The investigator will grant site monitors and auditors of the sponsor or designee 
and regulatory authorities access to all source documents for verification of data collected 
on the eCRFs and for verification of the data collection process. The subject’s 
confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations. The investigator and the sponsor are 
responsible for ensuring that sensitive information is handled in accordance with local 
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Appropriate consent and authorization for use and disclosure and/or transfer (if 
applicable) of protected information must be obtained. 
Data on subjects collected on eCRFs during the study will be documented in an 
anonymous fashion, and the subject will only be identified by the subject number. In the 
emergent or rare event that for safety or regulatory reasons it is necessary to identify a 
subject, the sponsor and the investigator are bound to keep this information confidential. 
10.6 Study Monitoring 
The sponsor or designee will monitor the study to ensure that the study is conducted in 
accordance with ICH GCP requirements and protocol. The study monitoring will be 
performed by a representative of the sponsor (site monitor) through on-site monitoring 
visits as frequently as necessary and by frequent communications (e-mail, letter, 
telephone, and fax). The site monitor will review data recorded in the eCRFs, verify the 
eCRF entries with direct access to source documents, collect any safety/efficacy 
information on subjects, verify that amounts of unused study drugs are accurate, and 
check retention of source documents and essential documents.  
10.7 Case Report Forms and Source Documents 
10.7.1 
Case Report Forms 
The eCRFs for each subject who signed informed consent will be made accessible to the 
investigator, and historical information and study data, which are specified by the 
protocol, will be recorded in the eCRFs by the investigator. All subject data from the 
study evaluations must be collected on source documents and promptly entered in the 
eCRFs in accordance with the specific instructions. The eCRF entries will be performed 
by an investigator, subinvestigator, and study coordinator who are authorized in 
documentation.  
When queries are generated by the sponsor or designee to the participating medical 
institutions for resolution, eCRF data may be changed or a response will be recorded in 
accordance with the specific instructions. Appropriate documentation of any changes to 
the eCRF will be maintained in the study record. The investigator must ensure that data 
reported on the eCRF are accurate, complete, legible, and timely and sign the eCRFs to 
verify the integrity of the data recorded. 
A list of the reference ranges for all laboratory tests to be undertaken will be a part of the 
documentation to be collated prior to the initiation of study. The list of reference ranges 
for all laboratory tests should be updated if changes occur during the study. If a central 
laboratory has been selected to perform any or all tests, it is essential that all the reference 
ranges for the laboratory tests should also be collected.  
10.7.2 
Source Documents 
Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, 


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AEs, and subject status. However, the following data can be recorded directly in the 
eCRF as source data: 
• Reason for use of prior therapy or concomitant therapy 
• Severity, seriousness, and causal relationship to the study treatment of AE 
• Any comments inserted into eCRF 
Data automatically calculated by the eCRF system do not have to be captured in source 
documents, eg, QTc. 
The investigator must maintain source documents, such as laboratory reports and 
complete medical history and physical examination reports. All the source documents 
must be accessible for verification by the site monitor, auditor, IRB/IEC, and inspectors 
from regulatory authorities. Direct access to these documents must be guaranteed by the 
investigator, subinvestigator, or study coordinator, who must provide support at all times 
for these activities. For all sources of original data required to complete the eCRF, the 
nature and location of the source documents will be identified by the sponsor and the site 
staff. If electronic records are maintained at the medical institution, the method of 
verification must be specified in a document within the medical institution.  
10.7.3 
External Data 
The following data will be reported in documents that are separate from the eCRFs.  
• Microbiological results from central laboratory 
• Clinical laboratory results from central laboratories 
• Concentration of S-649266 in plasma, ELF, or other biological fluids/tissues 
determined by the bioanalytical laboratory, according to procedures specified in a 
separate document 
• Population pharmacokinetics and PK/PD analyses results 
10.8 Committees 
10.8.1 
Independent Data Safety Monitoring Board 
An independent DSMB will be established for this study. Details of the DSMB 
composition, roles, and responsibilities, and processes will be documented in a separate 
DSMB charter. 
10.9 Termination or Suspension of the Study 
10.9.1 
Termination or Suspension of the Entire Study 
The sponsor may prematurely terminate or suspend the study at any time for the 
following reasons:  
• Ensuring subject safety becomes difficult due to safety concerns (eg, the 
occurrence of many treatment-related SAEs) 


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• Achieving the purpose of the study is considered impossible (eg, data suggest lack 
of efficacy/safety, inadequate recruitment of subjects) 
If the study is prematurely terminated or suspended, the sponsor should promptly inform 
the investigators. The investigator or subinvestigator should promptly inform the 
participating subjects and change the study treatment to other appropriate therapy.  
For withdrawal criteria for individual subjects, see Section 7.7. 
10.9.2 
Termination or Suspension of the Study by Medical Institution 
The investigator may prematurely terminate or suspend the study in the medical 
institution with agreement of the sponsor at any time when the investigator considers that 
ensuring safety of the study is difficult due to safety concerns (eg, the occurrence of 
many treatment-related SAEs). 
The sponsor may request the investigator to prematurely terminate or suspend the study 
in the medical institution at any time due to major violations/deviations from the 
protocol, other procedures, or ICH GCP guidelines. 
If the study is prematurely terminated or suspended, the investigator or subinvestigator 
should promptly inform the corresponding IRB/IEC and participating subjects and 
change the study treatment to other appropriate therapy.  
10.10 Protocol Deviations and Modifications 
The investigator will conduct the study in compliance with the protocol provided by the 
sponsor and the approval/favorable opinion given by the IRB/IEC and the regulatory 
authorities. Changes to the protocol will require written IRB/IEC approval/favorable 
opinion prior to implementation, except when the modification is needed to eliminate an 
immediate hazard to subjects.  
The investigator or subinvestigator should document any deviation from the protocol and 
the reason. If the investigator deviates from the protocol or a change of the protocol to 
eliminate an immediate hazard to subjects, the record should be immediately submitted to 
the sponsor, the medical institution, and the IRB/IEC by the investigator, and the 
IRB/IEC will provide expedited review and approval/favorable opinion. After the 
investigator obtained approval/favorable opinion of the IRB/IEC, the investigator should 
obtain written agreement of the sponsor. 
When a deviation from the protocol is required to eliminate immediate hazards to 
subjects, the investigator will contact the sponsor, if circumstances permit, to discuss the 
planned course of action. Any deviations from the protocol must be fully documented on 
source documentation. 


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10.11 Data Management 
The sponsor or designee will be responsible for data management and data analysis. 
These procedures are specified in a separate document. 
10.12 Retention of Data 
The study documents must be maintained as specified in the ICH GCP guidelines and as 
required by the applicable regulatory requirements. The investigator and study site should 
take measures to prevent accidental or premature destruction of these documents. 
If the sponsor is granted manufacturing and marketing approval for the drug, the sponsor 
will promptly notify the investigator or the head of the study center in writing. 
Records will be retained for any of the following periods: 
• At least 2 years after the last marketing application approval 
• 2 years after formal discontinuation of the clinical development of the 
investigational product 
• Another period according to applicable country regulatory requirements, 
whichever is later  
However, the duration of retention may be prolonged in accordance with an agreement 
with the sponsor. In the event that the institution or investigator is unable or unwilling to 
retain study records as outlined in the clinical study agreement, the institution or 
investigator shall notify the sponsor, and the sponsor shall be entitled, at its expense, to 
take custody of the study records. In no event shall any study records be destroyed or 
disposed of without the prior written consent of the sponsor. 
10.13 Quality Control and Assurance 
The sponsor or designee will implement and maintain quality control and quality 
assurance procedures with written standard operating procedures to ensure that the study 
is conducted and data are generated, documented, and reported in compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
This study will be conducted in accordance with the provisions of the Declaration of 
Helsinki and all revisions thereof, in accordance with ICH GCP, and as required by the 
applicable regulatory requirements. 
Necessary training for the study will be provided at the investigator's meeting and for 
study center personnel prior to the initiation of the study.  
10.14 Publication and Disclosure Policy 
All information regarding S-649266 supplied by the sponsor to the investigator is 
privileged and confidential. The investigator agrees to use this information to accomplish 
the study and will not use it for other purposes without consent from the sponsor. It is 


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understood that there is an obligation to provide the sponsor with complete data obtained 
during the study. The information obtained from the clinical study will be used toward 
the development of S-649266 and may be disclosed to regulatory authorities, other 
investigators, corporate partners, or consultants as required. 
The sponsor will retain ownership of all data. All proposed publications based on the 
study will be subject to the sponsor's approval requirements. 
The key design elements of this protocol will be posted in a publicly accessible 
database(s), eg, ClinicalTrials.gov, European registries, and the Japan Pharmaceutical 
Information Center Clinical Trial Information.  
10.15 Financial Disclosure 
The information on financial disclosure for investigators will be addressed in a separate 
agreement between the sponsor and the investigator. 


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29. Guidance for Industry. Drug Interaction Studies. — Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations. U.S. Department of Health 
and Human Services Food and Drug Administration Center for Drug Evaluation and 
Research (CDER) 2012 February.  
30. Guideline on the investigation of drug interactions. European Medicine Agency, 
Committee for Human Medicinal Products (CHMP) 21 June 2012 
EMA/CPMP/EWP/560/95/Rev. 1 Corr. 2. 
31. Concept Paper on revision of the points to consider on pharmacokinetics and 
pharmacodynamics in the development of antibacterial medicinal products 
(CHMP/EWP/2655/99) and conversion to a CHMP guideline. European Medicine 
Agency, Committee for Human Medicinal Products (CHMP) 2014, February. 
32. Levey AS, Greene T, Kusek J, Beck G. A simplified equation to predict glomerular 
filtration rate from serum creatinine [abstract]. J Am Soc Nephrol 2000;11:155A. 
33. Irie F, Iso H, Sairenchi T, et al. The relationships of proteinuria, serum creatinine, 
glomerular filtration rate with cardiovascular disease mortality in Japanese general 
population. Kidney Int 2005;69:1264-71. 
34. Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:31-41. 
35. Merrem I.V. [Package Insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 
2016. http://www.azpicentral.com/merrem/merremiv.pdf Accessed 09 December 
2016.  


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Appendix 1 
Time and Events Schedule 
Evaluation 
Screening/ 
Baseline  
 
Treatment Period 
Test of 
Cure 
(TOC) 
 
Follow-up 
(FU) 
End of Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
 
Day 1 
EA 
Day 
3 to 4 
Day 14b 
EOTc 
EOT + 7  
(± 2) 
Day 28b 
EOT + 14  
(± 3)  
EOT + 28 
(± 3) 
Informed Consent 
X 
Randomization                                                  
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical Historyd 
X 
 
 
 
 
 
 
 
 
Physical Examination 
Xe 
 
Xf 
Xf 
Xf 
Xf 
 
Xf 
Xf, g 
GCS 
X 
 
X 
X 
X 
X 
 
X 
 
APACHE II Score 
X 
 
 
 
 
 
 
 
 
SOFA Score 
X 
 
X 
X 
X 
X 
 
X 
 
Clinical Assessment of 
Signs and/or Symptoms 
X 
 
X 
X 
X 
X 
 
X 
 
Oxygenation Status 
X 
X 
X 
X 
X 
X 
 
X 
 
Chest Radiographs  
X 
 
Xh 
X 
X 
X 
 
Xh 
 
CPIS Parametersi 
X 
X 
X 
X 
X 
X 
 
Xi 
 
Pregnancy Testj 
X 
 
 
 
 
 
 
 
 
Hematology Tests, Blood 
Chemistry Tests, and 
Urinalysis (see  
Table 7-1) 
X 
 
X 
X 
X 
X 
 
X 
Xg 
Specialized Tests (see 
Table 7-1) 
X 
 
 
 
 
X 
 
 
 


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Evaluation 
Screening/ 
Baseline  
 
Treatment Period 
Test of 
Cure 
(TOC) 
 
Follow-up 
(FU) 
End of Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
 
Day 1 
EA 
Day 
3 to 4 
Day 14b 
EOTc 
EOT + 7  
(± 2) 
Day 28b 
EOT + 14  
(± 3)  
EOT + 28 
(± 3) 
CrCl from Serumk 
Creatinine and MDRD-
eGFR  
X 
 
X 
 
 
 
 
 
 
CrCl from Urinary 
Creatininek 
X 
 
X 
 
 
 
 
 
 
Vital Signsl 
X 
X 
X 
X 
X 
X 
 
X 
Xg 
12-lead ECG  
X 
 
 
 
 
 
 
 
 
Drug Administrationm 
 
X 
X 
X 
X 
 
 
 
 
Assess Clinical Outcome 
 
 
X 
X 
X 
X 
 
X 
 
Microbiological Outcome 
 
 
X 
X 
X 
X 
 
X 
 
Lower Respiratory 
Specimens for 
Microbiologic Culturesn 
X 
 
X 
X 
X 
X 
 
X 
 
Blood Cultureso 
X 
 
X 
X 
X 
X 
 
X 
 
Blood PK Samplesp  
 
 
 
Xp 
 
Xp 
 
 
 
 
AE Assessment 
X 
 
 
 
 
 
 
 
 
X 
Concomitant Therapy 
X 
 
 
 
 
 
 
 
X 
Hospitalization 
(see Section 7.2.1) 
X 
 
 
 
 
 
 
 
X 
Survivalq 
X 
 
 
 
 
 
 
 
X 
AE= adverse event; APACHE II = Acute Physiology and Chronic Health Evaluation II; CPIS = Clinical Pulmonary Infection Score; CrCl = creatinine clearance; EA = Early 
Assessment; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = End of Study; EOT = End of Treatment; FU = Follow-up; GCS = Glasgow Coma 
Scale; I/E = inclusion/exclusion; MDRD = modification of diet in renal disease, PK = pharmacokinetics; q8h = every 8 hours; q12h = every 12 hours; SOFA = Sequential Organ 
Failure Assessment; TOC = Test of Cure 
a 
If Screening and Randomization (Day 1) occur on the same day, the activities of Screening and Day 1 should be completed, without duplication of assessments. 
b 
Additional assessment will be conducted on Day 14, if treatment duration is extended beyond 14 days to up to 21 days; survival will be recorded on Day 14 and Day 28. 


