Clinical trial NCT02714595
Conditions: Healthcare-associated Pneumonia (HCAP) Bloodstream Infections (BSI) Hospital Acquired Pneumonia (HAP) Complicated Urinary Tract Infection (cUTI) Sepsis Ventilator Associated Pneumonia (VAP)
Keywords: cefiderocol Bloodstream infections (BSI) Complicated urinary tract infection (cUTI) Ventilator associated pneumonia (VAP) Hospital acquired pneumonia (HAP) Sepsis multi-drug resistant pathogens S-649266 Gram-negative pathogens Healthcare-associated pneumonia (HCAP) carbapenem resistant pathogens
Sponsor: Shionogi
Start date: 2016-09-07; Completion date: 2019-04-22
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to provide evidence of efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens.

Detailed description:
This study is designed to provide evidence of efficacy of cefiderocol in the treatment of serious infections in adult patients with either hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), healthcare-associated pneumonia (HCAP), complicated urinary tract infection (cUTI), or bloodstream infections (BSI)/sepsis caused by carbapenem-resistant Gram-negative pathogens.

Arms: arm 1: Participants will receive cefiderocol 2 g administered intravenously over 3 hours, every 8 hours for 7-14 days. Treatment could be extended to 21 days at the discretion of the investigator. arm 2: Best available therapy (BAT) will be chosen by the investigator and may include up to three antibacterial agents for carbapenem resistant Gram-negative bacteria, intravenously administered per country-specific guidelines for 7-14 days. Treatment could be extended to 21 days at the discretion of the investigator.
Interventions: intervention 1: Cefiderocol intervention 2: Best Available Therapy
Intervention descriptions: intervention 1: 2 g intravenously over 3 hours every 8 hours for a period of 7 to 14 days, or 2 g every 6 hours for participants with creatinine clearance \>120 mL/min. intervention 2: Standard of care with either a polymyxin-based or non-polymyxin-based regimen as determined by the investigator and consisting of one to three marketed antibacterial agent(s).

Protocol documents:
Prot_001.pdf: 
 
Shionogi Study Title:  
A Multicenter, Randomized, Open-label Clinical Study 
of S-649266 or Best Available Therapy for the 
Treatment of Severe Infections Caused by Carbapenem-
resistant Gram-negative Pathogens 
Shionogi Study Number: 
1424R2131  
ClinicalTrials.gov 
Registration No. 
NCT02714595  
Study Document 
Protocol Version 4 (Amendment 3) 16 November 2017 
 
History of Protocol Amendments 
Version 1 (Original) 
11 November 2015 
This version of the protocol was not used to enroll participants 
Version 2 
18 January 2016 
This version of the protocol was not used to enroll participants 
Version 3 
09 November 2016 
• Better defined the inclusion criteria for patients that had fail previous empiric 
antibiotic therapy 
• Improved the descriptions of acceptable birth control methods and patients who 
were eligible without birth control 
• Better described vasopressor therapy use as far a inclusion criteria were concerned 
• Clarified the WBC type which is used to define neutropenia and the minimum 
allowed cell count thereof 
• Clarified the time limits for previous use of potentially effective antibiotic therapy  
• Added exclusion criteria for patients on peritoneal dialysis   
• Removes the post-ventilation time criterion as a definition of HAP 
• Provides guidance on other means of measuring temperature which would qualify a 
patient as having fever or hypothermia 
• Clarifies that de-escalation of Gram-negative antibiotics in BAT subjects should 
also be considered at EA visit 
• The number of sites was increased to reduce the overall time to complete the study 
• Clarified that resistance to a carbapenem, which might be different in different 
countries, is defined as any carbapenem 
• A section was added to introduce the use of diagnostic tests for carbapenem-
resistant, Gram-negative bacteria that could help physicians identify drug resistant 
pathogens earlier in the treatment process 
• Description of the results of the thorough QTc study were included 
• The requirement that the planned standard of care regimen needs to be recorded 
prior to randomization of the patient 
• Clarified the timing of the use of an adjunctive Gram-negative antibiotic and 


explicitly does not permit adding systemic antibiotics until the TOC 
• Described the possible use of investigation diagnostics to establish treatment plans 
and the requirement that an informed consent form be signed if that was the case  
• Described the means of obtaining data needed to complete various Scoring systems 
or vital signs if the typical means were prevented by the nature of the infection or 
treatment 
• Established a time frame for acceptable cultures from patients that had failed 
previous therapy 
• Changed the procedure for retaining study records at a site that is unable to store 
the records  
 
Version 4 
16 November 2017 
• Clarified and better defined the acceptability of bronchiectasis patients  
• Removed methotrexate, procainamide, and probenecid from the list of unacceptable 
concomitant medications 
• Additional new information from ongoing or completed studies was added to drug 
information background 
• Required that the history of the patient for systemic antibiotics go back in time to 
45 days instead of just 2 weeks. 
• Added an independent Data Safety Monitoring Board to the study in place of an 
ad hoc Medical Review Committee 
 
  


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CLINICAL STUDY PROTOCOL: 1424R2131 
Study Title:  
A Multicenter, Randomized, Open-label Clinical 
Study of S-649266 or Best Available Therapy for the 
Treatment of Severe Infections Caused by 
Carbapenem-resistant Gram-negative Pathogens 
Study Number: 
1424R2131 
EudraCT Number: 
2015-004703-23 
Study Phase: 
3 
IND Number: 
116,787 
Product Name:  
S-649266 (INN generic name: Cefiderocol) 
Sponsor* for North America, 
South America: 
Shionogi Inc. 
300 Campus Drive, Florham Park, NJ 07932 USA 
Sponsor* for Europe: 
Shionogi Ltd. 
33 Kingsway, Holborn, London 
WC2B 6UF, United Kingdom 
Sponsor* for Asia-Pacific: 
Shionogi & Co., Ltd. 
(Head Office) 3-1-8 Doshomachi, Chuo-ku, Osaka 
541-0045, Japan 
Sponsor Contact: 
 
Shionogi Inc. 
300 Campus Drive, Florham Park, NJ 07932 USA 
Tel: 
 
 
 
Shionogi Ltd. 
33 Kingsway, Holborn, London 
WC2B 6UF, United Kingdom 
Tel: 
 
 
  
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. 
Tel: 
 
Medical Monitor 
 – 
North America and South 
America: 
 Medical Monitor 
North America - Tel: 
 
South America - Tel: 
  
Medical Monitor 
 – 
Europe and Asia-Pacific: 
Medical Monitor 
Tel: 
 


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Issue Date: 
 
Version 1: 
11 November 2015 
Version 2: 
18 January 2016 
Version 3: 
09 November 2016 
Version 4 
16 November 2017 
 
* The study sponsor may be one 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. 
 
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, Open-label Clinical Study of S-649266 or Best Available 
Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant 
Gram-negative Pathogens 
Study Number: 1424R2131 
Study Phase: 3  
Primary Objectives: 
● To assess, at test of cure (TOC)1, the clinical outcome of treatment with S-649266 
or best available therapy (BAT) in adult patients with either hospital-acquired 
pneumonia (HAP)/ventilator-associated pneumonia (VAP)/healthcare-associated 
pneumonia (HCAP) or bloodstream infections/sepsis (BSI/sepsis)2 caused by 
carbapenem-resistant Gram-negative pathogens  
● To assess, at TOC, the microbiologic outcome of treatment with S-649266 or 
BAT in adult patients with complicated urinary tract infection (cUTI) caused by 
carbapenem-resistant Gram-negative pathogens  
Secondary Objectives: 
● To assess the safety of S-649266 
The other secondary objectives of this study are established as follows: 
● To assess the clinical outcome of treatment with S-649266 or BAT in patients 
with either HAP/VAP/HCAP or BSI/sepsis at End of Treatment (EOT)3 and 
Follow-up (FUP) 
● To assess the clinical outcome of treatment with S-649266 or BAT in patients 
with cUTI at EOT, TOC, and FUP 
● To assess the microbiologic outcome of treatment with S-649266 or BAT in 
patients with either HAP/VAP/HCAP or BSI/sepsis at EOT, TOC, and FUP4 
● To assess the microbiologic outcome of treatment with S-649266 or BAT in 
patients with cUTI at EOT and FUP 
● To assess the microbiologic outcome of treatment with S-649266 or BAT in 
patients with bacteremia (regardless of the primary infection diagnosis) at EOT, 
TOC, and FUP 
● To assess the composite clinical and microbiologic outcome of treatment with 
S-649266 or BAT in patients with cUTI at EOT, TOC, and FUP 
 
1  
TOC is defined as end of treatment (EOT) + 7 days (± 2 day). 
2  
BSI/sepsis is a group of patients with documented carbapenem-resistant Gram-negative infections in 
the blood stream (BSI) or in a body site other than the urinary tract (cUTI) or lung (HAP/VAP/HCAP) 
and in case of sepsis, evidence of systemic inflammatory response syndrome (SIRS). 
3  
EOT = end of treatment is defined as the last day of study therapy. 
4  
FUP = follow-up is defined as EOT + 14 days (± 3 days). 


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● To assess the all-cause mortality at Day 14 and Day 28 in patients with 
HAP/VAP/HCAP and BSI/sepsis 
● To assess the relationship between the pharmacodynamic parameter %fT>MIC 
based on plasma drug concentrations at steady state and the clinical and 
microbiologic outcomes of treatment with S-649266 in patients with 
HAP/VAP/HCAP, cUTI, or BSI/sepsis  
● To assess the resource utilization required for the treatment of the study- 
qualifying infection 
● To compare S-649266 with BAT in patients with HAP/VAP/HCAP, cUTI, or 
BSI/sepsis based on the composite endpoint of survival and no change in 
antibiotic treatment due to either lack of therapeutic benefit or drug-related 
toxicity at TOC   
Study Design: 
This is a Phase 3, multicenter (multinational), open-label, parallel group, randomized, 
active-controlled study in approximately 150 patients with documented 
carbapenem-resistant Gram-negative bacterial infections.  Patients meeting eligibility 
criteria and assessed by the investigator to require 7 to 14 days of intravenous treatment 
in hospital will be randomized (2:1) to either S-649266 2 g administered intravenously 
over 3 hours, every 8 hours (q8h) or BAT. 
Study Population: 
Patients with the following infections caused by a carbapenem-resistant Gram-negative 
pathogen will be enrolled: 
● HAP/VAP/HCAP or 
● cUTI or 
● BSI/sepsis  
General Inclusion Criteria: 
Patients who fulfill the following criteria at Screening will be included in the study: 
1. Hospitalized male and female patients, 18 years or older at the time of signing 
informed consent  
2. Patients who have provided written informed consent or their informed consent 
was provided by legal guardian.  (Note: Country specific rules and local Ethics 
Committee approval for legal guardian informed consent will determine whether 
or not and how a patient unable to comprehend or sign the informed consent is 
allowed to be enrolled in the study) 
3. Patients with clinically documented infection (HAP/VAP/HCAP, cUTI, or 
BSI/sepsis) caused by a Gram-negative pathogen with evidence of carbapenem 
resistance 
4. Patients who have been treated previously with an empiric antibiotic regimen and 
failed treatment, both clinically and microbiologically, are eligible for the study, if 
they have an identified carbapenem-resistant, Gram-negative pathogen which has 
either been shown to be nonsusceptible in vitro to each of the antibiotic(s) of the 


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empiric antibiotic regimen or been grown from a culture performed after at least 2 
days of the empiric antibiotic regimen   
5. Patient is male (no contraception required) or female and meets one of the 
following criteria:  
• Surgically sterile by hysterectomy and/or bilateral oophorectomy or bilateral 
salpingectomy or tubal ligation for the purpose of contraception for at least 6 
weeks with appropriate documentation of such surgery  
• Postmenopausal (defined as older than 45 years of age with cessation of 
regular menstrual periods for 6 months and confirmed by a follicle-stimulating 
hormone level of > 40 mIU/mL, or amenorrhea for at least 12 months) 
• 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 (IUD), or intrauterine 
hormone-releasing system (IUS) for the entire duration of the study 
• Of childbearing potential and practice abstinence as a preferred and usual 
lifestyle, and agrees to continue practicing abstinence from Screening and for 
the entire duration of the study 
• Of childbearing potential, whose sole heterosexual partner has been 
successfully vasectomized and agrees to not have other heterosexual partners 
for the entire duration of the study 
6. Patients meeting specific inclusion criteria for each infection site (See Diagnosis-
Specific Inclusion Criteria) 
General Exclusion Criteria: 
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Patients who have a history of any moderate or severe hypersensitivity or allergic 
reaction to any β-lactam (Note: for β-lactams, a history of a mild rash followed by 
uneventful re-exposure is not a contraindication to enrollment) 
2. Patients who need more than 3 systemic antibiotics as part of BAT for the 
treatment of the Gram-negative infection (patients with mixed Gram-positive or 
anaerobic infections may receive appropriate concomitant narrow-spectrum 
antibiotics [eg, vancomycin, linezolid, metronidazole, clindamycin]) 
3. Patients with coinfection caused by invasive aspergillosis, mucormycosis or other 
highly lethal mold 
4. Patients who have a central nervous system infection (eg, meningitis, brain 
abscess, shunt infection) 
5. Patients with infection requiring > 3 weeks of antibiotic treatment (eg, bone and 
joint infection, endocarditis) 
6. Patients with cystic fibrosis or moderate to severe bronchiectasis  


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7. Patients in refractory septic shock defined as persistent hypotension despite 
adequate fluid resuscitation or despite vasopressive therapy at the time of 
Randomization 
8. Patients with severe neutropenia, ie, polymorphonuclear neutrophils 
(PMNs) < 100 cells/µL  
9. Female patients who have a positive pregnancy test at Screening or who are 
lactating  
10. Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) 
score > 30 
11. Patients who have received a potentially effective antibiotic regimen for the 
carbapenem-resistant, Gram-negative infection for a continuous duration of more 
than 24 hours in cUTI, or 36 hours in HAP/VAP/HCAP or BSI/sepsis during the 
72 hours leading to Randomization   
12. Patients with any condition or circumstance that, in the opinion of the 
investigator, would compromise the safety of the patient or the quality of the 
study data   
13. Patients who have received another investigational drug or device within 30 days 
prior to study entry 
14. Patients who have previously been randomized in this study or received S-649266 
15. Patients receiving peritoneal dialysis 
16. Patients meeting specific exclusion criteria for each infection site (See Diagnosis-
Specific Exclusion Criteria) 
Diagnosis-Specific Inclusion and Exclusion Criteria 
HAP/VAP/HCAP Definitions:  
The diagnosis of HAP, VAP, or HCAP will be specified and recorded in the eCRF.   
HAP is defined as an acute bacterial pneumonia in a patient hospitalized for more than 48 
hours or developing within 7 days after discharge from a hospital.  Patients may 
experience acute respiratory failure and require mechanical ventilation for HAP 
(ventilated-HAP).  
VAP is defined as an acute bacterial pneumonia in a patient receiving mechanical 
ventilation via an endotracheal (or nasotracheal) tube for a minimum of 48 hours. 
HCAP is defined as below when at least one of the criteria is met: 
• an acute bacterial pneumonia in a patient who was hospitalized in an acute care 
hospital for 2 or more days within 90 days of the infection;  
• resided in a nursing home or long-term care facility;  
• received intravenous antibiotic therapy, chemotherapy, or wound care; or 
attended a hemodialysis clinic within the past 30 days of the current infection.  


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HAP/VAP/HCAP Specific Inclusion Criteria 
Patients who fulfill the following criteria at Screening will be included in the study: 
1. All patients must have at least one of the following clinical features: 
a. New onset or worsening of pulmonary symptoms or signs, such as cough, 
dyspnea, tachypnea (eg, respiratory rate greater than 25 breaths/minute), 
expectorated sputum production, or requirement for mechanical ventilation 
b. Hypoxemia (eg, a partial pressure of oxygen less than 60 mmHg while the 
patient is breathing room air, as determined by arterial blood gas [ABG] or 
worsening of the ratio of the partial pressure of oxygen to the fraction of 
inspired oxygen [PaO2/FiO2]) 
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 
2. All patients must have at least one of the following signs: 
a. Documented fever (eg, core body temperature [tympanic, rectal, esophageal] 
greater than or equal to 38°C [100.4°F], oral temperature greater than or equal 
to 37.5°C or axillary temperature greater than or equal to 37°C)  
b. Hypothermia (eg, core body temperature [tympanic, rectal, esophageal] less 
than or equal to 35°C [95°F], oral temperature less than or equal to 35.5°C or 
axillary temperature less than or equal to 36°C)  
c. Leukocytosis with a total peripheral white blood cell (WBC) count greater 
than or equal to 10,000 cells/mm3 
d. Leukopenia with total peripheral WBC count less than or equal to 
4,500 cells/mm3 
e. Greater than 15% immature neutrophils (bands) noted on peripheral blood 
smear  
3. All patients must have a chest radiograph or lung computed tomography (CT) 
scan within 48 hours prior to randomization showing the presence of new or 
progressive infiltrate(s) suggestive of bacterial pneumonia.   
HAP/VAP/HCAP Specific Exclusion Criteria 
The diagnosis of HAP, VAP or HCAP will be specified and recorded in the eCRF.  
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Patients who have known or suspected community-acquired bacterial pneumonia, 
atypical pneumonia, viral pneumonia or chemical pneumonia (including 
aspiration of gastric contents, inhalation injury) 
2. Patients receiving concomitant aerosolized antibiotics with Gram-negative 
activity 


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cUTI Definition   
cUTI is defined as a clinical syndrome characterized by pyuria and a documented 
microbial pathogen on urine culture, accompanied by local and systemic signs and 
symptoms including fever, chills, malaise, flank pain, back pain, and/or costovertebral 
angle pain or tenderness that occur in the presence of a functional or anatomical 
abnormality of the urinary tract or in the presence of catheterization and who require 
hospitalization for the parenteral (intravenous) treatment of cUTI will be enrolled in the 
study.  
cUTI Specific Inclusion Criteria 
Patients who have a clinical diagnosis of either cUTI with pyelonephritis or cUTI without 
pyelonephritis and fulfill the following criteria at Screening will be included in the study: 
1. All patients must have a cUTI with a history of at least one of the following: 
a. Indwelling urinary catheter or recent instrumentation of the urinary tract 
(within 14 days prior to Screening) 
b. Urinary retention caused by benign prostatic hypertrophy 
c. Urinary retention of at least 100 mL or more of residual urine after voiding 
(neurogenic bladder) 
d. Obstructive uropathy (nephrolithiasis, fibrosis, etc) 
e. Azotemia caused by intrinsic renal disease (BUN and creatinine values greater 
than normal clinical laboratory values) 
2. All patients must have at least 2 of the following signs or symptoms:  
a. Chills, rigors, or warmth associated with fever (body temperature greater than 
or equal to 38°C [100.4°F]) 
b. Flank pain (pyelonephritis) or suprapubic/pelvic pain (cUTI) 
c. Nausea or vomiting 
d. Dysuria, urinary frequency, or urinary urgency 
e. Costovertebral angle tenderness on physical examination 
3. All patients must have evidence of pyuria on urinalysis demonstrated by either: 
a. Dipstick analysis positive for leukocyte esterase  
OR 
b. ≥ 10 WBCs /μL in unspun urine, or ≥ 10 WBCs /high power field in spun 
urine 
4. Patients who had a positive urine culture within 48 hours prior to Randomization 
containing ≥ 105 colony forming unit (CFU)/mL of a carbapenem-resistant Gram-
negative uropathogen are eligible for this study (Note: patients may be 
randomized prior to the results of the urine culture if they have evidence of a 
carbapenem-resistant pathogen) 
5. Patients receiving antibiotic prophylaxis for cUTI who present with signs and 
symptoms consistent with an active new cUTI may be enrolled provided all other 
eligibility criteria are met including obtaining a pretreatment qualifying urine 
culture 