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c 
EOT evaluations occur on the last day of study treatment; EOT can be any time after the subject had at least 1 dose of study treatment, duplication of assessments for a given 
day and EOT is not necessary. 
d 
Include a review of prior/concomitant therapies. 
e 
A complete physical examination, including measurement of body weight and height, will be performed at Screening only. 
f 
A limited physical examination relevant to the subject’s current condition will be performed. 
g 
If EOS evaluation is by phone, physical examination, laboratory tests, and vital signs will not be performed. 
h 
Chest radiographs will be performed if clinically indicated. Applicable only to Germany due to local requirements: In sites where chest radiographs after Screening are part of 
the standard of care, ie, a chest radiograph is clinically indicated by the treating physicians, it can be performed as usual without a special informed consent. If a chest 
radiograph is not standard of care (no clinical indication), and is planned based on the study protocol, an informed consent from a conscious patient is mandatory. Chest 
radiographs without clinical indication cannot be performed in unconscious patients. 
i 
Most recent chest radiograph is used for the CPIS calculation. 
j 
Urine or serum pregnancy test only for females who are not postmenopausal or surgically sterile. 
k 
The CrCl (the Cockcroft-Gault equation) and eGFR (the MDRD equation) will be calculated from the serum creatinine. For subjects with eGFR ≥ 90 mL/min/1.73 m2 and 
CrCl ≥ 120 mL/min at baseline and EA, urine samples will be collected a time interval as short as 2 hours or up to 8 hours. 
l 
Blood pressure (systolic/diastolic pressures), body temperature, pulse rate, and respiratory rate. Once a day during Screening, and 3 times a day during treatment in hospital. 
m 
Drug administration is q8h daily for S-649266 and meropenem unless change is made because of renal function. Linezolid is dosed q12h daily for at least 5 days. 
n 
Lower respiratory tract specimens for microbiologic cultures must be obtained at specified times. When subjects are recovering from pneumonia and produce little respiratory 
secretion, at least an attempt to collect respiratory specimen needs to be made (eg, ask subjects to cough, cough up sputum, or conduct suction from endotracheal tube). 
o 
Two blood samples from separate venipunctures will be collected within 48 hours prior to start of the first dose of study treatment. Subsequent blood cultures are to be 
completed only if the immediate previous culture is positive. 
p 
PK blood samples will be drawn on Day 3 or Day 4 of study drug treatment; 1 draw just prior to the infusion of the dose, 1 hour after start of infusion, before the end of 
infusion, and at 1 hour after the end of infusion. Subjects with nonstable renal function resulting in a dosage adjustment after EA will undergo another blood PK sampling 24 
to 72 hours after their dosing adjustment. If possible, a single blood draw should be performed as soon as possible (within 24 hours of last dose) in the case of premature EOT, 
which is defined as receiving < 7 days of intravenous treatment.  
q 
Survival is confirmed daily and continuously during the study. Mortality at Days 14 and 28 are study endpoints      


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Appendix 2 
Glasgow Coma Scale 
Eye Opening 
Spontaneous 
4 
To speech 
3 
To pain 
2 
None 
1 
Best Verbal 
Response 
Orientated 
5 
Confused 
4 
Words 
3 
Sounds 
2 
None 
1 
Best Motor 
Response 
Obey commands 
6 
Localizing 
5 
Normal flexion 
4 
Flexing 
3 
Extension 
2 
None 
1 
In ventilated and sedated subjects, the Glasgow Coma Scale cannot be properly assessed, and a 
normal score of 15 could be used to complete the APACHE II and SOFA scores. If a reliable 
presedation score is available, it can be used. 
 
Reference: 
Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma 
Scale at 40 years: standing the test of time. Lancet Neurol 2014;13:844-54. 
 
 


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Appendix 3 
APACHE II Score 
The APACHE II Severity of Disease Classification System 
Physiologic Variable 
High Abnormal Range  
 
 
Low Abnormal Range 
  
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
Temperature – Rectal* 
(°C) 
>41 
39 to 
40.9 
  
38.5 to 
38.9 
36 to 
38.4 
34 to 
35.9 
32 to 
33.9 
30 to 
31.9 
<29.9 
Mean Arterial Pressure - 
mm Hg 
>160 
130 to 
159 
110 to 
129 
  
70 to 
109 
  
50 to 69 
  
<49 
Heart Rate (ventricular 
response) 
>180 
140 to 
179 
110 to 
139 
  
70 to 
109 
  
55 to 69 
40 to 54 
<39 
Respiratory Rate 
(non-ventilated or 
ventilated) 
>50 
35 to 49 
  
25 to 34 
12 to 24 
10 to 11 
6 to 9 
  
<5 
Oxygenation: A-aDO2 or 
PaO2 (mm Hg) 
a. FIO2 >0.5 record A-
aDO2 
 
 
b. FIO2 <0.5 record PaO2 
 
 
>500 
 
 
350 to 
499 
 
 
200 to 
349 
  
 
 
<200 
 
  
  
>70 
  
  
  
  
 
 
61 to 70 
  
  
  
  
 
 
  
55 to 60 
  
  
  
  
 
 
<55 
Arterial pH (preferred)  
 or 
 
Serum HCO3 (venous 
mEq/L) 
(not preferred, but may 
use if no ABGs) 
>7.7 
  
  
 
>52 
7.6 to 
7.69 
  
 
41 to 
51.9 
  
7.5 to 
7.59 
  
 
32 to 
40.9 
7.33 to 
7.49 
  
22 to 
31.9 
  
7.25 to 
7.32 
  
18 to 
21.9 
7.15 to 
7.24 
  
15 to 
17.9 
<7.15 
  
  
 
<15 
Serum Sodium (mEq/L) 
>180 
160 to 
179 
155 to 
159 
150 to 
154 
130 to 
149 
  
120 to 
129 
111 to 
119 
<110 
Serum Potassium 
(mEq/L) 
>7 
6 to 6.9 
  
5.5 to 
5.9 
3.5 to 
5.4 
3 to 3.4 
2.5 to 
2.9 
  
<2.5 
Serum Creatinine 
(mg/dL) 
Double point score for 
acute renal failure 
>3.5 
2 to 3.4 
1.5 to 
1.9 
  
0.6 to 
1.4 
  
<0.6 
  
  
Hematocrit (%) 
>60 
  
50 to 
59.9 
46 to 
49.9 
30 to 
45.9 
  
20 to 
29.9 
  
<20 
White Blood Cell Count 
(total/mm3) 
(in 1000s) 
>40 
  
20 to 
39.9 
15 to 
19.9 
3 to 
14.9 
  
1 to 2.9 
  
<1 
Glasgow Coma Score 
(GCS) 
Score = 15 minus actual GCS 
A.  Total Acute Physiology Score (sum of 12 above points) 
B.  
Age points (years) <44=0; 45 to 54=2; 55 to 64=3; 65 to 74=5; >75=6 
C.  
Chronic Health Points (see below) 
Total APACHE II Score (add together the points from A+B+C) 
A-aDO2 = alveolar-arterial pressure difference for oxygen; ABG = arterial blood gas; APACHE II = Acute Physiology and Chronic 
Health Evaluation II; FiO2 = fraction of inspired oxygen; GCS = Glasgow Comma Score; PaO2 = partial pressure of oxygen 
* 
If core temperature measurement is not available (ie, tympanic, rectal, esophageal), oral and axillary temperatures could be 
adjusted by adding 0.5°C and 1°C, respectively. 
 
Chronic Health Points: If the subject has a history of severe organ system insufficiency 
or is immunocompromised as defined below, assign points as follows: 5 points for 


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nonoperative or emergency postoperative subjects and 2 points for elective postoperative 
subjects.  
Definitions: organ insufficiency or immunocompromised state must have been evident 
prior to this hospital admission and conform to the following criteria:  
• 
Liver – biopsy proven cirrhosis and documented portal hypertension; episodes of 
past upper gastrointestinal bleeding attributed to portal hypertension; or prior 
episodes of hepatic failure/encephalopathy/coma  
• 
Cardiovascular – New York Heart Association Class IV  
• 
Respiratory – chronic restrictive, obstructive, or vascular disease resulting in 
severe exercise restriction (eg, unable to climb stairs or perform household duties; 
or documented chronic hypoxia, hypercapnia, secondary polycythemia, severe 
pulmonary hypertension [> 40 mm Hg], or respirator dependency)  
• 
Renal – receiving chronic dialysis  
• 
Immunocompromised – the subject has received therapy that suppresses 
resistance to infection (eg, immunosuppression, chemotherapy, radiation, 
long-term or recent high dose steroids, or has a disease that is sufficiently 
advanced to suppress resistance to infection [eg, leukemia, lymphoma, AIDS]) 
 
Reference: 
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med. 1985;13(10):818-29.  
 
 


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Appendix 4 
Sequential Organ Failure Assessment Score 
The Sequential Organ Failure Assessment (SOFA) Scorea 
 
SOFA Score 
Variables 
0 
1 
2 
3 
4 
Respiration 
 PaO2/FiO2, mm Hg 
> 400 
≤ 400 
≤ 300 
≤ 200b 
≤ 100b 
Coagulation 
 Platelets ×103/μL 
> 150 
≤ 150 
≤ 100 
≤ 50 
≤ 20 
Liver 
 Bilirubin, mg/dLc 
< 1.2 
1.2 – 1.9 
2.0 – 5.9 
6.0 – 11.9 
> 12.0 
Cardiovascular 
 Hypotension 
No 
hypotension 
Mean 
arterial 
pressure 
< 70 mm Hg 
Dop ≤ 5 or 
dob (any 
dose)d 
Dop > 5, epi 
≤ 0.1, or 
norepi 
≤ 0.1d 
Dop 
> 15, epi 
> 0.1, or 
norepi 
> 0.1d 
Central Nervous System 
 Glasgow Coma Score 
Scale 
15 
13 - 14 
10 - 12 
6 -9 
< 6 
Renal 
 Creatinine, mg/dL or 
Urine Output, mL/de 
< 1.2 
1.2 – 1.9 
2.0 – 3.4 
3.5 – 4.9 
or < 500 
> 5.0  
or < 200 
FiO2 = fraction of inspired oxygen; PaO2 = partial pressure of oxygen, norepi = norepinephrine; dob = 
dobutamine; Dop = dopamine; epi = epinephrine; and FiO2 =, fraction of inspired oxygen.  
a 
In nonventilated subjects, a respiration score of 0 may be assigned.  
b 
Values are with respiratory support. 
c 
To convert bilirubin from mg/dL to μmol/L, multiply by 17.1. 
d 
Adrenergic agents administered for at least 1 hour (doses given are in μg/kg/minute). 
e 
To convert creatinine from mg/dL to μmol/L, multiply by 88.4. 
Reference: 
Ferreira FL, Bota DP, Bross A, Mélot C, Vincent JL. Serial evaluation of the SOFA score 
to predict outcome in critically ill patients. JAMA. 2001;286(14):1754-8.  
 
 


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Appendix 5 
Clinical Pulmonary Infection Score Parameters 
CPIS Points 
0 
1 
2 
Tracheal 
Secretionsa 
Few 
Moderate 
Large 
Chest radiograph 
Infiltratesb 
None 
Patchy or diffuse 
Localized 
Temperature (°C) 
≥ 36.1 and ≤ 38.4 
≥ 38.5 and ≤ 38.9 
≥ 39.0 or ≤ 36.0 
Leukocytes (/mm3)  
≥ 4,000 and 
≤ 11,000 
< 4,000 or 
> 11,000 
 
PaO2/FiO2 (mm 
Hg)b 
> 240 or evidence of 
Acute Respiratory 
Distress Syndrome 
(ARDS) 
 
≤ 240 and no 
evidence of ARDS 
ARDS = Acute Respiratory Distress Syndrome; CPIS = Clinical Pulmonary Infection Score Parameters; 
FiO2 = fraction of inspired oxygen; PaO2 = partial pressure of oxygen 
In nonventilated subjects in whom blood gasses are not drawn, a PaO2/FiO2 score of 0 may be assigned. 
a 
If purulent: +1. 
b 
When multiple blood gas measured in 1 day, use first blood gas measure in the morning. 
Reference: 
Luna CM, Blanzaco D, Niederman MS, et al. Resolution of ventilator-associated 
pneumonia: prospective evaluation of the Clinical Pulmonary Infection Score as an early 
clinical predictor of outcome. Crit Care Med. 2003;31:676-82. 
 
 


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Appendix 6 
Management and Discontinuation Criteria for 
Abnormal Liver Function Tests 
Management and Discontinuation Criteria for Abnormal Liver Function tests have been 
designed to ensure subject safety and evaluate liver event etiology (see Guidance for 
Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, FDA: July 2009).  
Abnormal Liver Chemistry Criteria: 
The investigator or subinvestigator must review study subject laboratories to identify if 
any levels meet the following criteria: 
a. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 × upper 
limit of normal (ULN)  
b. AST or ALT > 3 × ULN and total bilirubin (TBL) > 2 × ULN or prothrombin 
time-international normalized ratio (PT-INR) > 1.5, if PT-INR measured 
c. AST or ALT > 3 × ULN with signs or symptoms compatible with hepatitis or 
hypersensitivity (eg, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, jaundice, fever, rash, or eosinophilia [> 5%]) 
Action to Be Taken by Investigator: 
If any 1 of the abnormal liver chemistry criteria is met, the investigator or subinvestigator 
must do the following: 
 Instruct the subject to discontinue study drug immediately if the abnormal 
laboratory values cannot be explained by an alternate reason (eg, PT-INR values 
increase due to administration of warfarin). Investigators are advised to use 
medical judgment in such cases and consult with the sponsor if in doubt. If an 
alternate reason is not available, the investigator or subinvestigator should not 
rechallenge the subject with the investigational product without consulting the 
sponsor. 
 Following the initial observed elevation, every effort should be made to have the 
subject reassessed within 48 to 72 hours to repeat liver function chemistries and 
for further hepatic evaluation.  
 Every effort should be made to monitor the subject 2 to 3 times per week until 
liver function chemistries (ALT, AST, alkaline phosphatase, TBL) resolve, 
stabilize, or return to within the normal range or to baseline levels. 
 Report the event to the sponsor as soon as possible, but not later than 72 hours 
after learning of its occurrence on the Liver Event Form.  
 Consider consultation with a specialist, such as a hepatologist. 
 Consider liver imaging (ie, ultrasound, magnetic resonance imaging, 
computerized tomography). 
For Criterion b, the case must be reported as a serious adverse event.  