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cUTI-specific Exclusion Criteria 
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Patient’s urine culture at study entry isolates more than 2 uropathogens, regardless 
of colony count, or patient has a confirmed fungal cUTI 
2. Patients with asymptomatic bacteriuria, the presence of > 105 CFU/mL of a 
uropathogen and pyuria but without local or systemic symptoms  
3. Patients with an ileal loop for urine outflow (for patients with BSI/sepsis and an 
ileal loop are eligible) 
4. Patients with acute uncomplicated pyelonephritis, ie, absence of anatomic urinary 
tract abnormality 
5. Patients with vesico-ureteric reflux 
BSI/Sepsis Definitions 
The BSI/sepsis category includes bacteremia or sepsis caused by infections other than 
HAP/VAP/HCAP or cUTI.  The diagnosis of BSI or sepsis and the causal infection will 
be specified and recorded in the eCRF.  Patients will be enrolled in the BSI/sepsis group 
with either: 
a. Documented BSI caused by a carbapenem-resistant Gram-negative pathogen   
OR 
b. Systemic response to infection, meeting the clinical criteria of SIRS and an 
identified infection source (eg, severe skin infection, intra-abdominal infection) 
caused by a carbapenem-resistant Gram-negative pathogen   
Note: The inclusion/exclusion criteria for BSI and sepsis are not the same.  It is 
possible to meet the criteria for one without the other.   
Bloodstream Infection-specific Inclusion Criteria 
Patients who fulfill the following criteria at Screening will be included in the study: 
1. Patients who have one or more positive blood cultures identifying a carbapenem-
resistant Gram-negative pathogen that is consistent with the patient’s clinical 
condition  
2. Patients who have signs or symptoms associated with bacteremia 
Bloodstream Infection Specific Exclusion Criteria 
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Patients who have a positive blood culture only obtained from an intravenous 
catheter.  If both peripheral venipuncture blood culture and intravenous catheter 
blood culture show the same organism, the patient is eligible 
2. Patients with BSI considered to be due to an endovascular source, eg, endocarditis, 
infected vascular graft, a permanent intravascular device that cannot be removed 
during the course of treatment 
Sepsis Specific Inclusion Criteria:  
Patients who fulfill the following criteria at Screening will be included in the study: 


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1. Patients defined for SIRS, indicated by having 2 or more of the following 
responses: 
a. Oral or tympanic body temperature greater than 38°C (100.4°F) or less than 
36°C (96.8°F) 
b. Tachycardia, heart rate greater than 90 beats/minute 
c. Tachypnea, manifested by a respiratory rate greater than 20 breaths/minute or 
hyperventilation, as indicated by an arterial partial pressure of carbon dioxide 
(PaCO2) of less than 32 mmHg 
d. WBC greater than 12,000 cells/mm³, less than 4000 cells/mm³, or > 10% 
immature (band) forms 
2. Patients with an identified infection site from which a carbapenem-resistant 
Gram-negative pathogen has been isolated using an appropriate clinical specimen 
Sepsis-Specific Exclusion Criteria: 
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Patient does not have an identified source of a bacterial infection and an identified 
carbapenem-resistant Gram-negative pathogen 
2. Patient has an alternative explanation for the physiologic parameters of SIRS, eg, 
cardiogenic shock, cardiac arrhythmia, or hyperthyroid storm 
3. Patients with infections where isolation of a Gram-negative pathogen is unlikely 
to be causing the infection such as that in the upper respiratory system, head and 
neck, pelvic or genital organ, etc. 
Test Drug, Dose, and Mode of Administration:  
S-649266 2 g administered intravenously q8h as a 3-hour infusion with/without 
adjunctive Gram-negative antibiotic therapy in patients with normal renal function.  Dose 
adjustment is shown in the following table.  The solution volume for infusion must be at 
least 100 mL.  Under no circumstances is S-649266 to be administered in a saline 
solution of less than 100 mL.   
S-649266 Dosing Adjustments for Various Degrees of Renal Function and 
Augmented Renal Clearance 
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)a 
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/1.73m2) 
1.5 g, q8h, 3-hour infusion 


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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  
Patient 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; ESRD = end-stage 
renal disease; HD = hemodialysis; MDRD-eGFR = modification of diet in renal disease-estimated 
glomerular filtration rate calculated with the MDRD equation; q6h = every 6 hours; q8h = every 8 hours; 
q12h = every 12 hours. 
a 
A CrCl will be calculated by Cockcroft-Gault equation at Screening. A urine measured CrCl will be 
calculated by using timed urine collections of 2-8 hours at early assessment (EA).  
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 an excessive exposure and complexity of clinical operation.  
c 
The dose will be determined based on MDRD-eGFR on nondialysis days. 
Adjunctive Antibiotic Therapy: 
Patients with cUTI should receive S-649266 monotherapy, ie, without combining with 
any additional Gram-negative antibiotics. 
Patients with HAP/VAP/HCAP or BSI/sepsis randomized to treatment with S-649266 
may receive a second (but not a third) Gram-negative antibiotic other than a polymyxin 
(colistin or polymyxin B) or a cephalosporin/carbapenem including combination with 
beta-lactamase inhibitor (eg, ceftazidime/avibactam, or ceftolozane/tazobactam) at the 
initiation of study drug.  This decision should be based on the investigators consideration 
of the patient’s condition, the causative pathogen, and current best practices.   
If a second Gram-negative antibiotic is administered with S-649266 at the time of 
Randomization, the investigator must reassess the need for the second Gram-negative 
antibiotic upon availability of susceptibility testing to S-649266 no later than Early 
Assessment (EA) visit.  The adjunctive antibiotic therapy should be discontinued (de-
escalated) accordingly.   
Control Treatment Regimen:  
The control population will be treated with BAT, locally sourced by study sites, within 
the local standard of care determined by the investigator for each infection diagnosis.  
This will usually involve 1 or 2 or possibly 3 antibiotic agents specifically for the 
carbapenem-resistant Gram-negative pathogen.   
If the investigator chooses to use a polymyxin (either polymyxin B or colistin 
[polymyxin E]), the investigator is encouraged to follow European Medicines Agency's 
(EMA’s) dosing recommendations. 
De-escalation in the BAT arm should also be considered in line with best local standard 
of care. 
Duration of Treatment: 


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The treatment duration for S-649266 or BAT is anticipated to be 7 to 14 days which are 
consistent with published treatment guidelines for serious infections.  Based on the 
investigator’s clinical assessment of the patient, treatment may be extended up to 21 days. 
The reason for the extension should be clearly documented.  All study treatments will be 
performed in the hospital. 
Prohibited Concomitant Therapy: 
For patients randomized to S-649266 
● Systemic antibiotics with Gram-negative activity, other than a single Gram-
negative adjunctive antibiotic therapy for HAP/VAP/HCAP or BSI/sepsis patients, 
are not permitted until TOC 
● Aerosolized antibiotics are not permitted until TOC 
● Refer to the label of any adjunctive antibiotic therapy being used in combination 
with S-649266 for information about contraindicated therapies to those adjunctive 
antibiotic therapies 
For patients randomized to BAT 
● More than 3 systemic antibiotics with Gram-negative activity are not permitted 
until TOC 
● Aerosolized antibiotics are not permitted until TOC 
● Refer to label of BAT drugs for contraindicated therapies 
Efficacy Assessment: 
Both clinical and microbiological outcomes will be assessed by the investigator at EA, 
EOT, TOC, and FUP.  In case treatment duration is extended beyond 14 days, an 
additional clinical outcome will be assessed on Day 14.   
Safety Assessments: 
Patient safety will be assessed daily from the time of informed consent, while the patient 
is hospitalized, and through to EOS by the identification of adverse events (AEs).  
Adverse events defined as new or worsening symptoms since the time of Randomization 
will be used to determine the safety of the study treatment.  In case treatment duration is 
extended beyond 14 days, additional safety assessments will be conducted on Day 14.  
Safety surveillance will extend to up to 28 days after the last dose of the study drug.  
Clinical laboratory tests of blood chemistry, hematology, and urinalysis will be 
performed at Screening, EA, EOT, TOC, and FUP.  In addition, an electrocardiograph 
(ECG) will be performed at Screening/baseline.  Vital signs including body temperature 
and AEs will be recorded daily.   
Pharmacokinetic Assessments:  
All patients treated with S-649266 will have blood drawn for sparse pharmacokinetic 
(PK) sampling of plasma concentrations of study drug.  The actual sampling date and 
time will be recorded.  PK blood sampling will occur on Day 3 (after at least 6 doses of 
drug) at 4 timepoints: (1) just prior to the start of infusion, (2) 1 hour after start of 
infusion, (3) at the end of infusion, and (4) 1 hour after the end of the infusion.   
Patients with non-stable renal function resulting in a dosage adjustment (dose or interval) 
at EA will undergo another blood PK sampling (4 samples at the above specified 


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timepoints) within 24 to 72 hours after their dosing adjustment.  The timing for PK blood 
draws is same as above timing on Day 3.  If possible, a single blood sampling should be 
performed as soon as possible at EOT in case of premature EOT. 
Statistical Methods: 
For the primary endpoint, that is clinical response at TOC with patients of 
HAP/VAP/HCAP or BSI/sepsis and microbiological response at TOC with patients of 
cUTI, each response rate will be provided with the 95% confidence interval (CI) by 
treatment group.  For the secondary efficacy endpoints of clinical response and 
microbiological response, each response rate will be also provided with 95% CI by 
treatment group.  For the other secondary endpoints, similar statistics will be provided. 
Descriptive statistics for all efficacy parameters will be provided. 
Sample Size: 
Approximately 150 patients 
Given the challenges involved in recruiting patients meeting the criteria for inclusion in 
this study, and, after discussions with the EMA, it was agreed that approximately 
150 patients would be enrolled and randomized 2:1 to S-649266 and BAT, respectively.   
Stratification at Randomization:  
Randomization will be performed by the stochastic minimization method using their 
infection site (HAP/VAP/HCAP, cUTI, and BSI/sepsis), APACHE II score (≤ 15 and 
≥ 16), and region (N. America, S. America, Europe, and Asia-Pacific) as allocation 
factors. 
Number of Study Sites/Countries: 
It is estimated that approximately 100 study sites from US, Asia-Pacific including Japan, 
EU, Israel, Turkey, and Latin America will participate in this clinical study.   
Study Duration:  
Study duration for individual patients: approximately 5 to 7 weeks 
Planned duration of the study is approximately 37 months (35 months for enrollment and 
5 to 7 weeks to complete the study).  
Date of Original (Version 1): 11 November 2015 
Date of Latest Version 4: 16 November 2017 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ...................................................................................................14 
LIST OF IN-TEXT TABLES ............................................................................................18 
LIST OF IN-TEXT FIGURES...........................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................20 
GLOSSARY ......................................................................................................................23 
1. 
INTRODUCTION .....................................................................................................24 
1.1 
Background and Rationale ...............................................................................24 
1.2 
Biological Features of S-649266 for Injection.................................................25 
1.2.1 
Use of Rapid Diagnostic Tests ...............................................................27 
1.3 
Nonclinical Experience ....................................................................................27 
1.3.1 
Pharmacokinetics/Pharmacodynamics ...................................................29 
1.4 
Clinical Experience ..........................................................................................33 
1.4.1 
Phase 1 ...................................................................................................33 
1.5 
Phase 2 and Phase 3 .........................................................................................34 
1.5.1 
Phase 2 Complicated Urinary Tract Infections ......................................34 
2. 
STUDY OBJECTIVES ..............................................................................................36 
2.1 
Primary Objectives...........................................................................................36 
2.2 
Secondary Objectives.......................................................................................36 
3. 
INVESTIGATIONAL PLAN ....................................................................................38 
3.1 
Overall Study Design and Plan ........................................................................38 
3.2 
Rationale for Study Design and Control Group ...............................................39 
3.2.1 
Rationale for Patient Population ............................................................39 
3.2.2 
S-649266 Dose Regimen .......................................................................40 
3.2.3 
BAT Regimens.......................................................................................42 
3.2.4 
Duration of Study Treatment .................................................................42 
3.3 
Study Duration .................................................................................................43 
3.3.1 
Study Duration in Individual Patients ....................................................43 
4. 
STUDY POPULATION SELECTION .....................................................................43 
4.1 
Study Population ..............................................................................................43 
4.2 
General Inclusion Criteria ................................................................................45 
4.3 
General Exclusion Criteria ...............................................................................45 
4.4 
Diagnosis Specific Inclusion and Exclusion Criteria .......................................46 
4.4.1 
HAP/VAP/HCAP Patients .....................................................................46 
4.4.2 
cUTI Patients .........................................................................................48 
4.4.3 
Bloodstream Infections/Sepsis Patients .................................................49 
5. 
STUDY TREATMENT(S) ........................................................................................52 