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Follow-up Examination: 
If any of abnormal liver chemistry criteria are met, the following assessments should be 
performed at the Follow-up visits and documented in the Liver Event Form: 
 Clinical signs and symptoms course 
 Alcohol use 
 Risk factors for nonalcoholic steatohepatitis, such as diabetes, obesity, and 
hypertriglyceridemia 
 Autoimmune hepatitis/cholangitis 
 Wilson’s disease 
 Laboratory assessments 
– Viral hepatitis serology 
o Hepatitis A (IgM) antibody 
o Hepatitis B surface antigen and Hepatitis B core antibody (IgM) 
o Hepatitis C RNA 
o Hepatitis E IgM antibody 
o Cytomegalovirus IgM antibody 
o Epstein-Barr viral capsid antigen IgM antibody 
– For subjects with TBL of > 1.5  ULN, conjugated bilirubin should be 
measured 
– Complete blood count with differential to assess for eosinophilia 
 


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Appendix 7 
Empiric Therapy Case: Eligibility Flow Chart 
 
 
 
 


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Appendix 8 
Sponsor Signature 
Form 510-01 
 
Study Protocol Title: A Multicenter, Randomized, Double-blind, Parallel-group, Clinical 
Study of S-649266 Compared with Meropenem for the Treatment 
of Hospital-acquired Bacterial Pneumonia, Ventilator-associated 
Bacterial Pneumonia, or Healthcare-associated Bacterial Pneumonia 
Caused by Gram-negative Pathogens 
Study Protocol Number: 1615R2132 
Version Number: 4 
Issue Date: 22 Feb 2019 
 
 
Sponsor signatory: 
 
 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor: 
 
 
See electronic signature page 
 
See electronic signature page 
  
 
 
Date: day-month-year 
 
 


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Appendix 9 
Investigator’s Signature 
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel-group, 
Clinical Study of S-649266 Compared with Meropenem for the 
Treatment of Hospital-acquired Bacterial Pneumonia, 
Ventilator-associated Bacterial Pneumonia, or Healthcare-
associated Bacterial Pneumonia Caused by Gram-negative 
Pathogens 
Study Number: 
1615R2132 
Date of Original: 
(Version 1) 
2 Aug 2016 
Date of Latest 
Amendment 
(Version 4) 
22 Feb 2019 
 
I have read the protocol described above. I agree to comply with all applicable 
regulations and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
 
 
 
 
Date:  
 
 
 
 
Printed Name: ____________________________ 
Title: ___________________________________ 
Affiliation: ______________________________ 
 
 
 
 
 
 

SAP_000.pdf: 
 
Shionogi Study Title:  
A Multicenter, Randomized, Double-blind, Parallel-
group, Clinical Study of S-649266 Compared with 
Meropenem for the Treatment of Hospital-acquired 
Bacterial Pneumonia, Ventilator-associated Bacterial 
Pneumonia, or Healthcare-associated Bacterial 
Pneumonia Caused by Gram-negative Pathogens 
Shionogi Study Number: 
1615R2132 
ClinicalTrials.gov 
Registration No. 
NCT03032380    
Study Document 
Statistical Analysis Plan Version 1.2     09 July 2019 
 
History of Statistical Analysis Plan Amendments 
Version 1 (Original) 
03 December 2018 
Version 1.1 
22 February 2019 
Version 1.2 
09 July 2019 
Revisions  to Version  1 and 1.1 are document within Version 1.2 
 


STATISTICAL ANALYSIS PLAN 
Study Title: 
A phase 3, multicenter, randomized, double-blind, 
parallel-group, clinical study of S-649266 Compared 
with meropenem for the treatment of hospital-acquired 
bacterial pneumonia, ventilator-associated bacterial 
pneumonia, or healthcare-associated bacterial 
pneumonia caused by gram-negative pathogens 
Study Number: 
1615R2132 
Study Phase: 
3 
Product Name: 
S-649266 
Sponsor: 
Shionogi Inc. 
Version Number: 
1.2 
Issue Date: 
9JUL2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi Inc.. This Confidential Material 
should only be viewed by those individuals or companies that have been given prior 
written authorization to do so by Shionogi Inc. (“Authorized Users”). This Confidential 
Material should not be made available in any form to any person or company, other than 
the Authorized Users and their respective employees or associates on a need-to-know 
basis, without the written consent from Shionogi Inc. 
 


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9 Jul 2019 
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SIGNATURE PAGE 
Document Title: 
Statistical Analysis Plan 
Study Title: 
A phase 3, multicenter, randomized, double-blind, 
parallel-group, clinical study of S-649266 Compared 
with meropenem for the treatment of hospital-acquired 
bacterial pneumonia, ventilator-associated bacterial 
pneumonia, or healthcare-associated bacterial 
pneumonia caused by gram-negative pathogens. 
Study Number: 
1615R2132 
Version Number: 
1.2 
Issue Date: 
9JUL2019 
 
Approved by: 
 
< Refer to electronic signature page> 
 
 
 
 
Date 
 
 
 
Biometrics, Shionogi Inc. 
 
 
 
 
 
 
 
 
 
<Refer to electronic signature page> 
 
 
 
 
Date 
  
 
 
Clinical Development, Shionogi Inc. 
 
 
 
Prepared by: 
 
<Refer to electronic signature page> 
 
 
 
 
Date 
 
 
 
Biometrics, Shionogi Inc. 
 
 
 
 
 


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9 Jul 2019 
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Page 3 of 46 
RECORDS ON REVISIONS 
Document History 
Version Number 
Date 
1.0 
03 Dec 2018 
Added additional analyses  
 Added analysis for Distribution of Gram-negative 
pathogens Isolated at Baseline pathogen  
 Added Analyses for Baseline pathogen per MIC 
and CLSI interpretation 
 Added Analyses for Clinical outcome per pathogen 
 Added Analyses for Clinical outcome per MIC and 
CLSI interpretation 
 Added analyses Microbiological outcome per 
pathogen 
 Added analyses for Microbiological outcome per 
MIC and CLSI interpretation 
 Added analyses for Listing for 4 fold increase of 
MIC from baseline 
 Added analyses for Summary for Microbiological 
Outcome Per Subject whose Gram-Negative 
Pathogens Isolated from Blood Culture are the 
Same as Lung at Baseline 
 Added analyses for Summary of Minimum 
Inhibitory Concentration of Baseline Gram-
negative Pathogens Isolated from the Blood 
Culture That Are the Same as Lung at Baseline   
 Summary of All-cause Mortality at Day 28 by 
Predefined Subgroups 
 Summary of Microbiological Outcome Per Subject 
at Test of Cure by Predefined Subgroups  
 Summary of Clinical Outcome Per Subject at Test 
of Cure by Predefined Subgroups  
 
22 Feb 2019 
 Section 1 :Updated Protocol version to version 4 
 Section 9.1 and 9.3.6: changed Day 14 and Day 28 
all-cause mortality calculation based on timing of 
first dose instead of randomization as these two can 
differ by a day 
 Section 8.3: changed definition of prior and 
 


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concomitant medication based on first dose date 
instead of randomization date. 
 Section 9.2: Added superiority analysis at Day 14 
as a key secondary endpoint 
 Section 9.3.6: Added superiority at Day 28 as a 
secondary endpoint 
 Section 9.1.1 : Added that 2 sided p-value will be 
calculated for non-inferiority and superiority 
testing. 
 Table 6-1: Added the text:+1 day for EOT and 
unexpected  EOT analysis window based on 
protocol amendment. +1 day was added instead of 
24 hours as sometimes time of last infusion may 
not be collected within EDC 
 Section6.4: Added missing time strategy for 
classifying prior and concomitant medications. 
 Section 6.4:Added missing data strategy for 
missing EOS survival status 
 Section 8.3 : Added 3 hours grace period for 
concomitant medications as in CR study 
 Section 9.1.3: Added supplementary analysis for 
Day 14 ACM by excluding subjects who are 
Meropenem resistant. 
 Section  9.3.1: Clarified presence of colonizer or 
contaminant of a baseline pathogen will be 
associated with micro-outcome of eradication 
 Section 9.3.7.2: Added subgroup analysis for all-
cause mortality until EOS visit based on death 
study day 
 Section 10.3: Removed PTT from summary of lab 
parameters. 
 Section 13: Added Haybittle-Peto alpha spend of 
0.0001 will be used for any unplanned looks of the 
interim efficacy data  
1.1 
 Section 4.1 : Clarified that for purposes of analysis 
as randomized strata will be employed.For 
subgroup analysis the actual strata values will be 
employed. 
 Section 5.2 : Corrected the typo in mITT definition 
 Section 6.4 : Updated missing data strategy for 
cases all-cause mortality upto EOS endpoint and 


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matched definition as in protocol. 
 Section 9.1.4 : Added post-hoc subgroup categories 
for Meropenem non-susceptible status and for 
subjects with MIC value greater than 8 for 
Meropenem for any baseline gram-negative 
pathogen. 
 Section 9.3.7 : Updated definition of all-cause 
mortality up to EOS to match the protocol 
definition. 
 Section 9.1.3: Added sensitivity analysis for 
missing Day 14 survival status. 
 Section 9.1.4: Added subgroup analyses for micro 
outcome per subject by meropenem non-
susceptible status and time point 
 Section 9.1.4: Added subgroup analyses for clinical 
outcome per subject by meropenem non-
susceptible status and time point 
 Section 9.1.4 : Added post-hoc subgroup category 
for top 5 baseline pathogens 
 Section 9.3.7 :Added separate analysis of all-cause 
mortality by EOS based on time from last dose. 
1.2 
 Section 6.3 : Added the statement that If a subject 
is received study drug more than 21 days, Day 21 
will be considered as the date of end of last 
infusion. 
 Section 6.3 : Clarified that if any visit is flagged as 
baseline then the corresponding analysis visit will 
be assigned as a screening/baseline and will not be 
considered it while deriving the analysis window 
 Section 6.3: Added that if PK samples are collected 
just before the 6th dose these will be included in the 
summary of concentration summary. 
 Section 10.3 : Added a statement that if the SI units 
for CRP are available in EDC as a value less than 
the lower limit then it will be set to the lower limit 
and then used for analysis. This was added after 
blinded review of the data during dry run. 
 Section 8.3: Removed the term respiratory 
inhalation from the routes of administration 
considered to be not systemic. 
 Section 10.2: Added EA and FU visits for 
summary of vital signs to align with mock-shells. 


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 Section 10.2 : Clarified that prespecified outlier 
category summarization during post dosing period 
will include any unscheduled visits for vital signs 
summary. 
 Section 10.3: Clarified that prespecified outlier 
category summarization during post dosing period 
will include any unscheduled visits for laboratory 
parameters summary. 
 Section 4.1 : Clarified that for patient baseline 
characteristics summaries as well as subgroup 
analysis the actual values of the stratification 
factors APACHE II score and clinical diagnosis 
will be used 
 Section 6.4 : Clarified that if micro sample 
collection times are missing the end time of day 
23:59PM will be used for imputation. 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ...........................................................................................................2 
RECORDS ON REVISIONS ..............................................................................................3 
LIST OF TABLES ...............................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................10 
1. 
INTRODUCTION .....................................................................................................12 
2. 
OVERVIEW ..............................................................................................................12 
3. 
STUDY OBJECTIVES ..............................................................................................12 
3.1 
Primary Objective(s) ........................................................................................12 
3.2 
Secondary Objectives .......................................................................................12 
3.2.1 
Key Secondary Objectives .....................................................................12 
3.2.2 
Other Secondary Objectives ..................................................................13 
3.3 
Safety Objective ...............................................................................................13 
4. 
STUDY DESIGN ......................................................................................................13 
4.1 
Study Blinding and Randomization .................................................................13 
4.2 
Sample Size ......................................................................................................14 
5. 
ANALYSIS POPULATIONS ...................................................................................15 
5.1 
Intention-to-treat Population ............................................................................15 
5.2 
Modified Intent-to-treat Population .................................................................15 
5.3 
Safety Analysis Population ..............................................................................15 
5.4 
Micro-evaluable Per-protocol Population ........................................................15 
5.5 
Pharmacokinetic Concentration Population .....................................................16 
6. 
STATISTICAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLINGS ............................................................................................................16 
6.1 
Statistical Reporting .........................................................................................16 
6.2 
Statistical Testing and Multiplicity Strategy ....................................................16 
6.3 
Analysis Visit Windows ..................................................................................16 
6.4 
Missing Data ....................................................................................................18 
6.5 
Definition .........................................................................................................19 
6.5.1 
Study Day...............................................................................................19 
6.5.2 
Baseline ..................................................................................................19 
6.6 
Handling of Microbiologic Data ......................................................................20 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHRACTERISTICS .......................20 
7.1 
Subject Disposition ..........................................................................................20 
7.2 
Demographic and Baseline Characteristics .....................................................21 
8. 
STUDY CONDUCT ..................................................................................................21 
8.1 
Protocol Deviation ...........................................................................................21 
8.2 
Treatment Exposure and Compliance ..............................................................22 


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8.3 
Prior and Concomitant Medication ..................................................................22 
9. 
EFFICACY ................................................................................................................23 
9.1 
Primary Endpoint .............................................................................................23 
9.1.1 
Primary Analysis ....................................................................................23 
9.1.2 
Sensitivity Analysis ...............................................................................25 
9.1.3 
Missing Day 14 Survival Status Sensitivity Analysis............................25 
9.1.4 
Supplementary Analysis ........................................................................25 
9.1.5 
Subgroup Analysis .................................................................................25 
9.2 
Key Secondary Endpoints ................................................................................27 
9.3 
Other Secondary Efficacy Endpoints ...............................................................27 
9.3.1 
Per Subject Microbiological Outcomes .................................................27 
9.3.2 
Microbiological Outcome per Subject for the Subset where Gram-
negative Pathogens Isolated from Blood Culture are the Same as 
Lung at Baseline ....................................................................................29 
9.3.3 
Per pathogen Microbiological Outcomes ...............................................30 
9.3.4 
Per Subject Clinical Outcomes ..............................................................30 
9.3.5 
Clinical Outcome per Pathogen .............................................................31 
9.3.6 
All-cause Mortality at Day 28 ................................................................32 
9.3.7 
All-cause Mortality during treatment and follow-up period (until 
EOS) .......................................................................................................32 
9.4 
Sequential Organ Failure Assessment Score ...................................................33 
9.5 
Clinical Pulmonary Infection Score .................................................................33 
10. SAFETY ....................................................................................................................33 
10.1 
Adverse Events ................................................................................................33 
10.2 
Vital Signs ........................................................................................................34 
10.3 
Clinical Laboratory Evaluations ......................................................................35 
10.4 
Electrocardiograms ..........................................................................................37 
11. Pharmacokinetic Analyses .........................................................................................37 
12. Pharmacokinetic/Pharmacodynamic Analyses ..........................................................38 
13. INTERIM ANALYSES .............................................................................................38 
14. PROGRAMMING CONVENTIONS ........................................................................39 
14.1 
Formatting and Programming Rule .................................................................39 
15. CHANGES FROM PROTOCOL SPECIFIED ANALYSES ...................................41 
16. REFERENCE .............................................................................................................42 
17. APPENDIX 1 STUDY SCHEMATIC ......................................................................43 
18. APPENDIX 2 TIME AND EVENTS SCHEDULE ..................................................44 
 


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LIST OF TABLES 
Table 6-1 
Analysis Window .........................................................................17 
Table7-1 
Demographic and Baseline Characteristics .................................21 
Table 9-1 
Per Subject Microbiological Outcome at End of Treatment, 
Test of Cure and Follow-up .........................................................29 
Table 10-1 
Outliers for Each Parameter in Vital Sign Measurements ...........35 
Table 10-2 
Routine Laboratory Tests .............................................................36 
Table 10-3 
The Outlier for Each Parameter in Laboratory Test ....................37 
Table 14-1 
Display Digit of Statistics for Efficacy and Safety ......................39 
Table 14-2 
Subject Characteristics and Items of Therapeutic Process...........40 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
%Tf > MIC 
percentage of dosing interval for which free drug concentration in 
plasma exceeds minimum inhibitory concentration  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
ARC 
augmented renal clearance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BAL 
bronchoalveolar lavage 
BLA 
β-lactamase 
BUN 
blood urea nitrogen 
CABP 
community-acquired bacterial pneumonia 
CFU 
colony-forming unit 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
CPIS 
Clinical Pulmonary Infection Score 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CT 
computed tomography 
DSMB 
Data Safety Monitoring Board 
EA 
early assessment 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELF 
epithelial lining fluid 
EOS 
end of study 
EOT 
end of treatment 
FiO2 
fraction of inspired oxygen 
FU 
follow-up 
GCP 
good clinical practice 
GCS 
Glasgow Coma Scale 
HABP 
hospital-acquired bacterial pneumonia 
HCABP 
healthcare-associated bacterial pneumonia 
IC50 
half maximal inhibitory concentration 


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ICH 
International Council on Harmonisation  
ICU 
intensive care unit 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IWRS/IVRS 
interactive web or voice response system 
KPC 
Klebsiella pneumoniae carbapenemase 
MDR 
multidrug resistant 
MDRD 
modification of diet in renal disease 
ME-PP 
Micro-evaluable Per-protocol 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MIC 
minimum inhibitory concentration 
mITT 
Modified Intent-to-treat 
MRSA 
methicillin-resistant Staphylococcus aureus 
NOAEL 
no-observed-adverse-effect level 
OAT1 (3) 
organic anion transporter 1 (3) 
PaO2 
partial pressure of oxygen 
PD  
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
q6h 
every 6 hours 
q8h 
every 8 hours 
q12h 
every 12 hours 
QTc 
corrected QT interval 
QTcF 
Fridericia’s correction formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOFA 
Sequential Organ Failure Assessment  
SPC 
summary of product characteristics  
TBL 
total bilirubin  
TEAE 
treatment-emergent adverse event 
TOC 
Test of Cure 
ULN 
upper limit of normal 
VABP 
ventilator-associated bacterial pneumonia 
WBC 
white blood cell 
XDR 
extensively drug-resistant 
 
 
 


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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and data handlings to 
be employed for the analysis of the study Protocol 1615R2132, Version 4 dated 22 
February 2019. Table, listing and figure mock-ups are provided in the TLF shells 
prepared separately. Details of the analyses of pharmacokinetics/pharmacodynamics are 
not addressed in this SAP.  
All the analyses described in the SAP will be performed in the Biometrics, Shionogi Inc. 
Any deviations from the SAP will be documented in the clinical study report. 
2. OVERVIEW 
This clinical trial is performed as a global (North America, South America, Europe, and 
Asia-Pacific), multicenter, double-blind, parallel-group study with stratified 
randomization using the infection diagnosis (hospital-acquired bacterial pneumonia 
[HABP]/ventilator-associated bacterial pneumonia [VABP]/healthcare-associated 
bacterial pneumonia [HCABP]) and Acute Physiology and Chronic Health Evaluation II 
(APACHE II) score (≤ 15 and ≥ 16) as allocation factors, using meropenem as a 
comparator. Study drug is initiated in subjects with documented nosocomial pneumonia 
caused by Gram-negative bacteria. 
Subjects meeting eligibility criteria and assessed by the investigator to require 7 to 
14 days of intravenous treatment in the hospital will be randomized (1:1) to either 
cefiderocol, 2 g, administered intravenously over 3 hours, every 8 hours (q8h) or 
meropenem, 2 g, administered intravenously over 3 hours q8h. Linezolid will be 
administered to subjects in both arms to provide coverage for methicillin-resistant 
Staphylococcus aureus (MRSA) and to maintain the study blind and, in the cefiderocol 
arm, to provide coverage for Gram-positive bacteria. 
The study design and study events table are shown in Appendix 1 and Appendix 2, 
respectively. 
3. STUDY OBJECTIVES 
3.1 
Primary Objective(s) 
The primary objective of this study is: 
 To compare all-cause mortality at Day 14 of cefiderocol with that of the 
comparator, meropenem, in adults with HABP, VABP, or HCABP caused by 
Gram-negative pathogens. 
3.2 
Secondary Objectives 
3.2.1 
Key Secondary Objectives 
The key secondary objectives of the study are: 


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 To compare the microbiological outcome of treatment with cefiderocol with that 
of meropenem per subject at Test of Cure (TOC)1 
 To compare the clinical outcome of treatment with cefiderocol with that of 
meropenem per subject at TOC 
 To compare Day 14 all-cause mortality of cefiderocol with that of meropenem for 
superiority of cefiderocol 
3.2.2 
Other Secondary Objectives 
 To compare the microbiological outcome of treatment with cefiderocol with that 
of meropenem per subject at Early Assessment (EA)2, End of Treatment (EOT)3, 
and Follow-up (FU) 
 To compare the clinical outcome of treatment with cefiderocol with that of 
meropenem per subject at EA, EOT, and FU 
 To compare all-cause mortality at Day 28 of subjects treated with cefiderocol with 
that of meropenem 
 To compare Day 28 all-cause mortality of S-649266 with that of meropenem for 
superiority of S-649266 
 To compare the all-cause mortality during treatment and the follow-up period 
(until EOS) of subjects treated with cefiderocol with that of meropenem  
3.3 
Safety Objective 
 To assess the safety of cefiderocol 
4. STUDY DESIGN 
4.1 
Study Blinding and Randomization 
This is a double-blind, parallel-group, randomized, active-controlled study in 
approximately 300 subjects with documented nosocomial pneumonia caused by Gram-
negative bacteria. Subjects meeting eligibility criteria and assessed by the investigator as 
requiring 7 to 14 days of intravenous treatment in hospital will be randomized (1:1) to 
either cefiderocol, 2 g, administered intravenously over 3 hours, q8h or meropenem, 2 g, 
administered intravenously over 3 hours, q8h. Linezolid will be administered to subjects 
in both arms to provide coverage for MRSA and to maintain the study blind and, in the 
cefiderocol arm, to provide coverage for Gram-positive bacteria. 
The investigator, site personnel, the sponsor, and the sponsor’s designees involved in 
blinded monitoring, data management, or other aspects of the study will be blinded to 
treatment assignment. The site pharmacist or qualified designee who will prepare the 
                                                 
1 TOC is defined as End of Treatment (EOT) + 7 days (± 2 days). 
2 EA is defined as start of treatment + 3 days to 4 days. 
3 EOT is defined as the last day of study treatment. 


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intravenous infusion solution will be unblinded so that he/she may obtain the assigned 
drug and prepare the intravenous dosing solutions. The drug supply itself will not be 
blinded.  
Since this is a blinded study, cefiderocol will be prepared and administered within the 
same timeframe after preparation as meropenem. For comparability of the study drug and 
the comparator drug meropenem, the dosing solutions will be normal saline and dosed 
within the time limits established for meropenem. Linezolid will not require blinding. 
The treatments will be randomized to subject identification numbers by the interactive 
response technology (IRT) provider in a 1:1 fashion to cefiderocol or meropenem. The 
IRT will be used to assign subjects to identification numbers for which treatment has 
already been randomly assigned. Randomization will be performed by the stratified 
randomization method using their infection type (HABP, VABP, and HCABP) and 
APACHE II score (≤ 15 and ≥ 16) as allocation factors. 
In the event of cases where incorrect allocations factors for clinical diagnosis and 
APACHE II scores were used by the IRT provider during treatment randomization, for 
analysis purposes the as randomized values will be used for the primary and secondary 
efficacy analyses. 
For patient baseline characteristics summaries as well as subgroup analysis the actual 
values of the stratification factors APACHE II score and clinical diagnosis will be used.   
4.2 
Sample Size 
The study design and the primary objective are based on the hypothesis that cefiderocol is 
noninferior to meropenem for the treatment of nosocomial pneumonia; this will be 
established based on a 12.5% noninferiority margin to exclude the possibility that 
cefiderocol is more than 12.5% inferior to meropenem for the endpoint of all-cause 
mortality at Day 14. The 12.5% noninferiority margin for a limited use indication was 
discussed with and agreed to by the US Food and Drug Administration, Division of Anti-
Infective Products at a Type C meeting on October 13, 2015 and again with a 
communication dated April 25, 2016.  
A sample size of 244 evaluable subjects (122 evaluable subjects in the cefiderocol group 
and 122 evaluable subjects in the meropenem group) is required to have 90% power with 
a 1-sided significance level of 0.025, assuming a 10% all-cause mortality rate at Day 14 
in both groups with a 12.5% noninferiority margin. It is further estimated that 
approximately 20% of randomized subjects will be non-evaluable and therefore excluded 
from the primary population because they have not received any doses of a study drug 
treatment or they had a bacterial pneumonia caused by anaerobic and/or Gram-positive 
aerobic bacteria only. Therefore, it is expected that it will be necessary to randomize up 
to 300 subjects. The non-evaluable rate will be assessed based on a blinded estimate 
performed after approximately 150 subjects are enrolled and the randomized population 
size may be adjusted to meet study requirements. Additionally, the Sponsor will conduct 


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a blinded evaluation of all-cause mortality after approximately 150 subjects are enrolled 
and if necessary will perform a blinded re-estimation of sample size. 
5. ANALYSIS POPULATIONS 
5.1 
Intention-to-treat Population 
The Intent-to-treat (ITT) population is defined as all randomized subjects who received at 
least 1 dose of a study drug treatment. This population will be analyzed according to the 
treatment the subjects were randomized to, regardless of treatment the subjects actually 
received.  
5.2 
Modified Intent-to-treat Population 
The Modified ITT (mITT) population is defined as all subjects in the ITT population who 
meet either of the following: 
 Those who have evidence of a Gram-negative infection of the lower respiratory 
tract based on either a culture, Gram stain, or other diagnostic test. 
 Those who have evidence of a lower respiratory tract infection, but culture or 
other diagnostic tests do not provide a microbiological diagnosis. 
Note: Subjects with a bacterial pneumonia caused by Gram-positive aerobic or 
anaerobic (Gram-positive or Gram-negative) bacteria only will be excluded from the 
mITT Population. 
This population will be analyzed according to the treatment the subjects were randomized 
to, regardless of treatment the subjects actually received. 
The primary population for efficacy analysis will be mITT Population.  
5.3 
Safety Analysis Population 
The Safety population is defined as all randomized patients who receive at least 1 dose of 
the study treatment (ITT population). The population will be analyzed according to the 
treatment that the subjects actually received, rather than the treatment to which the 
subjects were randomized. If a wrong treatment is given and later corrected to the 
appropriate randomized treatment upon discovery of the error, the subject will be 
classified into the corrected treatment group. This population will be used in all safety 
analyses. 
5.4 
Micro-evaluable Per-protocol Population 
The Micro-evaluable Per-protocol (ME-PP) population is defined as all subjects in mITT 
population who do not have major protocol violations and have a culture confirmed 
diagnosis of a Gram-negative bacterium. These deviations will be determined prior to 
unblinding of the study.  


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5.5 
Pharmacokinetic Concentration Population 
The Pharmacokinetic (PK) Concentration population includes all subjects who undergo 
plasma sampling and have at least 1 evaluable PK assay result for cefiderocol.  
This population will be used for the concentration listing, plotting of the concentration-
time data, population PK analyses, PK/PD analyses, and the concentration summary. 
6. STATISTICAL CONSIDERATIONS FOR DATA ANALYSES 
AND HANDLINGS 
6.1 
Statistical Reporting 
Unless otherwise noted, continuous variables will be summarized by using the number of 
nonmissing observations, arithmetic mean, standard deviation (SD), median, minimum, 
and maximum values as summary statistics; categorical variables will be summarized by 
using the frequency count and the percentage of subjects in each category.   
Subject study data, including data not appearing in tables, will be presented in by-subject 
data listings. In general, all tables and associated graphics will be presented by treatment 
group. Individual subject data, PK data and any derived data will be presented by 
treatment and subject. 
All analyses will be performed using SAS Version 9.2 or higher (SAS Institute, Cary, 
NC, USA). 
6.2 
Statistical Testing and Multiplicity Strategy 
Statistical testing will be performed at the 2-sided significance level of 0.05 unless stated 
otherwise. A fixed-sequence approach will be applied for multiplicity adjustment with the 
primary and key secondary efficacy analyses: the primary noninferiority hypothesis will 
be tested first, and if satisfied, then move to (1) microbiological outcome at TOC, and 
then (2) the clinical outcome at TOC and (3) Day 14 all-cause mortality rates of S-
649266 with meropenem for superiority of cefiderocol 
6.3 
Analysis Visit Windows 
For analysis datasets no records after End of Study visit will be used for TLF purposes. 
Measurements for efficacy or safety endpoints will be performed according to the visit 
schedule and the procedures of the study as shown in Appendix 1. The following analysis 
windows (Table 6-1) will be used for analysis at a particular time point to be included in 
by-time-point summary statistics for the specified variables. Day 1 is defined as initial 
day of administration of study drug. 
If there are multiple available values in an analysis time window, the following approach 
will be applied. For the efficacy outcome, the closest value to the scheduled time point 
captured from a scheduled or unscheduled time point will be used for analysis, and if 
there are multiple values within same day, the latest value will be used. Also, if 2 visits 


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are equidistant from the scheduled day, the later visit will be assigned to the windowed 
visit. For the safety endpoints, the closest value to the scheduled time point will be used 
for the analysis, and if there are multiple values within same day, the earliest value will 
be used. Also, if the differences between the observed time point and scheduled time 
point are the same among values, the earlier will be used. 
Measurements that are taken outside the visit window will be considered missing for 
analysis and will not be imputed. 
Table 6-1 
Analysis Window 
Time Point 
Target Day/Time 
Analysis Time Window 
Blood PK Sampling 
After at least 6 doses , before any 
dosing regimen change according to 
EA evaluation 
Day 3 or Day 4 
 
Just prior to the next infusion 
-1 to 0 hours 
 
1 hour after the start of infusion 
± 15 minutes 
 
At the end of infusion 
-30 minutes to just before the end of 
infusion 
 
1 hour after the end of infusion 
(4 hours after the start of 
infusion) 
± 0.5 hours 
EA 
Day 3 or Day 4 
Not applicable 
EOT 
End of last infusion 
As soon as possible after last dose 
(same calendar day or +1 day) 
Unexpected EOT 
Last day of study treatment clinical 
evaluations, and a blood sample 
should be obtained if possible 
Same calendar day or + 1 day 
TOC 
EOT + 7 
± 2 days 
FU 
EOT + 14  
± 3 days 
EOS 
EOT + 28 
± 3 days 
EA = Early Assessment; EOS = End of Study; EOT = End of Treatment; FU = Follow-up; 
PK = pharmacokinetic; TOC = Test of Cure  
If a subject has received study drug more than 21 days, Day 21 will be considered as the 
date of end of last infusion. 
If any visit is flagged as baseline then the corresponding analysis visit will be assigned as 
a screening/baseline and will not be considered it while deriving the analysis window. 
Subjects who have PK data collected before at least 6 doses will be listed, however they 
will be excluded from plotting of the concentration-time data and the concentration 
summary in CSR (Pharmacokinetic samples just prior to the sixth dose will be included) 


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6.4 
Missing Data 
For clinical and microbiological outcomes, patients who were lost to follow-up or had 
missing or had “indeterminate” outcomes will be included in the denominator as 
indeterminate for cure/eradication rate i.e. considered as non-responders.  
For clinical outcome, subjects who died due to pneumonia will be considered as a clinical 
failure after death. 
If a subject dies due to other reasons, they will be considered as “indeterminate” except 
for the cases when subject is a clinical failure at EA and missing after that or when a 
subject is a clinical failure at EOT, and missing after that. For these cases clinical failure 
will be carried forward to the remaining visits. 
If subjects withdraw before Day 14 since their first infusion of study drug their survival 
status at Day 14 would be unknown or missing for the analysis of the primary endpoint of 
14 day all-cause mortality. These subjects would not be included in the numerator or 
denominator in the calculation of all-cause mortality rate at Day 14 since first infusion of 
study drug. If subjects withdraw before Day 28 since their first infusion their survival 
status at Day 28 would be unknown or missing for the analysis of 28 day all-cause 
mortality. These subjects would not be included in the numerator or denominator in the 
calculation of all-cause mortality rate at Day 28 since first infusion. 
If subjects discontinue before their End of study visit and are lost to follow up before End 
of Study visit their survival status at End of Study would be unknown or missing for the 
analysis of all-cause mortality during treatment and the follow-up period (until EOS). 
These subjects would not be included in the numerator or denominator in the calculation 
of all-cause mortality rate during treatment and the follow-up period (until EOS). 
If dates are missing or partial the following strategies will be employed. Adverse events 
that started on or after the first dose of the study drug and up to “End of Study” are 
defined as treatment-emergent. 
For the start date of each AE, the date will be confirmed and recorded and no imputation 
will be performed.  
For classification of prior and concomitant medications, if the medication cannot be 
classified into concomitant medications or prior medications due to a partial missing date, 
the rules below will be applied for the classification. 
For start date, 

If the year and month are observed but the day is missing, the first day of the
month will be used.