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5.1 
Description of Treatment(s) .............................................................................52 
5.1.1 
Test Drug ...............................................................................................52 
5.1.2 
Control Treatment Regimen ..................................................................52 
5.2 
Treatments To Be Administered ......................................................................52 
5.2.1 
S-649266 Group .....................................................................................53 
5.2.2 
BAT Group ............................................................................................54 
5.3 
Selection and Timing of Dose for Each Patient ...............................................54 
5.4 
Randomization to Treatment Groups ...............................................................56 
5.5 
Blinding............................................................................................................56 
5.6 
Packaging and Labeling, Storage and Accountability .....................................57 
5.6.1 
S-649266 ................................................................................................57 
5.6.2 
BAT........................................................................................................57 
5.7 
Investigational Product Retention at Study Site ..............................................58 
5.8 
Treatment Compliance .....................................................................................58 
5.8.1 
Changes in Treatment Regimen .............................................................58 
6. 
RESTRICTIONS .......................................................................................................59 
6.1 
Prior Therapy ...................................................................................................59 
6.2 
Concomitant Therapy during the Study ...........................................................59 
6.2.1 
Antibiotic Therapies...............................................................................59 
6.2.2 
Nonantibiotic Therapies and Procedures ...............................................60 
6.2.3 
Prohibited Therapy.................................................................................60 
6.2.4 
Rescue Therapy ......................................................................................60 
7. 
STUDY PROCEDURES AND METHODS OF ASSESSMENTS ..........................62 
7.1 
Informed Consent.............................................................................................62 
7.2 
Baseline Patient Characteristics and Medical History .....................................62 
7.3 
Hospitalization .................................................................................................63 
7.4 
Physical Examination.......................................................................................63 
7.4.1 
Glasgow Coma Scale .............................................................................63 
7.4.2 
APACHE II ............................................................................................64 
7.5 
Vital Signs ........................................................................................................64 
7.6 
Electrocardiography .........................................................................................64 
7.7 
Clinical Laboratory Tests .................................................................................65 
7.7.1 
Microbiologic Cultures ..........................................................................65 
7.7.2 
Clinical Laboratory Parameters .............................................................68 
7.8 
Efficacy, and Safety Evaluations .....................................................................70 
7.8.1 
General Evaluations ...............................................................................70 
7.8.2 
HAP/VAP/HCAP Specific Evaluations .................................................71 
7.8.3 
Complicated Urinary Tract Infection Specific Evaluation ....................71 


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7.8.4 
Blood Stream Infection/Sepsis Specific Evaluations .............................72 
7.9 
Pharmacokinetic Sample Collection, Storage, and Shipping...........................72 
7.9.1 
Pharmacokinetic Blood Sampling..........................................................72 
7.9.2 
Other Tissue or Body Fluid Sampling for Pharmacokinetics ................72 
7.10 
Enrollment in the Study and Dispensing Study Drug ......................................72 
7.11 
Efficacy Assessments.......................................................................................73 
7.11.1 
Efficacy Criteria for Infection Site Specific Clinical Outcomes for 
EA, EOT, and TOC ................................................................................73 
7.11.2 
Clinical Outcomes for FUP ....................................................................74 
7.11.3 
Microbiological Outcomes for EA, EOT, and TOC ..............................75 
7.11.4 
Microbiological Outcomes for FUP.......................................................76 
7.11.5 
New Pathogens.......................................................................................77 
7.12 
Adverse Events Assessments ...........................................................................77 
7.12.1 
Performing Adverse Events Assessments ..............................................77 
7.12.2 
Timing ....................................................................................................78 
7.12.3 
Severity ..................................................................................................78 
7.12.4 
Relationship ...........................................................................................78 
7.12.5 
Expectedness ..........................................................................................78 
7.12.6 
Clinical Laboratory Adverse Events ......................................................79 
7.12.7 
Serious Adverse Events .........................................................................79 
7.12.8 
Special Situations-Abuse, Misuse, Overdose, and Medication Error ....81 
7.12.9 
Pregnancy ...............................................................................................82 
7.12.10 Treatment-Emergent Adverse Events ....................................................82 
7.13 
Withdrawal or Discontinuation of Patients from the Study or Study 
Treatment .........................................................................................................82 
7.14 
Appropriateness of Measurements ...................................................................83 
7.15 
Acceptable Time Windows ..............................................................................83 
8. 
STUDY ACTIVITIES ...............................................................................................85 
8.1 
Screening (Day –2 to Randomization) .............................................................85 
8.2 
Treatment Period (Day 1 to up through Day 14) .............................................86 
8.2.1 
Randomization and Treatment Initiation Day 1 .....................................86 
8.2.2 
All Treatment Days ................................................................................86 
8.2.3 
Treatment Day 3 ....................................................................................86 
8.2.4 
Early Assessment (EA) (Occurs once at investigator’s discretion 
during Days 3 to 4) ................................................................................86 
8.2.5 
Treatment Day 14 ..................................................................................87 
8.2.6 
Last Day of Study Treatment (EOT) .....................................................87 
8.3 
Test of Cure (TOC [EOT + 7 days]) ................................................................88 


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8.4 
Follow-up (FUP [EOT + 14 days]) ..................................................................88 
8.5 
End of Study (EOS [EOT + 28 days]) .............................................................89 
9. 
PLANNED STATISTICAL METHODS ..................................................................90 
9.1 
General Considerations ....................................................................................90 
9.2 
Determination of Sample Size .........................................................................90 
9.3 
Analysis Populations ........................................................................................90 
9.4 
Handling of Missing Data ................................................................................91 
9.5 
Patient Disposition ...........................................................................................91 
9.6 
Demographics and Baseline Characteristics ....................................................91 
9.7 
Prior Therapies .................................................................................................91 
9.9 
Efficacy Analyses ............................................................................................92 
9.9.1 
Primary Efficacy Endpoint ....................................................................92 
9.9.2 
Secondary Efficacy Endpoints ...............................................................92 
9.9.3 
Primary Efficacy Analyses ....................................................................93 
9.9.4 
Secondary Efficacy Analyses ................................................................93 
9.10 
Safety Analyses ................................................................................................93 
9.10.1 
Adverse Events ......................................................................................94 
9.10.2 
Vital Signs ..............................................................................................94 
9.10.3 
Clinical Laboratory Analysis .................................................................94 
9.11 
Pharmacokinetic Analysis ................................................................................94 
9.12 
Pharmacokinetic/Pharmacodynamic Analysis .................................................94 
9.13 
Pharmacoeconomics Associated with Treatment ............................................95 
9.14 
Interim Analysis ...............................................................................................95 
10. ADMINISTRATIVE CONSIDERATIONS ..............................................................96 
10.1 
Investigators and Study Administrative Structure ...........................................96 
10.2 
Institutional Review Board or Institutional Ethics Committee Approval ........98 
10.3 
Ethical Conduct of the Study ...........................................................................98 
10.4 
Patient Information and Consent .....................................................................98 
10.5 
Patient Confidentiality .....................................................................................98 
10.6 
Study Monitoring .............................................................................................99 
10.7 
Case Report Forms and Source Documents.....................................................99 
10.7.1 
Case Report Forms .................................................................................99 
10.7.2 
Source Documents ...............................................................................100 
10.7.3 
External Data .......................................................................................100 
10.8 
Committees ....................................................................................................100 
10.8.1 
Independent Data Safety Monitoring Board ........................................100 
10.9 
Termination or Suspension of the Study ........................................................101 
10.9.1 
Termination or Suspension of the Entire Study ...................................101 


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10.9.2 
Termination or Suspension of the Study by Medical Institution .........101 
10.10 Protocol Deviations and Modifications .........................................................101 
10.11 Data Management ..........................................................................................102 
10.12 Retention of Data ...........................................................................................102 
10.13 Quality Control and Assurance ......................................................................102 
10.14 Publication and Disclosure Policy .................................................................103 
10.15 Financial Disclosure.......................................................................................103 
11. REFERENCE LIST .................................................................................................104 
Appendix 1 
Time and Events Schedule ...................................................................107 
Appendix 2 
SIRS Criteria ........................................................................................110 
Appendix 3 
European Medicines Agency Completes Review of Polymyxin-
based Medicines .......................................................................................................111 
Appendix 4 
Microbiology Tests ..............................................................................113 
Appendix 5 
Glasgow Coma Scale ...........................................................................116 
Appendix 6 
APACHE II Score ................................................................................117 
Appendix 7 
SOFA Score .........................................................................................119 
Appendix 8 
Clinical Pulmonary Infection Score (CPIS) Parameters ......................120 
Appendix 9 
Management Criteria for Abnormal Liver Function Tests ..................121 
Appendix 10 
Sponsor Signature ................................................................................123 
Appendix 11 
Investigator’s Signature .......................................................................124 
LIST OF IN-TEXT TABLES 
Table 1-1 
%fT>MIC Required for Static Effect and 1-log10 Reduction in 
Murine Thigh Infection Model ....................................................31 
Table 1-2 
%fT>MIC Required for Static Effect and 1-log10 Reduction in 
Murine Lung Infection Model .....................................................32 
Table 3-1 
Probability of Target Attainment for Patients with Augmented 
Renal Clearance ...........................................................................42 
Table 5-1 
Study Treatment Administration ..................................................53 
Table 5-2 
S-649266 Dosing Adjustments for Various Degrees of Renal 
Function and Augmented Renal Clearance ..................................55 
Table 7-1 
Clinical Laboratory Tests .............................................................68 
Table 7-2 
Acceptable Time Windows ..........................................................84 
LIST OF IN-TEXT FIGURES 
Figure 1-1 
Depiction of Cefiderocol Cell Entry and Mechanism of 
Action ...........................................................................................26 