If the year is observed but the month is missing, the first day of the year, 01 Jan,
will be used.


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
If the year is observed but the time is missing, the first time of the day, 00:00 AM
will be used. 
And, for end date,

If the year and month are observed but the day is missing, the last day of the
month will be used.

If the year is observed but the month is missing, the last day of the year, 31 Dec,
will be used.

If the year is observed but the time is missing, the end time of the day, 23:59 PM
will be used.
If micro sample collection time is missing then end time of the day 23:59 PM, will be 
used. 
The imputed dates will not be displayed in the listings. 
Missing values for other individual data points will remain as missing unless otherwise 
specified. All analysis will be based on observed case unless otherwise stated. However, 
in the summary of adverse events (AEs), the AEs that have not been coded will be 
included as ‘Not coded adverse events’ in tables or listings.  
Measurements for efficacy or safety endpoints will be performed according to the 
schedule of assessments shown in Appendix 1. The time window, shown in  
Table 6-1 is acceptable. 
6.5 
Definition 
6.5.1 
Study Day 
Study Day is defined as the relative day of the observation starting with the reference 
date as Day 1. Study Day 1 will refer to the date of initial dose of the study drug. In 
addition, dates prior to the reference date are decremented by 1, with the date preceding 
Day 1 designated as Study Day -1 (there is no Study Day 0). 
6.5.2 
Baseline 
For microbiological endpoints, baseline pathogens are determined from appropriate 
clinical specimens collected within the 3 days prior to randomization in this study for 
subjects who have been treated previously with an empiric antibiotic regimen and failed 
treatment, both clinically and microbiologically (as defined in general inclusion No. 9). 
For the other subjects, baseline pathogens are determined from appropriate specimens 
collected within the 48 hours prior to the start of the first infusion of study treatment. If 
appropriate specimens are collected on multiple dates before the first infusion, the 
specimens collected on the latest date for each pathogen will be used to determine 
baseline pathogens. If multiple specimens are collected within the above time range for 
baseline, the following rule will be applied: 


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 In case different Gram-negative pathogens are obtained from different specimens, 
all of them are considered as baseline pathogens 
The appropriate clinical specimen type is sputum, tracheal aspirate, bronchoalveolar 
lavage (BAL) fluid, protected specimen brush, pleural fluid, or lung biopsy. Specimen 
that was collected from other site may be considered as appropriate specimen. This will 
be determined by the medical monitor.   
For the other efficacy and safety endpoints, baseline is defined as the last measurement 
obtained prior to receipt of the first infusion of study drug. 
Eligibility of subjects into mITT analysis population will be based on local lab results of 
baseline pathogens if the microbiological culture results are not sent to central lab for 
confirmation or if central lab results are missing. 
6.6 
Handling of Microbiologic Data 
If a pathogen is identified from local laboratory data but it is not sent to central 
laboratory, the name reported by local laboratory will be used for analysis. In this case, 
MIC will be treated as unknown. 
If a pathogen name is different between local and central laboratory, the name of the 
central laboratory will be used for the analysis. However, if the sample sent to IHMA was 
not tested and reported as “unknown”, the local laboratory name of pathogen will be used 
for analysis. 
7.
DEMOGRAPHIC AND OTHER BASELINE CHRACTERISTICS
7.1 
Subject Disposition 
The number of subjects who failed at Screening Period (ie, screen failure) will be 
summarized along with the reason for not randomized to treatment with study drug. 
A summary table will be produced detailing the number of screened subjects, the number 
of subjects who screen failed. In addition, the subjects who screen failed will be 
summarized by respective reasons. 
Among the randomized subjects in the ITT population, the mITT population and the 
safety population, the number and percentage of subjects who complete the study and 
those who prematurely discontinue from the study will be summarized. 
A summary table will be produced detailing the number of subjects randomized, the 
number of subjects who treated with study drug, the number of subjects who completed 
the study, and the number of subjects who prematurely discontinued from the study. In 
addition, the reason for discontinuation from the study will be summarized. 


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The number and proportion of subjects in each analysis population will be summarized as 
well as the reasons for exclusion from the ITT Population, mITT Population, the ME-PP 
Population and the Safety Analysis Population. 
7.2 
Demographic and Baseline Characteristics 
Demographic data and baseline characteristic shown in Table 7-1 will be summarized 
descriptively as described in Section 6.1 for the ITT population, mITT population and the 
Safety Analysis population. Categories used in summary of items are shown in  
Table 14-2. 
The baseline pathogen will be summarized for mITT population. The baseline pathogen 
with the highest minimum inhibitory concentration (MIC) for cefiderocol will also be 
summarized for the MIC values and susceptibility defined by Clinical and Laboratory 
Standards Institute (CLSI) of the baseline pathogen. For this analysis, MIC for 
cefiderocol, amikacin, aztreonam, ceftazidime-avibactam, imipenem, ceftolozane-
tazobactam, ciprofloxacin, meropenem, cefepime, colistin, and tigecycline will be used 
and number of subjects, MIC 50, MIC 90, and range will be calculated for summary 
statistics of MIC. MIC 50 and 90 are defined as the smallest value no less than 50% and 
90% of the data, respectively; MIC 50 and 90 will be calculated only when the number of 
subject with particular bacteria is 10 or more. 
Table 7-1 
Demographic and Baseline Characteristics 
Continuous variable 
Age, height, weight, body mass index, creatinine clearance, MDRD-eGFR, 
total APACHE II score , number of Gram-negative pathogens from 
appropriate specimen,  CPIS, SOFA score,  
Categorical variable 
Age, gender, race, ethnicity, region, weight,  clinical diagnosis at 
randomization, severity, empiric treatment failure status, prior therapy, 
medical history, top baseline gram-negative pathogens, bacteremia 
pathogens, ICU admission, ventilation status at randomization, type of 
baseline pathogens, Type of blood culture, CPIS, SOFA ,creatinine 
clearance renal grading group, Augmented renal clearance 
APACHE II = Acute Physiology and Chronic Health Evaluation II; CPIS = Clinical Pulmonary Infection 
Score; ICU = intensive care unit; MDRD-eGFR = estimated glomerular filtration rate calculated with the 
modification of diet in renal disease equation; SOFA = Sequential Organ Failure Assessment 
Note-See Section 14 for category.  
Medical histories will be summarized by treatment group for the mITT and Safety 
populations for each treatment group by MedDRA system organ class and preferred term 
(PT). The reported medical history terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 18.1 or higher. 
8.
STUDY CONDUCT
8.1 
Protocol Deviation 
For all randomized subjects, major protocol deviations will be listed. Major protocol 
deviations will be specified in the “Protocol deviation specifications document” 


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separately. A final list of major protocol deviations will be determined based on the data 
review prior to database lock. 
8.2 
Treatment Exposure and Compliance 
The duration of treatment in days will be calculated as the last infusion date of study 
minus the first infusion date of study drug plus 1. It will be summarized for the Safety 
population by treatment group using descriptive statistics. The number of subjects and its 
proportion for categorized duration of treatment in each treatment group will be 
summarized. The category for duration will be presented in Section 14. 
In addition, study drug dosing status during the treatment period (from the first infusion 
to last infusion) will be summarized for each treatment group. The following infusion 
status will be summarized: 
 The number of subjects who had an infusion interruption at least once during 
treatment period and its proportion 
 The percentage of appropriate infusion dose administered 
 The number of subjects who had a dose change/adjustment at least once during 
treatment period and its proportion 
All study drug administration data will be listed by subject. 
8.3 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (September 2016). 
Prior medications are defined as medications that were taken prior to randomization for 
the study. During blinded review of the data it was found that a few subjects had 
randomization date different from first dose of study medication. Hence for purpose of 
analysis prior medications are defined as medications that were taken before the first dose 
date and time of the study medication. 
Concomitant medications are defined as medications that were taken on or after first dose 
date and time of study medication. 
The number and percentage of subjects taking prior antibiotic medications will be 
summarized by anatomic therapeutic class (ATC) and preferred term for each treatment 
group and in total for the Safety population and the mITT population. Although a subject 
may have taken two or more medications, the subject is counted only once within an 
ATC classification. The same subject may contribute to two or more preferred terms in 
the same classification. Concomitant antibiotic medications, concomitant non-antibiotic 
medications, and prior non-antibiotic medications will be summarized in the same 
manner.  
All prior and concomitant medications will be listed by subject. 


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Prior therapies are defined as therapies that were taken prior to first dose date for the 
study drug. Concomitant therapies are defined as therapies administered after first dose 
date and time of the study drug. Prior and concomitant therapies will be summarized for 
the Safety population and the mITT population. Subjects for whom a particular therapy 
name was reported more than once will be counted only once for that therapy.  
If the route of administration is subcutaneous, nasal, ophthalmic, rectal, transdermal, 
topical or vaginal the medication will not be considered as a systemic antibiotic. 
The following rules will be used to classify prohibited concomitant medications: 
 Systemic antibiotics, other than linezolid, meropenem, and cefiderocol, are not 
permitted from randomization until TOC 
 Aerosolized antibiotics are not permitted from randomization until after TOC 
 Probenecid, methotrexate, procainamide, monoamine oxidase inhibitors, and 
valproic acid are not permitted from screening until EOT 
 Inhalation antibiotics are prohibited medication from randomization until EOT 
Concomitant medications ending before initial study treatment start date/time plus 3 
hours will not be considered as additional antibiotics. 
9. EFFICACY 
Efficacy analyses will be performed for the mITT Population, unless otherwise specified.  
9.1 
Primary Endpoint 
The primary endpoint is all-cause mortality at Day 14 since first infusion of study drug.  
All-cause mortality rate at Day 14 since first infusion of study drug will be calculated as 
the proportion of patients who experienced mortality regardless of the cause at or before 
Day 14 since first infusion. 
9.1.1 
Primary Analysis 
The study hypothesis to demonstrate noninferiority (NI margin of 12.5%) of cefiderocol 
to meropenem on all-cause mortality (ACM) at Day 14 can be written as follows: 
Null hypothesis        H0:  π1 - π2 > 12.5% 
Alternative hypothesis   H1:  π1 - π2 ≤ 12.5% 
where π1 is the ACM rate for cefiderocol and π2 is the ACM rate on meropenem. 
All-cause mortality rate at Day 14 by treatment group will be calculated as the proportion 
of patients who experienced mortality regardless of the cause at or before Day 14. The 
adjusted estimates of the difference in the all-cause mortality at Day 14 between 
cefiderocol and meropenem will be presented along with 95% confidence intervals (CIs) 
based on a stratified analysis using Cochran-Mantel-Haenszel (CMH) weights. The CI 


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will be 2-sided. Cochran-Mantel-Haenszel weights will be calculated with APACHE II 
score (≤ 15 and ≥ 16) as the stratified factor.  Since we expect only a limited number of 
events based on our assumption of 10% mortality in both treatment groups we are likely 
to see sparse data including zeros in certain 2 x 2 tables based on both stratification 
factors. APACHE II scores were chosen to stratify data for analysis as studies have 
shown that APACHE II scores predict mortality well [1,2,3].  Noninferiority can be 
concluded if the upper bound of a 2-sided 95% CI for the difference in mortality at Day 
14 between the 2 treatment groups (cefiderocol – meropenem) is smaller than a 
noninferiority margin of 12.5%. The associated 2 sided p-value for non-inferiority testing 
will also be calculated. The all-cause mortality at Day 14 will also be analyzed in ITT 
and ME-PP populations similarly.  
Superiority of cefiderocol over meropenem for the day 14 all-cause mortality endpoint 
can be concluded if the 2-sided 95% CI for the difference in Day 14 all-cause mortality 
between the two treatment groups (cefiderocol and meropenem) lies completely below 
zero. The associated 2 sided p-value for superiority testing will also be calculated. 
Let xij and nij denote the number of deaths and the total number of subjects in treatment i 
and stratum j, respectively, where i = 1, 2 represents the treatment arm (cefiderocol vs. 
meropenem) and j = 1, 2  represents the stratum based on the  stratification factor: acute 
physiology and chronic health evaluation II (APACHE II) score (≤ 15 and ≥ 16), the 
following 2 × 2 contingency table shows the total number of subjects and the number of 
deaths in each treatment arm at stratum j: 
Category 
cefiderocol 
meropenem 
Dead 
x1j 
x2j 
Alive 
n1j- x1j 
n2j- x2j 
Total 
n1j 
n2j 
The all-cause mortality rate (πij) in treatment i and stratum j can be estimated by: 
πෝ௜௝= ݔ௜௝݊௜௝
⁄
 
and the stratum-specific proportion difference (dj) is estimated by: 
݀መ௝= πෝଵ௝−πෝଶ௝ 
The CMH weights of stratum j are defined as: 
ݓ௝=
൬݊ଵ௝݊ଶ௝
݊ଵ௝+݊ଶ௝൰
∑
݊ଵ௝݊ଶ௝
݊ଵ௝+݊ଶ௝
ଶ
௝ୀଵ
 
The adjusted estimate of the difference in the all-cause mortality rate between the 
2 treatment arms (dadj) based on the CMH weights is given as: 
݀መ௔ௗ௝= ෍
ݓ௝݀௝
ଶ
௝ୀଵ
 


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The 2-sided stratified 95% Wald-type confidence intervals of dadj based on the CMH 
weights is constructed as: 
݀መ௔ௗ௝± ݖఈ/ଶඨ෍
ݓෝ௝
ଶቆߨොଵ௝(1 −ߨොଵ௝)
݊ଵ௝
+ ߨොଶ௝(1 −ߨොଶ௝)
݊ଶ௝
ቇ
ଶ
௝ୀଵ
 
Where zα/2 is the 97.5th percentile of the standard normal distribution. 
9.1.2 
Sensitivity Analysis 
For each of ITT and ME-PP populations primary analyses stated in Section 9.1.1 will be 
performed as sensitivity analyses. 
9.1.3 
Missing Day 14 Survival Status Sensitivity Analysis 
Primary endpoint sensitivity analysis for missing Day 14 all-cause mortality status will be 
implemented as follows: subjects with unknown mortality status at Day 14 in the 
cefiderocol group will be imputed as “Death ” while any subject with unknown mortality 
status at Day 14 in the Meropenem arm will be imputed as “ Alive “. The data will be 
then be analyzed in the same way as described in Section 9.1.1. 
9.1.4 
Supplementary Analysis 
Analysis for Day 14 all-cause mortality stated in Section 9.1.1 will be performed by 
excluding subjects who are meropenem resistant in the mITT analysis population as a 
supplementary analysis. Subjects who are meropenem resistant will be determined from 
central laboratory culture results. 
9.1.5 
Subgroup Analysis 
Analyses of all-cause mortality (ACM) at Day 14 will be presented for the following 
subgroups. The category for each item will be presented in Section 14. 
The estimates of the difference in the all-cause mortality rates at Day 14 between 
cefiderocol and meropenem will be presented along with 95% confidence intervals (CIs) 
(Wald method) if data warrant. If the number of subjects within a subgroup is less than 
10 in any treatment arm, only the difference in the all-cause mortality between the two 
treatment arms (no CI) will be presented. The CI will be 2-sided. A similar analysis will 
also be carried out for Day 28 all-cause mortality. 
1. Clinical diagnosis 
2. Gender 
3. Race 
4. Age 
5. Region 
6. Baseline clinical characteristics 


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Baseline clinical characteristics include: 
 APACHE II score 
 CPIS score 
 Bacteremia status 
 Creatinine clearance/MDRD-eGFR 
 Empiric treatment failure status 
 ICU admission 
 Ventilation status at randomization  
 Top 5 baseline gram-negative pathogens 
 Creatinine Clearance renal grading groups 
The top 5 baseline gram-negative pathogens will be based on overall frequency across 
both groups determined before unblinding. 
Subgroup analyses will also be carried out for the key secondary outcomes, per subject 
microbiological outcome at TOC and per subject clinical outcome at TOC for the 
subgroups defined above. 
For the key secondary endpoints (per subject microbiological outcome at TOC and per 
subject clinical outcome at TOC) the estimates of the difference in the eradication rate 
and cure rate respectively between the two treatment arms along with the 95% CIs (Wald 
method) if data warrant. If the number of subjects within a subgroup is less than 10 in any 
treatment arm, only the difference in the eradication rate or cure rate between the two 
treatment arms (no CI) will be presented. The reason we are using 10 as a threshold value 
for displaying CI is because we are using Wald CI which is appropriate when we have at 
least 5 successes and at least 5 failures in each sample [5].  
Other subgroup analyses may be performed if deemed necessary. 
The subgroup analysis category for Meropenem non-susceptible status for Day 14 all-
cause mortality, Day 28 all-cause mortality, per subject microbiological outcome at 
EOT,TOC and FU and per subject clinical outcome at EOT ,TOC and FU , top 5 baseline 
gram-negative pathogens and creatinine clearance renal grading sub group category was 
specified after the study team had viewed the aggregate mortality results by treatment 
group on April 1st , 2019 and is hence is a post-hoc analysis. 
The Meropenem non-susceptible status for subjects will be Yes if for any baseline gram-
negative pathogens (including stenotrophomonas maltophilia) the CLSI results are non-
susceptible to Meropenem. The carbapenem resistant (CR) criteria for Pseudomonas spp. 
is MIC >= 4µg/mL, for Acinetobacter spp. is MIC >= 8 µg/mL and for 
Enterobacteriaceae is MIC >= 2 µg/mL. 
Subjects who have MIC values > 8 µg/mL for Meropenem for any baseline gram-
negative pathogen is another post-hoc subgroup category for Day 14 all-cause mortality, 


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Day 28 all-cause mortality, per subject microbiological outcome and clinical outcome at 
EOT, TOC and FU  
9.2 
Key Secondary Endpoints 
The key secondary efficacy endpoints include the following: 
 Microbiologic outcome of treatment with cefiderocol or meropenem per subject at 
Test of Cure (TOC) 
 Clinical outcome of treatment with cefiderocol or meropenem per subject at TOC 
 To compare Day 14 all-cause mortality of S-649266 with that of meropenem for 
superiority of S-649266 
9.3 
Other Secondary Efficacy Endpoints 
 To compare the microbiological outcome of treatment with cefiderocol with that 
of meropenem per subject at Early Assessment(EA),End of Treatment (EOT)4, 
and Follow-up (FU) 
 To compare the clinical outcome of treatment with cefiderocol with that of 
meropenem per subject at EA, EOT and FU 
 To compare all-cause mortality at Day 28 of subjects treated with cefiderocol with 
that of meropenem 
 To compare all-cause mortality up to EOS visit of subjects treated with cefiderocol 
with that of meropenem. 
9.3.1 
Per Subject Microbiological Outcomes 
The microbiological outcomes by baseline pathogens will be determined according to the 
following criteria at EA, EOT and TOC: 
 Eradication: Absence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. Presence of colonizers or contaminants associated 
with a baseline pathogen will be associated with microbiological outcome of 
eradication.  If it is not possible to obtain an appropriate clinical culture, and the 
subject has a successful clinical outcome, the response will be presumed as 
eradication. 
 Persistence: Continued presence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. Persistence at End of Treatment or Test Of Cure 
will be carried forward. 
 Indeterminate: No culture obtained from an appropriate clinical specimen or if 
the microbiological outcome is eradication after additional antibacterial therapy 
for the treatment of the current infection. 
                                                 
4 EOT is defined as the last day of study treatment. 


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The microbiological outcomes by baseline pathogens will be determined according to the 
following criteria at FU: 
 Sustained Eradication: Absence of the baseline Gram-negative pathogen from 
an appropriate clinical specimen after TOC. Presence of colonizers or 
contaminants associated with a baseline pathogen will be associated with 
microbiological outcome of sustained eradication. If it is not possible to obtain an 
appropriate clinical culture, and the subject has a successful clinical response after 
TOC, the response will be presumed eradication. 
 Recurrence: Recurrence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen taken after TOC, and the TOC culture was negative. 
 Persistence: Persistence of any baseline Gram-negative pathogen from an 
appropriate specimen 
 Indeterminate: No culture obtained from an appropriate clinical specimen or if 
the microbiological outcome is eradication after the subject received additional 
antibacterial therapy for the treatment of the current infection. 
As shown in Table 9-1, subjects who experience eradication of all baseline Gram-
negative pathogen(s) at EA, EOT and TOC their per subject microbiological outcome 
will be considered “eradication” and subjects who experience persistence of any baseline 
Gram-negative pathogens, their per subject microbiological outcome will be considered 
“persistent”.” Subjects whose experiences are other than the above will be considered 
“indeterminate.” 
At FU, the per subject microbiological outcome for subjects who experience sustained 
eradication of all baseline Gram-negative pathogens will be considered as “sustained 
eradication” and subjects who experience recurrence of any baseline Gram-negative 
pathogens will have a per subject microbiological outcome of “recurrence”. Subjects who 
show persistence of any baseline Gram-negative pathogens will have a per subject 
microbiological outcome of “persistence”. Subjects whose experiences are other than 
above at FU will be considered “indeterminate”. 


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Table 9-1 
Per Subject Microbiological Outcome at End of 
Treatment, Test of Cure and Follow-up 
Visit 
Per Subject Microbiological 
Outcome 
Definition 
Early 
Assessment, 
End Of 
Treatment and 
Test Of Cure  
Eradication 
Eradication of all baseline Gram-negative 
pathogens 
Persistence 
Persistence of any baseline Gram-negative 
pathogens 
Indeterminate 
Other than those above 
Follow-up 
Sustained eradication 
Absence of baseline Gram-negative pathogens 
from appropriate clinical specimen after TOC. 
Persistence 
Persistence of any baseline Gram-negative 
pathogen 
Recurrence 
Recurrence of any baseline Gram-negative 
pathogen 
Indeterminate 
Other than those above 
 
9.3.1.1 
Analysis of the Microbiological Outcome per Subject at Early 
Assessment, End of Treatment, and Test of Cure 
The microbiological response rate at EA, EOT and TOC will be calculated as the 
proportion of subjects who experience eradication at EA, EOT and TOC respectively by 
treatment group. The adjusted estimate of the difference in the response rate between the 
2 treatment groups will be presented along with the 95% CIs based on a stratified 
analysis using the CMH weights: infection diagnosis (HABP/VABP/HCABP) and 
APACHE II score (≤ 15 and ≥ 16). In addition, the number and proportion of subjects 
having microbiological outcome as persistence and indeterminate will be summarized by 
treatment group. 
9.3.1.2 
Analysis of Microbiological Outcome per Subject at Follow-up 
The microbiologic response rate at FU will be calculated as the proportion of subjects 
who experience sustained eradication of all baseline Gram-negative pathogens after 
documented eradication at the TOC. 
The same analysis method as described in Section 9.3.1.1 above for microbiological 
outcome per subject at EA, EOT and TOC will be performed for the microbiologic 
outcome per subject at FU. The outcome will be tabulated for each treatment group. The 
adjusted estimate of the difference in the response rate between the 2 treatments arms 
along with the adjusted 95% CIs based on the CMH weights will be presented. 
9.3.2 
Microbiological Outcome per Subject for the Subset where Gram-
negative Pathogens Isolated from Blood Culture are the Same as 
Lung at Baseline 
In addition to the analyses described above, the microbiological response rate will be 
summarized for the subset where gram-negative pathogens isolated from blood culture 


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are the same as lung at baseline at EA, EOT, TOC and FU. The same analysis method 
described in Sections 9.3.1.1 and 9.3.1.2 will be implemented for this analysis. 
9.3.3 
Per pathogen Microbiological Outcomes 
The microbiological outcomes by baseline pathogens will be determined according to the 
criteria defined in Section 9.3.1 above. 
For the microbiological outcome per pathogen, the outcomes will be summarized and the 
eradication rate with 95% CI will be calculated by treatment group at EA, EOT, TOC and 
FU will be calculated. The estimate of the eradication rate between the two treatment 
arms along with the 95% CIs will be presented for pathogens with a frequency of at least 
10 in each treatment arm. In case of baseline pathogens with a frequency less than 10 in 
any treatment arm, only the difference in the eradication rate between the two treatment 
arms (no CI) will be presented. 
In addition to the analyses described above, the eradication rate per pathogen at TOC will 
also be tabulated by the MIC values and susceptibility defined by CLSI of the baseline 
pathogen. For this analysis, MIC for cefiderocol, amikacin, aztreonam, ceftazidime-
avibactam, imipenem, ceftolozane-tazobactam, ciprofloxacin, meropenem, cefepime, 
colistin, and tigecycline will be summarized. 
A listing of per pathogen microbiological assessment for emergence resistance will be 
provided for the cefiderocol arm. The emergence of resistance will be determined by 
assessing for at least 4-fold increases in MICs from baseline value for baseline pathogens 
that persist at EA, EOT, TOC or recurrence at FUP. 
9.3.4 
Per Subject Clinical Outcomes 
The clinical outcomes will be assessed by the investigator according to the following 
criteria at EA, EOT and TOC: 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms of pneumonia, including a reduction in Sequential Organ Failure 
Assessment (SOFA) and Clinical Pulmonary Infection (CPIS) scores, and 
improvement or lack of progression of chest radiographic abnormalities such that 
no additional antibacterial therapy is required for the treatment of current 
infection at the EA and EOT visits, and no antibacterial therapy is required for the 
treatment of the current infection at the TOC. 
 Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms of pneumonia; reappearance of signs and/or 
symptoms of pneumonia; development of new signs and/or symptoms of 
pneumonia requiring antibiotic therapy other than, or in addition to, study 
treatment therapy; progression of chest radiographic abnormalities; or death due 
to pneumonia.  
 Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 


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The clinical outcome at FU will be assessed by the investigator according to the 
following criteria: 
 Sustained Clinical Cure: Continued resolution or substantial improvement of 
baseline signs and symptoms of pneumonia, such that no antibacterial therapy has 
been required for the treatment of pneumonia in a subject assessed as cured at 
TOC.  
 Relapse: Recurrence of signs and/or symptoms of pneumonia, appearance of new 
signs and/or symptoms of pneumonia, or new chest radiographic evidence of 
pneumonia in a subject assessed as cured at TOC.  
 Clinical Failure: Clinical failure at TOC will be carried forward regardless of 
lost to follow-up. 
 Indeterminate: Lost to follow-up, such that a determination of clinical sustained 
cure/relapse cannot be made, or subject received additional antibacterial therapy 
for the treatment of the current infection.  
9.3.4.1 
Analysis of Clinical Outcome per Subject at Early Assessment, End of 
Treatment and Test of Cure 
The clinical response rate at Early Assessment, End of Treatment and Test of Cure will 
be calculated as the proportion of subjects who have a clinical outcome of cure. The 
adjusted estimate of the difference in the cure rate between the 2 treatment groups will be 
presented along with the adjusted 95% CIs based on the CMH weights: diagnosis and 
APACHE II score. In addition, the number and proportion of subjects having clinical 
outcome as failure and indeterminate will be summarized by treatment group. 
9.3.4.2 
Analysis of Clinical Outcome per Subject at Follow-up 
The cure rate at FU will be calculated as the proportion of subjects with clinical outcome 
of sustained clinical cure. In addition, the number and proportion of subjects having 
clinical outcome as relapse, clinical failure and indeterminate will be summarized by 
treatment group. 
The same analysis method as described in Section 9.3.4.1 above for clinical outcome per 
subject at EA, EOT and TOC will be performed for the clinical outcome per subject FU. 
The outcome will be tabulated for each treatment group. The adjusted estimate of the 
difference in the response rate between the 2 treatments arms along with the adjusted 
95% CIs based on the CMH weights will be presented. 
9.3.5 
Clinical Outcome per Pathogen 
For the clinical outcome per pathogen, the outcomes will be summarized and the cure 
rate and its 95% CI at EA, EOT, TOC and FU will be calculated by treatment group for 
each time point. The 95% CIs (2-sided) are calculated using a normal approximation to 
the difference between 2 binomial proportions (Wald method). For baseline pathogens 
with a frequency less than 10 in any treatment arm, the 95% CIs are not presented. 