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Figure 1-2 
Efficacy of S-649266 (Human 3 hr 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 ............................................................30 
Figure 3-1 
Study Schematic ...........................................................................39 
Figure 3-2 
Probability of Target Attainment for 50% or 75% fT > MIC ..........41 
Figure 4-1 
Study Schematic Showing Possible Pathways for Study Entry ...44 
Figure 7-1 
Schematic of Clinical Specimen Handling ..................................67 
 


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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 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
ARC 
augmented renal clearance 
ABG 
arterial blood gas 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BAL 
bronchoalveolar lavage 
BAT 
best available therapy (see glossary for definition) 
BSI 
bloodstream infection (bacteremia) 
BUN 
blood urea nitrogen 
CFU 
colony forming unit 
CI 
confidence interval  
CR 
carbapenem-resistant 
CR-ME 
carbapenem-resistant microbiologically evaluable population  
CR Micro-ITT 
carbapenem-resistant microbiological intent to treat population  
CrCl 
creatinine clearance 
CRO 
contract research organization 
cUTI 
complicated urinary tract infection 
DMPK 
drug metabolism and pharmacokinetics 
DSMB 
data safety monitoring board 
EA 
Early Assessment 
ECG 
electrocardiograph 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate  
ELF 
epithelial lining fluid 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
EOS 
End of Study 
ESBL 
extended-spectrum beta-lactamase  
FDA 
Food and Drug Administration 
FUP 
Follow-up 


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GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
HAP 
hospital-acquired pneumonia 
HCAP 
healthcare-associated pneumonia 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Council for Harmonisation  
ICU 
intensive care unit 
IEC 
Institutional Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat population 
IWRS/IVRS 
interactive web or voice response system  
LDH 
lactate dehydrogenase  
MDR 
multidrug resistant 
MDRAB 
multidrug resistant Acinetobacter baumannii 
MDRD 
modification of diet in renal disease 
MDRP 
multidrug resistant Pseudomonas aeruginosa 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
Micro-ITT 
Microbiological Intent-to-treat population  
NOAEL 
no observed adverse-effect level  
OAT1 (3) 
organic anion transporter with associated identifier, eg, 1 (3) 
OCT2 
organic cation transporter with associated identifier, eg, 2  
PBP 
penicillin-binding protein 
PCR 
polymerase chain reaction 
PD  
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PTA 
probability of target attainment 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SIRS 
systemic inflammatory response syndrome 
SOC 
system organ class  
SOFA 
Sequential Organ Failure Assessment  
SmPC 
Summary of Product Characteristics   
TBL 
total bilirubin  
TEAE 
treatment-emergent adverse event 
TOC 
test of cure 


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ULN 
upper limit of normal 
VAP 
ventilator-associated pneumonia 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 
XDR 
extensively drug-resistant  
 


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GLOSSARY 
Adjunctive 
Antibiotic 
Therapy 
An antibiotic combined with S-649266 specifically to treat the 
target carbapenem-resistant Gram-negative bacterial infections 
except in cUTI, where S-649266 is to be used as monotherapy 
ARC 
Augmented renal clearance (ARC) 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 (eGFR)(≥ 90 mL/min/1.73 m2) and a creatinine 
clearance (CrCl ≥ 120 mL/min). 
BAT 
Best available therapy (BAT) is the standard of care treatment as 
determined by the investigator based on his/her assessment of the 
patient’s clinical condition, the site of infection and the causative 
organism (including available susceptibility data).  BAT consists 
of 1 to 3 antibiotics prescribed for the carbapenem-resistant 
Gram-negative pathogen. BAT is considered a treatment regimen, 
but is not considered study drug. 
Carbapenem 
Resistance  
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 the purpose of this study, resistance is defined as ‘non-
susceptible,” ie, resistance would include intermediate 
breakpoints to any carbapenem.   
Concomitant 
Antibiotic 
A concomitant antibiotic is an antibiotic added to the primary 
Gram-negative antibiotic treatment regimen to treat Gram-
positive and/or anaerobic bacterial infections.  Antibiotics used 
for prophylaxis, ie, to prevent, not to treat an infection, would also 
be considered a concomitant antibiotic. 
Effective 
Antibiotic 
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 
Study Drug 
Study drug refers only to S-649266 
Study Treatment 
Refers to either S-649266 with/without adjunctive antibiotic 
therapy or BAT antibiotics used to treat the protocol specific 
Gram-negative infection.  It does not include concomitant 
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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 bacilli, including Enterobacteriaceae and the non-
fermenters Pseudomonas aeruginosa 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 a metallo-β-lactamase, IMP-1, in P. aeruginosa, a serine 
carbapenemase, OXA-23, in A. baumannii, and a serine carbapenemase, KPC-1, in 
Klebsiella pneumonia, carbapenemase-encoding genes have spread worldwide, and are 
now distributed throughout different species of Gram-negative MDR bacteria, which are 
now responsible for a large and increasing numbers of nosocomial infections.  These 
carbapenemases inhibit almost all β-lactam antibiotics, including carbapenems, and are 
now 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) which are particularly 
prevalent among extensively drug-resistant P. aeruginosa [2, 3].  Not infrequently, 
several 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 [4].  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, to likely be caused mainly by nosocomial carbapenemase 
producing K. pneumoniae of all types.  
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 [5].  A pooled analysis of 9 studies showed that the death rate was higher 
among those patients infected with carbapenem-resistant Enterobacteriaceae than those 
infected with carbapenem-susceptible Enterobacteriaceae (Relative Risk [RR] 2.05, 95% 
confidence interval [CI] 1.56 -2.69) [5]. 
S-649266 now has an approved international nonproprietary name (INN) generic name: 
Cefiderocol.  For purposes of this protocol, S-649266 will be the name of the study drug.  


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S-649266 is being developed to address the unmet medical need to treat CR infections 
caused by Gram-negative bacteria, including Enterobacteriaceae, Pseudomonas, and 
Acinetobacter species independent of the underlying mechanism of CR.  Although 
S-649266 has bacterial killing ability for CR species of Gram-negative bacteria, it also 
has improved bacterial killing ability for common community acquired Gram-negative 
bacterial infections as demonstrated by reduced minimum inhibitory concentration (MIC) 
values (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 
to cefepime is the addition of a catechol group on the side chain at position 3.  
Furthermore, S-649266 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: 
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 β-lactamase enzymes including carbapenemases of the 
serine or metallo-β-lactamase classes. 
3. Enhanced activity against aerobic Gram-negative bacteria especially, 
Enterobacteriaceae particularly K. pneumoniae and E. coli, and the non-
fermenters P. aeruginosa 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 which scavenge 
for available free iron [7].  S-649266 is a siderophore compound which binds free iron 
and this antibiotic-iron complex is transported through the outer membrane of Gram-
negative bacteria into the periplasmic space using the bacteria’s active siderophore 
transport system [2, 6-11].  Figure 1-1below provides a pictorial description of the 
process.  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 


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carbapenem antibiotics by bacterial β-lactamases.  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  
 
 
The greatest unmet medical need in the treatment of bacterial infections is focused on 
multidrug resistant (MDR) aerobic Gram-negative bacilli, including broadly the 
Enterobacteriaceae and the non-fermenters P. aeruginosa and A. baumannii.  MDR 
bacteria, defined as > 3 class antibiotic resistance, include most Enterobacteriaceae 
producing AmpC or extended-spectrum beta-lactamase (ESBL) serine β-lactamases 
(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 Klebsiella pneumoniae carbapenemases (KPCs), oxacillinases 
(OXAs), and metallo-beta-lactamases , eg, verona integron-encoded metallo-beta-
lactamase (VIM), imipenemase (IMP), and New Delhi metallo-beta-lactamase-1 (NDM) 
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 and A. baumannii have also acquired 
carbapenemases and are also considered XDR bacteria.  Rarely, these XDR pathogens 


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may also be resistant to polymyxins, and, therefore, can be considered pandrug-resistant 
(PDR) or PDR organisms, defined as resistance to all classes [15]. 
The principal objective for S-649266 clinical development is to demonstrate efficacy for 
the treatment of carbapenem-resistant Enterobacteriaceae, carbapenem-resistant 
P. aeruginosa and carbapenem-resistant A. baumannii with appropriate benefit-risk for 
serious illness as outlined in the Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) guidances for bacterial infections, and currently considered as 
a highly important unmet medical need [16-18].  Consequently, the objective of the 
clinical development is to provide sufficient evidence of efficacy in the treatment of 
serious, potentially life-threatening Gram-negative infections from a variety of infection 
sites and an appropriate safety profile for these indications where there is a clear unmet 
medical need.   
1.2.1 
Use of Rapid Diagnostic Tests 
Although patients who fail empiric therapy microbiologically and clinically can be 
enrolled, it is in the patients’ best interest that diagnosis of resistance is made early and 
the most appropriate targeted antibacterial therapy initiated as soon as possible [19].  The 
use of rapid diagnostic procedures has the potential of identifying resistant organisms 
earlier than typical microbiological laboratory procedures, which would help in the 
selection of antibiotic regimens [20].  Successful incorporation of new diagnostic 
technologies has the potential benefit of improving not only patient treatment but also 
infection control and antimicrobial stewardship.  Rapid diagnostics based on gene content 
may provide results within hours of obtaining an appropriate clinical specimen.  Methods 
requiring culturing for either enhancing a sample for additional testing or using selective 
culture media for both identification of the species and the possibility of resistance 
potentially could give useable results after the initial culture.  Since the current rapid 
diagnostics are relatively early in development for Gram-negative bacteria, the usual and 
typical microbiological laboratory procedures will be required for confirmation of the 
rapid results and also to identify drug sensitivities.   
1.3 
Nonclinical Experience 
In vitro, S-649266 showed potent antibacterial activity against carbapenem-resistant 
Enterobacteriaceae including metallo-β-lactamase producing isolates, MDR A. baumannii 
(MDRAB), and MDR P. aeruginosa (MDRP).  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 MDRP, carbapenem-resistant 
A. baumannii, or enteric bacteria such as extended-spectrum β-lactamase-producing 
E. coli and K. pneumoniae.  
The safety and drug metabolism and pharmacokinetics (DMPK) profiles of S-649266 
have been evaluated in toxicity (general toxicity, genotoxicity, and antigenicity) studies, 
safety pharmacology studies and DMPK studies.  No severe toxic changes were observed 
in the rat 2-week and 1 month intravenous toxicity studies, the monkey 2-week, 1 month, 