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In addition to the analyses described above, the clinical cure rate per pathogen at TOC 
will also be tabulated by the MIC values and susceptibility defined by CLSI of the 
baseline pathogen. For this analysis, MIC for cefiderocol, amikacin, aztreonam, 
ceftazidime-avibactam, meropenem, ceftolozane-tazobactam, ciprofloxacin, imipenem, 
cefepime, colistin, and tigecycline will be summarized. 
9.3.6 
All-cause Mortality at Day 28 
All-cause mortality rate at Day 28 since first infusion of study drug will be calculated as 
the proportion of patients who experienced mortality regardless of the cause at or before 
Day 28 since first infusion. 
Superiority of cefiderocol over meropenem for the day 28 all-cause mortality endpoint 
can be concluded if the 2-sided 95% CI for the difference in Day 28 all-cause mortality 
between the two treatment groups (cefiderocol and meropenem) lies completely below 
zero. 
9.3.6.1 
Analysis of All-cause Mortality at Day 28 
All-cause mortality at Day 28 will be analyzed in a similar way to the primary efficacy 
endpoint described in Section 9.1.1 
9.3.7 
All-cause Mortality during treatment and follow-up period (until 
EOS) 
All-cause mortality rate during treatment and follow-up period (until EOS) will be 
calculated as the proportion of patients who experienced mortality regardless of the cause 
at or before EOS since the first infusion. If a subject discontinues from the study before 
this period and survival information was not available, then the survival status for this 
endpoint for the subject will be unknown. 
9.3.7.1 
Analysis of All-cause Mortality during treatment and follow-up period 
(until EOS) 
All-cause until EOS visit will be analyzed in a similar way to the Primary Efficacy 
endpoint described in Section 9.1.1 
9.3.7.2 
Subgroup Analysis for All-cause Mortality until EOS 
9.3.7.2.1 
From Time of First Dose 
Analyses of all-cause mortality during treatment and follow-up period (until EOS) will be 
presented for the subgroup associated with time period of death: ≤ 3 days after start of 
study treatment, 4 – 28 days of start of study treatment and > 28 days since start of study 
treatment. 
The estimates of the difference in the all-cause mortality rates between cefiderocol and 
meropenem will be presented along with 95% confidence intervals (CIs) (Wald method) 
if data warrant. If the number of subjects within a subgroup is less than 10 in any 


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treatment arm, only the difference in the all-cause mortality between the two treatment 
arms (no CI) will be presented. The CI will be 2-sided. 
9.3.7.2.2 
From Time of Last Dose 
Analyses of all-cause mortality during treatment and follow-up period (until EOS) will 
also be presented for the subgroup associated with the timing of last dose to death: 0 day 
(on the same day as last dose) , 1-7 days after last dose of study treatment, 8 – 14 days 
after last dose of study  treatment and >= 15 days after last dose of study treatment. The 
time will be calculated as death day – last dose of study drug day. 
The estimates of the difference in the all-cause mortality rates between cefiderocol and 
meropenem will be presented along with 95% confidence intervals (CIs) (Wald method) 
if data warrant. If the number of subjects within a subgroup is less than 10 in any 
treatment arm, only the difference in the all-cause mortality between the two treatment 
arms (no CI) will be presented. The CI will be 2-sided. 
9.3.7.3 
Survival Time Up to End of Study 
For the survival time up to EOS, the survival curve using Kaplan-Meier method by 
treatment group will be presented. For the subjects whose vital status is survival at EOS, 
the subjects will be treated as right-censored at EOS. For the subjects whose vital status is 
not collected or unknown, the subjects will be treated as right-censored since their last 
visit day. 
9.4 
Sequential Organ Failure Assessment Score 
Sequential Organ Failure Assessment score at Baseline and at each postbaseline visit 
(early assessment, end of treatment, test of cure and follow-up) will be summarized. 
Change from baseline for each postbaseline visit will also be summarized. 
9.5 
Clinical Pulmonary Infection Score 
Clinical Pulmonary Infection Score at Baseline and at each postbaseline visit (early 
assessment, end of treatment, test of cure and follow-up) will be summarized by 
treatment group. Change from baseline for each postbaseline visit will also be 
summarized. 
10. SAFETY 
Safety assessments included AEs, clinical laboratory safety tests (hematology, chemistry, 
endocrinology, and urinalysis), vital sign measurements, and 12-lead electrocardiograms 
(ECGs). All safety summaries and analyses will be performed based on the Safety 
population. 
10.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product (including investigational drug) during the course of a clinical 
investigation. An AE can therefore be any unfavorable and unintended sign (including an 


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abnormal laboratory finding), symptom, or disease temporarily associated with the use of 
an investigational product, whether or not considered related to the investigational 
product. Where symptoms or signs form part of a diagnosis, the diagnosis should be 
reported as AE instead of the individual symptoms and signs. 
Adverse events will be collected from the time of informed consent through EOS for 
randomized subjects. Adverse events will be classified by System Organ Class (SOC) 
and Preferred Term (PT) using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 18.1 or higher  
Adverse events that started after the first dose of the study drug and up to “End of Study” 
are defined as treatment-emergent. 
Unless otherwise noted, the summary of AEs will be performed for events of treatment-
emergent. An overview of AEs will be provided that summarizes subject incidence and 
the number of AEs, treatment-related AEs, SAEs, treatment-related SAEs, death due to 
AEs, AEs leading to discontinuation of study drug, and treatment-related AEs leading to 
discontinuation of study drug. The incidence proportion of treatment-emergent adverse 
events (TEAEs) will be calculated by treatment group. The incidence proportion will be 
calculated as the proportion of subjects experiencing TEAEs to total subjects in the safety 
population. Difference in the incidence proportion between cefiderocol and meropenem, 
and its 95% CI will be calculated using Wilson (score) method. Deaths due to AEs, 
serious adverse events (SAEs), AEs leading to discontinuation of study drug, treatment 
related AEs, treatment related SAEs, and treatment-related AEs leading to 
discontinuation of study drug will be analyzed in a similar way. 
The number and percentage of subjects with AEs will be summarized for each treatment 
group by SOC and PT. Subjects with more than 1 AE in the same SOC will be counted 
once for the SOC. Similarly, subjects with more than 1 AE in the same PT will be 
counted once for the PT. Difference in the incidence proportions between cefiderocol and 
meropenem, and its 95% CI will be calculated using the Wilson’s (score) method. 
Treatment-related AEs, SAEs, treatment-related SAEs, AEs leading to discontinuation of 
the study drug will be summarized in the same manner.  
Summaries will be provided by maximum severity for the number and percentage of 
subjects with AEs by SOC and PT. For the summary of AEs by maximum severity, 
missing severity will be assumed as “severe.” For these summaries, subjects with 
multiple AEs will be counted only once by the maximum severity within an SOC and PT. 
All AEs including AEs not considered treatment-emergent, which have occurred before 
or after the first dose of the study drug, will be listed by subject. 
10.2 Vital Signs 
Vital sign measurements, including diastolic blood pressure (mm Hg), systolic blood 
pressure (mm Hg), body temperature, pulse rate (beats per minute), and respiration rate 
(breaths/minute) will be measured at Screening and at specified times. 


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Summary statistics for vital sign measurements will be presented for EA, EOT, TOC, FU 
and for the change from baseline to each time point. Baseline will be the last value 
obtained before first dose of study drug. 
For postbaseline measurements, if multiple readings (ie, 3 readings) of vital sign 
measurements are obtained within a visit, the maximum body temperature within that 
visit and the associated systolic and diastolic blood pressure, pulse rate, and respiratory 
rate measured at the same time point will be used for the summary. 
In addition, the number and percentage of subjects with the following prespecified outlier 
category given in Table 10-1 during the post dosing period including unscheduled will be 
presented by treatment group. 
Table 10-1 
Outliers for Each Parameter in Vital Sign Measurements 
Parameter (Unit) 
Outlier Category 
Systolic blood pressure (mm Hg) 
Value ≥ 160 or increase from baseline ≥ 20 
Value ≤ 90 or decrease from baseline ≥ 20 
Diastolic blood pressure (mm Hg) 
Value ≥ 105 or increase from baseline ≥ 15 
Value ≤ 50 or decrease from baseline ≥ 15 
Heart rate (beats per minute) 
Value ≥ 120 or increase from baseline ≥ 15 
Value ≤ 50 or decrease from baseline ≥ 15 
10.3 Clinical Laboratory Evaluations 
Summary statistics for laboratory test data (hematology, blood chemistry, and other 
specialized tests) will be presented for each scheduled time point measured after first 
infusion and for the change from baseline to each time point. Since PTT and APTT were 
collected in the same data field a meaningful data summary cannot be made for PTT. All 
clinical laboratory summaries other than specialized tests will be based on the local 
laboratory measurements, and only the data that can be converted into standard units will 
be included in analysis. Summaries for specialized tests will be based on the central 
laboratory measurements. All central clinical laboratory data and local clinical laboratory 
data will be listed. If the SI units for CRP are available in EDC as a value less than the 
lower limit then it will be set to the lower limit and then used for analysis. 
Scheduled laboratory parameters shown in Table 10-2 include the following: 


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Table 10-2 
Routine Laboratory Tests 
Category 
Evaluation Items 
Hematology tests 
Hematocrit, hemoglobin, platelet count, RBC, WBC with differential and 
morphology indices, INR 
Blood chemistry tests 
ALP, ALT, AST, GGT, LDH, CPK, CRP, and amylase, BUN, creatinine, TBL, 
sodium, potassium, bicarbonate, chloride, calcium, magnesium, glucose, total 
protein, albumin, uric acid, and total cholesterol 
Urinalysis 
Glucose, blood, protein, ketones, bilirubin, urobilinogen, leukocyte esterase, and 
microscopica (WBC, RBC, crystals, and casts) 
Specialized tests 
Iron, total iron-binding capacity, transferrin iron saturation, and hepcidin at 
Screening and Test of Cure 
Others 
Serum or urine pregnancy test at screening   
CrCl and eGFR: at Screening and EA (Section 7.6.4.4 in the protocol) 
CrCl determined from a timed urine collection at EAb (Section 7.6.4.4 in the 
protocol) 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = 
blood urea nitrogen; CPK = creatine phosphokinase; CrCl = creatinine clearance; CRP = C-reactive 
protein; EA = Early Assessment; eGFR = estimated glomerular filtration rate; GGT = gamma-glutamyl 
transferase; INR = international normalized ratio; LDH = lactate dehydrogenase; PTT = partial 
thromboplastin time; RBC = red blood cell; TBL = total bilirubin; WBC = white blood cell   
a 
If sediment is present. 
b 
For subject with eGFR ≥ 90 mL/min/1.73 m2 at Screening. 
 
The number and percentage of subjects with the following prespecified outlier category 
listed in Table 10-3 below each postbaseline visit (Early assessment, End of Treatment, 
Test of Cure and Follow-up) including unscheduled visits will be presented by treatment 
group. 


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Table 10-3 
The Outlier for Each Parameter in Laboratory Test 
Parameter (Unit) 
Outlier Category 
Hemoglobin (g/dL) 
Decrease from baseline ≥ 1.5 g/dL 
Platelet count (103/µL)  
Decrease from baseline ≥ 25% and value < LLN 
  
Increase from baseline ≥ 100% and value > ULN 
White blood cell count (103/µL) 
Decrease from baseline ≥ 50% and value < LLN 
  
Increase from baseline ≥ 20% and value > ULN 
ALT (U/L) 
Value > 3 × ULN 
  
Value > 5 × ULN 
  
Value > 10 × ULN 
  
Value > 20 × ULN 
AST (U/L) 
Value > 3 × ULN 
 
Value > 5 × ULN 
 
Value > 10 × ULN 
Value > 20 × ULN 
AST (U/L) or ALT (U/L) 
value > 3 × ULN 
  
Value > 5 × ULN 
  
Value > 10 × ULN 
  
Value > 20 × ULN 
Total bilirubin (mg/dL) 
Value > 2 × ULN 
 
Increase from baseline ≥ 50% and value > ULN 
PT-INR 
Value > 1.5 
Blood urea nitrogen (mg/dL) 
Increase from baseline ≥ 50% and value > ULN 
Serum creatinine (mg/dL) 
Increase from baseline ≥ 0.3 mg/dL 
ALP (U/L) 
Increase from baseline ≥ 50% and value > ULN 
AST (U/L) or ALT (U/L) +  
total bilirubin (mg/dL) or PT-INR 
(AST > 3 × ULN or ALT > 3 × ULN) and  
(total bilirubin > 2 × ULN or PT-INR > 1.5 )  
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; LLN = lower 
limit of normal; PT-INR = prothrombin time-international normalized ratio; UN = upper limit of normal 
 
10.4 Electrocardiograms 
All ECG measurements and the overall interpretation will be listed by subject. 
11. PHARMACOKINETIC ANALYSES 
Individual plasma concentrations of cefiderocol will be listed and summarized by 
nominal sampling time window, and if possible, by dosing group based on renal function. 
The summary statistics will include the number of nonmissing observations (N), 
arithmetic mean (Mean), SD, and coefficient of variation (CV%, calculated by SD/Mean 
× 100), geometric mean and coefficient of variation for geometric mean (CV% 
Geometric Mean), and median, minimum, and maximum values. The CV% Geometric 
Mean will be calculated according to a formula CV% Geometric Mean = [exp (sd2) - 1]1/2 
× 100, where sd is the SD for natural log (ln)-transformed data. If the number of 


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nonmissing observations at a time point is less than 3, the data at the time point will not 
be summarized. The time course of individual and mean plasma concentrations will be 
presented by appropriate graphics. 
Individual plasma concentrations, if deemed to be anomalous, may be excluded from the 
analysis at the discretion of the PK study director. Any such exclusion will be clearly 
listed in the study report along with justification for exclusion. 
For the summary of plasma concentrations, plasma concentrations below the limit of 
quantification (BLQ) will be treated as 0 for calculations of Mean, SD, CV%, median, 
minimum, and maximum values and treated as missing for the calculation of geometric 
mean value and CV% Geometric Mean. 
12. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
The pharmacokinetics/pharmacodynamics will be planned and reported separately by the 
Clinical Pharmacology & Pharmacokinetics of Shionogi & Co., Ltd.  
For each subject randomized to cefiderocol with an identified Gram-negative pathogen, 
the percentage of the dosing interval for free-drug plasma concentration to be above the 
minimum inhibitory concentration (%Tf>MIC) will be calculated and the relationship 
between %Tf>MIC and clinical and microbiological outcome will be described. 
13. INTERIM ANALYSES 
After about 50 and 150 subjects have been randomized, completed treatment and follow-
up, the interim analysis to review un-blinded safety and efficacy data will be performed 
by the DSMB. After the first unblinded review of the first 50 subjects by the DSMB, a 
request was made to have an additional unblinded review of safety and efficacy data after 
100 subjects were randomized into the study. 
An alpha spend of 0.0001 based on Haybittle-Peto will be used for the two formal 
unblinded looks of the data related to the primary endpoint at ~ 50 patients and ~ 150 
patients . The same Haybittle-Peto alpha spend of 0.0001 will be used for any unplanned 
looks of the data.  
In the event of unplanned looks of the efficacy data for the entire study, a Haybittle-Peto 
alpha spend of 0.0001 will be used for every unplanned look of the data. 
 