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and 3-month intravenous toxicity study, the safety pharmacology studies, and the 
antigenicity study.   
In the rat 3-month intravenous toxicity study (dose levels: 0, 300, 1000, and 
1500 mg/kg/day), convulsions and subsequent deaths were noted at 1000 and 
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 in female and male rats, respectively) was approximately 17-fold 
of the maximum plasma concentration (Cmax) value in humans (89.7 μg/mL from the 
thorough QT [TQT] study [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 QTc interval 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 NOAEL and provides a minimum of a 9- to 10-fold margin relative to the expected 
Cmax of S-649266 in the current study (eg, C0 of 770 and 876 μg/mL 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 [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 


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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. 
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 [21] and EMA guideline 
[22] of drug interaction, and therefore, a clinical DDI study was performed 
(Study 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 area under the concentration time curve (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 clinical 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 (PBPs), the controlling 
pharmacodynamic (PD) parameter for S-649266 is the percentage of the dosing interval 
required for free-drug plasma concentration to be above the minimum inhibitory 
concentration (%fT>MIC), and while the plasma pharmacokinetic (PK) measurement can 
determine the drug exposure over time, corrected for protein binding, the MIC remains 
the key variable in determining %fT>MIC. 


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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 utilized 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 hr 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 
 
 
IV = intravenous; NTC = non-treatment 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 (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 (Table 1-1, and for additional information, refer to the current Investigator's 
Brochure).  
0
1
2
3
4
5
6
7
8
9
10
Log10 cfu/lungs
Limit of detection
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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Table 1-1 
%fT>MIC Required for Static Effect and 1-log10 Reduction 
in Murine Thigh Infection Model 
Species 
Strain 
Number 
Characteristic 
S-649266 MIC 
(µg/mL) 
%fT>MIC 
Static Effect 
1-log10 Reduction 
Pseudomonas 
aeruginosa 
ATCC27853 
Cephalosporin 
susceptible 
0.5 
74.8 
84.9 
SR27001 
MDRP, 
IMP-1 producer 
8 
41.7 
54.2 
Klebsiella 
pneumoniae 
ATCC43816 
Cephalosporin 
susceptible strain 
≤0.016 
≥38.3 
≥58.7 
ATCC13883 
0.125 
60.2 
74.1 
1478266 
0.5 
17.7 
27.6 
1478677 
CTX-M-3 
producer 
0.125 
67.4 
81.5 
NCTC13443 
NDM-1 producer 
16 
72.6 
80.0 
6560-MAR 
1 
94.2 
>100 
KI2 
8 
80.9 
88.8 
VA375 
KPC producer 
0.25 
82.7 
91.6 
VA357 
2 
41.4 
65.8 
VA391 
8 
65.5 
69.9 
VA361 
16 
66.2 
72.1 
VA384 
16 
71.0 
78.4 
VA360 
16 
76.3 
84.2 
Escherichia 
coli 
ATCC25922 
Cephalosporin 
susceptible strain 
0.125 
32.5 
49.7 
CTX-M = cefotaximase Munich, IMP-1 = imipenemase, KPC = Klebsiella pneumoniae beta-lactamase, MDRP = 
multidrug resistant Pseudomonas aeruginosa, MIC = Minimum inhibitory concentration by broth micro dilution 
method in Chelex-treated ISB, NDM-1 = New Delhi metallo-beta-lactamase   
Animal: Jcl:ICR, male, N=5. 
Neutropenic by intraperitoneal injection of cyclophosphamide with 150 and 100 mg/kg at 4 and 1 days before 
infection, respectively. 
Infection: intramuscularly injection. 
Treatment protocols: Administration was initiated at 2 hours post infection and repeated at regular intervals of every 
3 hours ie, a total of 8 doses. 
Evaluation item: Viable cells in thigh at 24 hours after initiation of treatment. 
 
The magnitude of the PK/PD parameter required for efficacy was also determined in a 
murine lung model of infection caused by 21 strains of Gram-negative bacilli with widely 
divergent MICs.  The %fT>MIC values of S-649266 required for a static effect and 1-log10 
reduction were approximately 50% to 70% and 70% to 90%, respectively.  The %fT>MIC 
values required for efficacy were similar among bacterial species (Table 1-2), and refer to 
the current Investigator's Brochure).   


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Table 1-2 
%fT>MIC Required for Static Effect and 1-log10 Reduction 
in Murine Lung Infection Model 
Species 
Strain 
Number 
Characteristic 
S-649266 MIC 
(µg/mL) 
%fT>MIC 
Static Effect 
1-log10 Reduction 
Pseudomonas 
aeruginosa 
ATCC27853 
Cephalosporin 
susceptible 
0.5 
48.7 
74.2 
SR27001 
MDRP, 
IMP-1 producer 
8 
31.4 
51.9 
NTU 
MDRP, 
VIM-2 producer 
0.5 
38.3 
62.8 
NCTC13437 
MDRP, 
VIM-10 producer 
2 
63.6 
75.4 
Acinetobacter 
baumannii 
ATCC19606 
Cephalosporin 
susceptible 
0.125 
66.1 
74.0 
1515988 
Carbapenem 
susceptible 
0.25 
40.3 
60.8 
1485176 
MDRAB 
0.25 
69.7 
77.4 
1485247 
2 
77.6 
85.8 
NCTC13301 
MDRAB, 
OXA-23 producer 
2 
67.4 
75.0 
BEN ST BRI 
MDRAB, 
OXA-24 producer 
0.5 
90.4 
92.9 
Klebsiella 
pneumoniae 
6560-MAR 
NDM-1 producer 
1 
68.4 
> 100 
KI2 
8 
50 
75.4 
NCTC13443 
16 
59.1 
88.3 
VA375 
KPC producer 
0.25 
34.4 
58.1 
VA357 
2 
37.4 
56.8 
VA391 
8 
93 
> 100 
VA361 
16 
83.3 
94.8 
VA384 
16 
77.9 
77.9 
PLE 
OXA-48 producer 
0.063 
41.2 
64.3 
Escherichia 
coli 
AB 
NDM-4 producer 
4 
96.5 
> 100 
IR-5 
NDM-1 producer 
4 
54.3 
83.9 
KPC = Klebsiella pneumoniae beta-lactamase, MDRP = multidrug resistant Pseudomonas aeruginosa, MIC = 
Minimum inhibitory concentration by broth micro dilution method in Chelex-treated ISB, NDM-1 = New Delhi 
metallo-beta-lactamase, OXA = oxacillinases, VIM = verona integron-encoded metallo-beta-lactamase.  
Animal: Jcl:ICR, male, N = 5. 
Neutropenic by intraperitoneal injection of cyclophosphamide with 150 and 100 mg/kg at 4 and 1 days before 
infection, respectively. 
Infection: intranasal injection. 
Treatment protocols: Administration was initiated at 2 hours post infection and repeated at regular intervals of every 
3 hours (q3h), ie, a total of 8 doses. 
Evaluation item: Viable cells in lung at 24 hours after initiation of treatment. 
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. 


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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 DDI 
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, electrocardiograph (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 [Study R2111]) and single 2- to 4-g doses, 
infused over 3 hours (thorough QT/QTc [TQTc] study [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 dosed every 8 hours (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 small 
amounts (2.8%) excreted in feces (Study R2114). 
A Phase 1 study was conducted to examine the intrapulmonary PK of S-649266 
following a single 2-g dose over 1-hour infusion of S-649266 in healthy adult male 
subjects (Study R2112).  Twenty subjects were enrolled and completed the study.  
Samples of bronchial secretions were obtained by bronchoalveolar lavage (BAL) at 
prespecified times post infusion.  Corresponding timed plasma samples were also 
obtained.  S-649266 levels in epithelial lining fluid (ELF) peaked at 14 µg/mL at the end 
of the infusion and decreased to 1.4 µg/mL by 6 hours.  The ELF levels appeared to 


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parallel the concentration time profile of plasma.  There were no deaths, SAEs, or AEs 
leading to withdrawal.   
A Phase 1 study of the PK of S-649266 in subjects with varying degrees of renal function 
(mild, moderate, severe, and end-stage renal disease on dialysis) was conducted (Study 
R2113).  A total of 38 subjects received a 1-g dose over 1-hour infusion of S-649266.  
The results of a PK analysis established dose adjustments that would be needed for 
patients with decreased renal function or for patients on hemodialysis.  The results for the 
mild impairment group were not significantly different from those of the healthy group.  
The moderate and severe impairment groups demonstrated significant differences that 
require a dosage adjustment for each group in order to maintain the plasma level of drug 
at the same level as patients with normal renal function.  One subject experienced a 
nonserious AE of urticaria resulting in premature discontinuation of study drug.   
A Phase 1 study to assess the repolarization effects of S-649266 on the human heart was 
conducted as a thorough QT/QTc (TQTc) study in accordance with the ICH E14 
Guidance and subsequent Q&A (Study R2116).  The first part of the study consisted of a 
sequential-group safety and tolerability study in which 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 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-g 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 timepoints.  For the moxifloxacin treatment, a 
prolongation of the QTcF interval was observed for all timepoints 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 the 1-sided 95% CI of LS means in the ΔΔQTcF > 5 msec).  
The results indicate that single 2-g 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.  
1.5 
Phase 2 and Phase 3 
1.5.1 
Phase 2 Complicated Urinary Tract Infections 
The primary objective of Study 1409R2121 was to compare the response rate for the 
composite of both clinical cure and microbiologic eradication of S-649266 at the Test of 
Cure (TOC) with those of imipenem/cilastatin (IPM/CS) in a patient population at risk 
for multidrug resistant (MDR) Gram-negative pathogens originating from a cUTI with or 
without pyelonephritis or acute uncomplicated pyelonephritis. The primary efficacy 
assessment was performed at the TOC (approximately 7 days following the End of 
Treatment [EOT]).  


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Randomization was 2:1 to receive intravenous S-649266 (2 g) or IPM/CS (1/1 g) over 1 
hour, every 8 hours for 7 to 14 days and no intravenous to oral antibiotic step down was 
permitted. The primary efficacy population was the Microbiological Intent-to-treat 
(Micro-ITT) Population, defined as subjects having received at least 1 dose of the study 
drug and with a Gram-negative uropathogen at baseline causing the cUTI.  
Four hundred and fifty-two subjects were randomized, and 448 subjects were treated. Of 
the 448 treated subjects, 371 subjects met the definition of the Micro-ITT Population.  
A higher percentage of S-649266-treated subjects were men (47.2% [119/252] compared 
with 40.3% [48/119] of IPM/CS-treated subjects) and had cUTIs (74.2% [187/252] 
compared with 70.6% [84/119] of IPM/CS-treated subjects). For the primary endpoint of 
composite of both clinical cure and microbiological eradication at the TOC, the response 
rate was 72.6% (183/252 subjects) for S-649266 and 54.6% (65/119 subjects) for IPM/CS. 
The adjusted treatment difference of 18.58% (95% CI: 8.23%, 28.92%) in favor of S-
649266 met the criteria to demonstrate noninferiority with a prespecified 20% margin, 
since the lower limit of the 95% CI exceeded -20%. The lower limit of the 95% CI also 
exceeded −15%, and noninferiority with another prespecified 15% margin was 
demonstrated. This result showed superiority of S-649266 to IPM/CS (the lower limit of 
95% CI was above 0).  
Forty point seven percent (122/300) of subjects treated with S-649266 experienced at 
least 1 AE, compared with 51.4% (76/148) of subjects treated with IPM/CS. The most 
frequently observed adverse event was diarrhoea, which was experienced by 4.3% 
(13/300) and 6.1% (9/148) of S-649266- and IPM/CS-treated subjects, respectively. 
Fourteen (4.7%) of the 300 subjects treated with S-649266 experienced at least 1 SAE, 
compared with 12 (8.1%) of the 148 subjects treated with IPM/CS. There was one death 
of cardiac failure in the S-649266 group which the investigator considered not related to 
study drug. One (0.3%) of the 300 subjects treated with S-649266 experienced a 
treatment-related SAE, and 1 (0.7%) of the 148 subjects treated with IPM/CS 
experienced a treatment-related SAE, both events were Clostridium difficile colitis, which 
resolved with treatment. The results from this study indicated no unexpected safety 
concerns with S-649266. 
Refer to the current Investigator's Brochure for additional details of completed studies. 
1.5.1.1 
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 nosocomial pneumonia caused by 
Gram-negative pathogens has been started (Study R2132). This randomized study 
(NCT03032380) is enrolling subjects with hospital-acquired pneumonia, ventilator-
associated pneumonia and health-care associated pneumonia caused by Gram-negative 
pathogens compared with meropenem. 
Refer to the current Investigator’s Brochure for additional details of completed studies. 


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2. STUDY OBJECTIVES 
2.1 
Primary Objectives 
● To assess, at test of cure (TOC1, the clinical outcome of treatment with S-649266 
or best available therapy (BAT) in adult patients with either hospital-acquired 
pneumonia (HAP)/ventilator-associated pneumonia (VAP)/healthcare-associated 
pneumonia (HCAP) or bloodstream infections/sepsis (BSI/sepsis)2 caused by 
carbapenem-resistant Gram-negative pathogens  
● To assess, at TOC, the microbiologic outcome of treatment with S-649266 or 
BAT in adult patients with cUTI caused by carbapenem-resistant Gram-negative 
pathogens  
2.2 
Secondary Objectives 
● To assess the safety of S-649266 
The other secondary objectives of this study are established as follows: 
● To assess the clinical outcome of treatment with S-649266 or BAT in patients 
with either HAP/VAP/HCAP or BSI/sepsis at End of Treatment (EOT)3 and 
Follow-up (FUP) 4  
● To assess the clinical outcome of treatment with S-649266 or BAT in patients 
with cUTI at EOT, TOC, and FUP 
● To assess the microbiologic outcome of treatment with S-649266 or BAT in 
patients with either HAP/VAP/HCAP or BSI/sepsis at EOT, TOC, and FUP  
● To assess the microbiologic outcome of treatment with S-649266 or BAT in 
patients with cUTI at EOT and FUP 
● To assess the microbiologic outcome of treatment with S-649266 or BAT in 
patients with bacteremia (regardless of the primary infection diagnosis) at EOT, 
TOC, and FUP 
● To assess the composite clinical and microbiologic outcome of treatment with 
S-649266 or BAT in patients with cUTI at EOT, TOC, and FUP 
● To assess the all-cause mortality at Day 14 and Day 28 in patients with 
HAP/VAP/HCAP and BSI/sepsis 
● To assess the relationship between the PD parameter %fT >MIC based on plasma 
drug concentrations at steady state and the clinical and microbiologic outcomes of 
treatment with S-649266 in patients with HAP/VAP/HCAP, cUTI, or BSI/sepsis  
 
1  
TOC is defined as end of treatment (EOT) + 7 days (± 2 days). 
2  
BSI/sepsis is a group of patients with documented carbapenem-resistant Gram-negative infections in 
the blood stream (BSI) or in a body site other than the urinary tract (cUTI) or lung (HAP/VAP/HCAP) 
and in case of sepsis, evidence of systemic inflammatory response syndrome (SIRS) is required. 
3  
EOT = end of treatment is defined as the last day of study therapy. 
4  
FUP = follow-up is defined as EOT + 14 days (± 3 days). 


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● To assess the resource utilization required for the treatment of the study-
qualifying infection 
● To compare S-649266 with BAT in patients with HAP/VAP/HCAP, cUTI, or 
BSI/sepsis based on the composite endpoint of survival and no change in 
antibiotic treatment due to either lack of therapeutic benefit or drug-related 
toxicity at TOC   


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3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 3, multicenter (multinational), open-label, parallel group, randomized, 
active-controlled study in approximately 150 patients with documented carbapenem-
resistant Gram-negative bacterial infections.  Patients meeting eligibility criteria and 
assessed by the investigator to require 7 to 14 days of intravenous treatment in a hospital 
will be randomized (2:1) to either S-649266 2 g administered intravenously over 3 hours, 
q8h or BAT. 
Patient eligibility is focused on the identification of carbapenem-resistant Gram-negative 
pathogens from a protocol-defined infection prior to Randomization.  The eligible 
pathogens include, but are not limited to, carbapenem-resistant Enterobacteriaceae, 
carbapenem-resistant P. aeruginosa, or carbapenem-resistant A. baumannii.  
Identification of pathogen and/or carbapenem resistance identification may be made with 
the use of approved and investigational rapid diagnostic tests.  After Randomization, 
pathogen identification will be confirmed through standard microbiological methods. 
Patients will be randomized to S-649266 or BAT in a 2:1 ratio.  Their infection site 
(HAP/VAP/HCAP, cUTI, and BSI/sepsis), baseline Acute Physiology and Chronic 
Health Evaluation II (APACHIE II) score (≤ 15 and ≥ 16) and region (N. America, S. 
America, Europe, and Asia-Pacific) will be balanced using the stochastic minimization 
method [21].  
BAT will be chosen by the investigator and may include up to 3 antibacterial agents.  
BAT will be categorized as either a polymyxin-based (polymyxin B or colistin) regimen 
or a nonpolymyxin based regimen.   
Since S-649266 is mainly eliminated unchanged in urine, patients with reduced renal 
function (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) determined 
by modification of diet in renal disease (MDRD) equation, will have their dose reduced 
based on the degree of renal impairment (Table 5-2).  Patients on various forms of 
hemodialysis, except peritoneal dialysis, are also eligible for the study and dosage will be 
adjusted as described in Section 5.2.  Patients with augmented renal clearance (ARC) 
determined by eGFR ≥ 90 mL/min/1.73 m2 and creatinine clearance 
(CrCl) ≥ 120 mL/min calculated by the Cockcroft-Gault equation will have their dosing 
interval shortened (Table 5-2).  Dose adjustment should be done both after study required 
renal function tests as well as those conducted per the best local clinical practice.   
Dose adjustment for patients randomized to BAT with reduced renal function will be 
made according to each drug’s country specific label based on the degree of renal 
impairment.   
Sequential oral antibiotic (step-down) therapy is not permitted by this protocol.  
De-escalation (withdrawal of unneeded antibiotics after consideration of the bacterial 
culture and susceptibility results) will be assessed no later than Early Assessment (EA).   


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A patient’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).  End of trial for this study is defined as the last visit of the last patient and is 28 
days (± 3 days) after the end of treatment for that patient.  
The study design is shown in Figure 3-1.  The study time and events table is shown in 
Appendix 1. 
Figure 3-1 
Study Schematic 
D −2 
to  
D 1 
D 1 
D 3 
(after 6 doses) 
D 3 to D 4 
up to  
D 14a 
EOT  
+ 7  
(± 2) 
EOT  
+ 14 
 (± 3) 
EOT  
+ 28 
 (± 3) 
Screening 
Randomization 
 
PK 
Early 
Clinical/Micro 
Assessment 
(EA) 
 
End of Treatment (EOT) 
Test of Cure (TOC) 
Follow-up (FUP) 
End of Study (EOS) 
Treatment Period 
S-649266 2 g intravenous dosing  
at 8-hour intervalsb 
BAT either polymyxin-based or  
non-polymyxin-based 
BAT = best available therapy; D = day; EA = early assessment; EOT = end of treatment (last day of study 
treatment); PK = pharmacokinetics 
Each day is a calendar date (ie, D2 is the next day/date after D1 in calendar). 
a 
The treatment duration can be extended up to 21 days based on the investigator’s clinical assessment of 
the patient. A clear reason should be documented in the eCRF. 
b 
Dosing adjustments for augmented renal clearance and renal impairment (see Table 5-2) 
 
3.2 
Rationale for Study Design and Control Group 
3.2.1 
Rationale for Patient Population 
This study is designed to provide evidence of efficacy of S-649266 in the treatment of 
serious infections caused by a variety of carbapenem-resistant Gram-negative pathogens 
for a range of infection sites, ie, HAP/VAP/HCAP, cUTI, and BSI/sepsis.  The target 
pathogens include, but are not limited to, carbapenem-resistant Enterobacteriaceae, 
carbapenem-resistant P. aeruginosa, or carbapenem-resistant A. baumannii.  The target 
pathogens do not include Gram-positive or anaerobic bacteria.  In cases of mixed 
infections with target and nontarget bacteria, additional antibiotic therapy may be used 
specifically to treat nontarget bacteria.  