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14. PROGRAMMING CONVENTIONS 
14.1 Formatting and Programming Rule 
The display digit of various tests (such as laboratory tests) is as specified for each 
respective test, in principle. Display digits of statistics for efficacy and safety analyses are 
defined in Table 14-1.  
Table 14-1 
Display Digit of Statistics for Efficacy and Safety 
Statistics 
Display Digit 
Number of subjects 
Displayed as integer. 
Mean, median, first quartile, least-square 
mean, 95% confidence interval, 
Standard deviation 
One more decimal place than raw data. 
Maximum, minimum 
Same number of decimal places as raw data. 
Percentage (%) 
Round off to 1 decimal place. 
P value 
Round off to 4 decimal places. 
Note: p < 0.0001 is displayed as “< .0001”. 
Summary statistics for pharmacokinetics 
analysis 
Three significant digit 
 
Handling of Outliers 
Possible outliers will not be omitted from analyses. 
Categories Used in the Summarization 
Categories used in the summarization of items are shown in Table 14-2. The breakdown 
of categories may be changed with blind inspection of distribution as needed.  


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Table 14-2 
Subject Characteristics and Items of Therapeutic 
Process 
Items  
Categories 
Gender  
Male, female 
Race 
American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or Other Pacific 
Islander, White, Other 
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino, Unknown 
Age (years) 
< 65, ≥ 65 and <75, ≥ 75 
Weight (kg) 
< 70, ≥ 70 
Clinical Diagnosis 
HABP, VABP, and HCABP 
APACHE II score 
≤ 15, 16-19, ≥ 20 
CPIS 
< 6, 6-7, 8-9, > 9 
Bacteremia 
Yes, No 
Medical History 
Yes, No 
Prior Therapy 
Yes, No 
Creatinine clearance renal grading 
>120mL/min, > 80-120mL/min, > 50-80mL/min, 30-
50mL/min, < 30mL/min 
Type of Baseline pathogen 
Gram-negative pathogens only, Gram-positive 
pathogens only, Mixed pathogens ,Fungal pathogens 
only, No respiratory sample, Culture negative, Others 
Type of Blood Culture 
Positive, Negative, Blood culture not done 
Augmented renal clearance 
MDRD-eGFR >= 90 mL/min/1.73 m2 and CrCl 
>=120 mL/min, MDRD-eGFR >= 90 mL/min/1.73 
m2 and CrCl < 120 mL/min, MDRD-eGFR 60 to < 90 
mL/min/1.73 m2,MDRD-eGFR 15 to < 30 
mL/min/1.73 m2 ESRD(MDRD-eGFR < 15 
mL/min/1.73 m2 ) 
Severity of disease 
Mild, Moderate, Severe 
Ventilation status at randomization 
Ventilated, Non-Ventilated 
ICU admission 
Yes, No 
Empiric therapy failure status 
Yes, No 
Number of Gram-negative pathogens isolated at 
baseline 
0,1, 2, 3, >3 
Duration of treatment (days) 
< 7,>= 7 to <= 14,> 14 to <= 21, > 21  
Country (region) 
North America, Asia-Pacific, Europe 
Meropenem non-susceptible status* 
Yes, No 
MIC > 8 µg/mL for Meropenem 
Yes, No 
* 
Non-susceptible by CLSI criteria (Pseudomonas spp. is MIC >= 4µg/mL, for Acinetobacter spp. is 
MIC >= 8 µg/mL and for Enterobacteriaceae is MIC >= 2 µg/mL) APACHE II = Acute Physiology 
and Chronic Health Evaluation II; eGFR = estimated glomerular filtration rate; HABP = hospital-
acquired bacterial pneumonia; HCABP = healthcare-associated bacterial pneumonia; VABP = 
ventilator- associated bacterial  
 


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15. CHANGES FROM PROTOCOL SPECIFIED ANALYSES 
 Added analysis for Distribution of Gram-negative pathogens Isolated at Baseline 
pathogen  
 Added Analyses for Baseline pathogen per MIC and CLSI interpretation 
 Added Analyses for Clinical outcome per pathogen 
 Added Analyses for Clinical outcome per MIC and CLSI interpretation 
 Added analyses Microbiological outcome per pathogen 
 Added analyses for Microbiological outcome per MIC and CLSI interpretation 
 Added analyses for Listing for 4 fold increase of MIC from baseline 
 Added analyses for Summary for Microbiological Outcome Per Subject whose 
Gram-Negative Pathogens Isolated from Blood Culture are the Same as Lung at 
Baseline 
 Added analyses for Summary of Minimum Inhibitory Concentration of Baseline 
Gram-negative Pathogens Isolated from the Blood Culture That Are the Same as 
Lung at Baseline   
 Summary of All-cause Mortality at Day 28 by Predefined Subgroups 
 Summary of Microbiological Outcome Per Subject at Test of Cure by Predefined 
Subgroups  
 Summary of Clinical Outcome Per Subject at Test of Cure by Predefined 
Subgroups  
 Summary of all-cause mortality until EOS visit based on study day of death 
 Added a post-hoc subgroup category for Meropenem non-susceptible status  
 Added a post-hoc subgroup category for subjects with MIC values greater than 8 
for Meropenem for any baseline gram-negative pathogen 
 Added a post hoc subgroup for top 5 baseline gram-negative pathogens. 
 


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16. REFERENCE 
1. Guidance for Clinical Trial Sponsors. Establishment and Operation of Clinical trial 
Data Monitoring Committees. March 2006. 
2. Wiskirchen DE, Kuti JL, Nicolau DP. Acute physiology and chronic health 
evaluation II score is a better predictor of mortality than IBMP-10 in patients with 
ventilator-associated pneumonia.SurgInfect (larchmt). 2011 Oct;12(5):385-90. 
3. Mirsaeidi M, Peyrani P, Ramirez JA; Improving Medicine through Pathway 
Assessment of Critical Therapy of Hospital-Acquired Pneumonia(IMPACT-HAP) 
Investigators. Predicting mortality in patients with ventilator-associated pneumonia: 
The APACHE II score versus the new IBMP-10 score. Clin Infect Dis. 2009 Jul; 
49(1):72-7. 
4. Zhou XY, ben SQ, Chen HL, Ni SS. A comparison of APACHE II and CPIS scores 
for the prediction of 30-day mortality in patients with ventilator-associated 
pneumonia. Int J Infect Dis. 2015 Jan;30:144-7. 
5. Agresti A. Categorical Data Analysis 2nd ed.,  New York: John Wiley & Sons, 2002. 
 
 
 


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17. APPENDIX 1 STUDY SCHEMATIC 
D −2 to D 1 
D 3 to D 4 
EOTa 
EOT  
+ 7  
(±2) 
EOT  
+ 14 
 (±3) 
EOT  
+ 28 
 (±3) 
Screening\Baseline 
Randomization 
Treatment Period 
Test of Cure (TOC) 
Follow-up (FU) 
End of Study (EOS) 
D 1 
Early Clinical/Micro Assessment 
(EA) 
Pharmacokinetic blood sampling 
Up to D 
14a 
S-649266 daily 2-g intravenous dosing at 
8-hour intervalsb as a 3-hour infusion 
 
Meropenem daily 2-g intravenous dosing 
at 8-hour intervalsb as a  
3-hour infusion 
 
D = Day; EOT = End of Treatment  
a. 
The treatment duration can be extended up to 21 days based on the investigator’s clinical assessment of 
the subject. A clear reason should be documented.  
b. Dosing adjustments for renal impairment (see Tables 5-1 and 5-2 in the protocol). 
 
 
 
 


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18. APPENDIX 2 TIME AND EVENTS SCHEDULE 
Evaluation 
Screening/ 
Baseline  
 
Treatment Period 
Test of Cure 
(TOC) 
 
Follow-up 
(FU) 
End of Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
 
Day 1 
EA 
Day 
3 to 4 
Day 14b 
EOTc 
EOT + 7  
(± 2) 
Day 
28b 
EOT + 14  
(± 3)  
EOT + 28 
(± 3) 
Informed Consent 
X 
Randomization                                                       
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical Historyd 
X 
 
 
 
 
 
 
 
 
Physical Examination 
Xe 
 
Xf 
Xf 
Xf 
Xf 
 
Xf 
Xf, g 
GCS 
X 
 
X 
X 
X 
X 
 
X 
 
APACHE II Score 
X 
 
 
 
 
 
 
 
 
SOFA Score 
X 
 
X 
X 
X 
X 
 
X 
 
Clinical Assessment of 
Signs and/or Symptoms 
X 
 
X 
X 
X 
X 
 
X 
 
Oxygenation Status 
X 
X 
X 
X 
X 
X 
 
X 
 
Chest Radiographs  
X 
 
Xh 
X 
X 
X 
 
Xh 
 
CPIS Parametersi 
X 
X 
X 
X 
X 
X 
 
Xi 
 
Pregnancy Testj 
X 
 
 
 
 
 
 
 
 
Hematology Tests, Blood 
Chemistry Tests, and 
Urinalysis (see  
Table 7-1) 
X 
 
X 
X 
X 
X 
 
X 
Xg 
Specialized Tests (see 
Table 7-1) 
X 
 
 
 
 
X 
 
 
 
CrCl from Serumk 
Creatinine and MDRD-
eGFR  
X 
 
X 
 
 
 
 
 
 
CrCl from Urinary 
Creatininek 
X 
 
X 
 
 
 
 
 
 
Vital Signsl 
X 
X 
X 
X 
X 
X 
 
X 
Xg 


S-649266: Study 1615R2132 
Shionogi Inc. 
Statistical Analysis Plan 
9 Jul 2019 
 _______________________________________________________________________________________________________________________________  
 
Confidential 
Page 45 of 46 
Evaluation 
Screening/ 
Baseline  
 
Treatment Period 
Test of Cure 
(TOC) 
 
Follow-up 
(FU) 
End of Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
 
Day 1 
EA 
Day 
3 to 4 
Day 14b 
EOTc 
EOT + 7  
(± 2) 
Day 
28b 
EOT + 14  
(± 3)  
EOT + 28 
(± 3) 
12-lead ECG  
X 
 
 
 
 
 
 
 
 
Drug Administrationm 
 
X 
X 
X 
X 
 
 
 
 
Assess Clinical Outcome 
 
 
X 
X 
X 
X 
 
X 
 
Microbiological Outcome 
 
 
X 
X 
X 
X 
 
X 
 
Lower Respiratory 
Specimens for 
Microbiologic Culturesn 
X 
 
X 
X 
X 
X 
 
X 
 
Blood Cultureso 
X 
 
X 
X 
X 
X 
 
X 
 
Blood PK Samplesp  
 
 
 
Xp 
 
Xp 
 
 
 
 
AE Assessment 
X 
 
 
 
 
 
 
 
 
X 
Concomitant Therapy 
X 
 
 
 
 
 
 
 
X 
Hospitalization 
(see Section 7.2.1 in the 
protocol) 
X 
 
 
 
 
 
 
 
X 
Survivalq 
X 
 
 
 
 
 
 
 
X 
AE= adverse event; APACHE II = Acute Physiology and Chronic Health Evaluation II; CPIS = Clinical Pulmonary Infection Score; CrCl = creatinine clearance; EA = Early 
Assessment; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = End of Study; EOT = End of Treatment; FU = Follow-up; GCS = Glasgow Coma 
Scale; I/E = inclusion/exclusion; MDRD = modification of diet in renal disease, PK = pharmacokinetics; q8h = every 8 hours; q12h = every 12 hours; SOFA = Sequential Organ 
Failure Assessment; TOC = Test of Cure 
a 
If screening and randomization (Day 1) occur on the same day, the activities of screening and Day 1 should be completed, without duplication of assessments. 
b 
Additional assessment will be conducted on Day 14, if treatment duration is extended beyond 14 days to up to 21 days; survival will be recorded on Day 14 and Day 28. 
c 
EOT evaluations occur on the last day of study treatment; EOT can be any time after the subject had at least 1 dose of study treatment, duplication of assessments for a given 
day and EOT is not necessary. 
d 
Include a review of prior/concomitant therapies. 
e 
A complete physical examination, including measurement of body weight and height, will be performed at screening only. 
f 
A limited physical examination relevant to the subject’s current condition will be performed. 
g 
If EOS evaluation is by phone, physical examination, laboratory tests, and vital signs will not be performed. 


S-649266: Study 1615R2132 
Shionogi Inc. 
Statistical Analysis Plan 
9 Jul 2019 
 _______________________________________________________________________________________________________________________________  
 
Confidential 
Page 46 of 46 
h 
Chest radiographs will be performed if clinically indicated. Applicable only to Germany due to local requirements: In sites where chest radiographs after screening are part of 
the standard of care, ie, a chest radiograph is clinically indicated by the treating physicians, it can be performed as usual without a special informed consent. If a chest 
radiograph is not standard of care (no clinical indication), and is planned based on the study protocol, an informed consent from a conscious patient is mandatory. Chest 
radiographs without clinical indication cannot be performed in unconscious patients. 
i 
Most recent chest radiograph is used for the CPIS calculation. 
j 
Urine or serum pregnancy test only for females who are not postmenopausal or surgically sterile. 
k 
The CrCl (the Cockcroft-Gault equation) and eGFR (the MDRD equation) will be calculated from the serum creatinine. For subjects with eGFR ≥ 90 mL/min/1.73 m2 and 
CrCl ≥ 120 mL/min at baseline and EA, urine samples will be collected a time interval as short as 2 hours or up to 8 hours. 
l 
Blood pressure (systolic/diastolic pressures), body temperature, pulse rate, and respiratory rate. Once a day during screening, and 3 times a day during treatment in hospital. 
m 
Drug administration is q8h daily for S-649266 and meropenem unless change is made because of renal function. Linezolid is dosed q12h daily for at least 5 days. 
n 
Lower respiratory tract specimens for microbiologic cultures must be obtained at specified times. When subjects are recovering from pneumonia and produce little respiratory 
secretion, at least an attempt to collect respiratory specimen needs to be made (eg, ask subjects to cough, cough up sputum, or conduct suction from endotracheal tube). 
o 
Two blood samples from separate venipunctures will be collected within 48 hours prior to start of the first dose of study treatment. Subsequent blood cultures are to be 
completed only if the first culture is positive. 
p 
PK blood samples will be drawn on Day 3 or Day 4 of study drug treatment;1 draw just prior to the infusion of the dose, 1 hour after start of infusion, before the end of 
infusion, and at 1 hour after the end of infusion. Subjects with nonstable renal function resulting in a dosage adjustment after EA will undergo another blood PK sampling 24 
to 72 hours after their dosing adjustment. If possible, a single blood draw should be performed as soon as possible (within 24 hours of last dose) in the case of premature EOT, 
which is defined as receiving < 7 days of intravenous treatment.  
q 
Survival is confirmed daily and continuously during the study. Mortality at Days 14 and 28 are study endpoint 
 


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