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Although the urinary tract is a common source of carbapenem-resistant 
Enterobacteriaceae, carbapenem-resistant bacteremia, septicemia, and lung infections are 
the more difficult to treat infections.  Therefore, the proportion of cUTI patients will be 
limited to no more than 30% of the total study population.  Additionally, the proportion 
of patients with lung infections (HAP/VAP/HCAP) will be approximately 50% with VAP 
accounting for a little more than half (approximately 30% of the total patient population) 
of those patients, and BSI or sepsis as the primary diagnosis will be the remaining 20% of 
the patient population for the study.   
BSI is defined as a documented bacteremia in a patient with a documented infection other 
than HAP/VAP/HCAP or cUTI.  Sepsis is defined as an infection other than 
HAP/VAP/HCAP or cUTI associated with systemic inflammatory response syndrome 
(SIRS).   
3.2.2 
S-649266 Dose Regimen 
The dose and dose regimen for this study were developed from extensive PK/PD analyses 
of treatment of infections in appropriate animal models and PK modeling based on 
human PK.  The controlling PD parameter for S-649266 is %fT>MIC.  Although the 
plasma PK measurement 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 infections caused by carbapenem-resistant Gram-negative bacteria including 
carbapenem-resistant Enterobacteriaceae and carbapenem-resistant strains of 
P. aeruginosa and A. baumannii (Section 1.3.1).   
Monte Carlo simulations using a population PK model, which was developed with data 
from the ascending dose Phase 1 study (Study R2111), were performed to assess the dose 
regimens which 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 (PTA) with administration of 2 g q8h with 1- or 3-hour infusion is 
shown in Figure 3-2. 


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Figure 3-2 
Probability of Target Attainment for 50% or 75% fT > MIC 
 
MIC = minimum inhibitory concentration; PTA = Probability of target attainment 
The results indicated that with administration of 2 g q8h with 1- or 3-hour infusion, more 
than 90% of patients with normal renal function would achieve 50% Tf > MIC at MIC of 
8 μg/mL and 75% Tf > MIC at MIC of 4 μg/mL.  A 2 g q8h dosage regimen with 3-hour 
infusion could be considered a potential treatment for > 90% of the target pathogens, ie, 
carbapenem-resistant Enterobacteriaceae, MDRP and MDRAB based on susceptibility 
testing (each of MIC90: ≤ 4 μg/mL, 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 proposed S-649266 dose regimen for the treatment of serious, life-threatening 
infections with carbapenem-resistant Gram-negative pathogen for diagnoses such as 
HAP/VAP/HCAP, cUTI, or BSI/sepsis is 2 g q8h over a 3-hour infusion.   
Adjustments for either impaired renal function or ARC are provided in this study to allow 
for enrollment of patients with significant comorbidities while maintaining the target 
drug exposure.   
The dosages of S-649266 for patients with various degrees of renal function were 
calculated based on the result of Study R2113.  Mild impairment did not result in a need 
to alter the dosage of drug.  Moderate and severe impairment required a decrease in the 
amount of drug administered during an 8-hour infusion cycle (Table 5-2).  Treatment 
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% T>MIC, 2 g with 1-hr infusion 
PTA for 75% T>MIC, 2 g with 1-hr infusion 
PTA for 50% T>MIC, 2 g with 3-hr infusion 
PTA for 75% T>MIC, 2 g with 3-hr infusion 


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regimens for patients on various forms of hemodialysis, except peritoneal dialysis, are 
proposed in Table 5-2.   
While it is usual to decrease drug dosage of cephalosporins in patients with impaired 
renal function, some patients, particularly trauma patients and those in intensive care unit 
(ICU) on ventilators, have increased renal clearance resulting in suboptimal drug 
exposure.  Therefore, dosing adjustment was evaluated for patients with ARC (CrCl 
≥ 120 mL/min) based on the population PK model that was developed by using the data 
from the healthy volunteer study (Study R2111) and the renal impairment study (Study 
R2113).  The PK structural model is a 3-compartment model and the model includes 
CrCl as a covariate for a renal function index (CL = 4.83 × [1 + 0.00404 × [CrCl − 100]).  
A 2 g every 6 hours (q6h) dosage regimen with a 3-hour infusion is proposed for patients 
with ARC, in which > 90% PTA would be expected against pathogens requiring an MIC 
of 4 µg/mL as shown in the Table 3-1. 
Table 3-1 
Probability of Target Attainment for Patients with 
Augmented Renal Clearance 
Dose Regimen 
CrCl: 120-150 mL/min 
CrCl: 150-200 mL/min 
2 g, q8h, 3-hour infusion 
82.0% 
72.7% 
2 g, q6h, 3-hour infusion 
96.4% 
94.1% 
Inter-individual variability of 40% was assumed. 
CrCl = creatinine clearance calculated by Cockcroft-Gault equation; q8h = every 8 hours. 
 
 
3.2.3 
BAT Regimens 
Because of the life-threatening nature of the protocol specified infections, a placebo-
controlled study is not appropriate.  A standardized comparator is not feasible because the 
most appropriate treatment for patients with carbapenem-resistant Gram-negative 
bacterial infection is often a highly variable combination of several antibiotics and is 
usually tailored to the patient’s specific infection, determined by both (a) the site of 
infection, microbiologic identification, and antibiotic susceptibility of the patient’s 
causative bacteria, and (b) the availability of approved antibiotics within a country 
[22-26].  Therefore, the comparator will be BAT which will be determined by the 
Investigator using clinical judgment and local standard of care and will include only 
products approved in their respective country.  Because BAT cannot be precisely defined 
in the protocol, blinding of this study is not possible.  
3.2.4 
Duration of Study Treatment  
The treatment duration for S-649266 or BAT is anticipated to be 7-14 days which are 
consistent with published treatment guidelines for serious infections [27-29].  Based on 
the investigator’s clinical assessment of the patient, treatment may be extended up to 21 
days.  The reason for the extension should be clearly documented.  All study treatments 
will be performed in the hospital. 


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3.3 
Study Duration 
3.3.1 
Study Duration in Individual Patients 
All patients will be followed for safety for approximately 28 days following EOT.  The 
total study participation from treatment initiation to EOS will be approximately 5 to 
7 weeks for each patient.  
4. STUDY POPULATION SELECTION 
4.1 
Study Population 
Male or female patients 18 years of age or older who have a documented infection caused 
by a carbapenem-resistant Gram-negative pathogen and who require hospitalization for 
the parenteral (intravenous) treatment of the infection may be enrolled in the study.   
Patients with the following infections will be enrolled: 
● HAP/VAP/HCAP or 
● cUTI or 
● BSI/sepsis  
Note: Patients with BSI/sepsis secondary to HAP/VAP/HCAP or cUTI will be 
categorized based on the primary infection diagnosis, ie, HAP/VAP/HCAP or 
cUTI.1 
The proportion of patients with the various infection diagnoses will be controlled at the 
time of Randomization through a central Randomization system.   
● Approximately 50% of randomized patients will have HAP/VAP/HCAP  
● No more than 30% of randomized patients will have cUTI   
● The remainder of randomized patients will have BSI/sepsis  
The initial evidence of carbapenem-resistant Gram-negative bacterial pathogen may be 
derived from various scenarios as follows: 
● Rapid diagnostic tests identifying the presence of carbapenemase or selective 
chromogenic media may be used to identify carbapenem-resistant Gram-negative 
bacterial infections prior to the availability of MIC results for the specific 
infection 
● Empiric treatment has failed and the target pathogen has been identified as a 
carbapenem-resistant Gram-negative pathogen 
● An identified infection with Stenotrophomonas maltophilia is eligible because it 
is inherently carbapenem resistant. 
 
1  
BSI/sepsis is a separate treatment group of patients with documented carbapenem-resistant Gram-
negative infections defined as either a blood stream infection (BSI) or an infection site other than cUTI 
or HAP/VAP/HCAP and in case of evidence of systemic inflammatory response syndrome (SIRS) 


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● Current hospital antibiogram for Gram negative bacteria showing a CR rate of 
> 90% is taken as evidence of CR for the isolated Gram-negative pathogens from 
the patient.  Supporting documentation, submitted to Shionogi for approval prior 
to implementation, may take the form of a copy of local hospital epidemiological 
data from within the past year, an official (annual) report containing aggregate 
data with sensitivities would be preferable, or a Note to File indicating sensitivity 
data prepared by the microbiologist or principle investigator may be acceptable.  
● Patient is known to be colonized (as evidenced by prior cultures from the same 
site as the infection) with a carbapenem-resistant Gram-negative pathogen prior to 
developing acute infection, ie, prior culture within the previous 72 hours   
The possible pathways for enrollment in the study are presented in Figure 4-1. 
Figure 4-1 
Study Schematic Showing Possible Pathways for Study Entry 
 
CR-GNB = Carbapenem-resistant Gram-negative bacilli, EA = early assessment; EOT = end of treatment; 
TOC = Test of Dure; hrs =  hours 
Patients who were initially randomized based on one of the above scenarios, but failed to 
demonstrate a study required carbapenem-resistant Gram-negative infection on central 
laboratory testing will remain in the study and continue to receive their study treatment 
regimen, if the treatment regimen is assessed by the investigator as adequate.   


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4.2 
General Inclusion Criteria  
Patients who fulfill the following criteria at Screening will be included in the study: 
1. Hospitalized male and female patients, 18 years or older at the time of signing 
informed consent  
2. Patients who have provided written informed consent or their informed consent 
was provided by legal guardian (Note: Country specific rules and local Ethics 
Committee approval for legal guardian informed consent will determine whether 
or not and how a patient unable to comprehend or sign the informed consent is 
allowed to be enrolled in the study)  
3. Patients with clinically documented infection (HAP/VAP/HCAP, cUTI, or 
BSI/sepsis) caused by a Gram-negative pathogen with evidence of carbapenem 
resistance (see Section 4.1).   
4. Patients who have been treated previously with an empiric antibiotic regimen and 
failed treatment, both clinically and microbiologically, are eligible for the study, if 
they have an identified carbapenem-resistant, Gram-negative pathogen which has 
either been shown to be nonsusceptible in vitro to each of the antibiotic(s) of the 
empiric antibiotic regimen or been grown from a culture performed after at least 2 
days of the empiric antibiotic regimen  
5. Patient is male (no contraception required) or female and meets one of the 
following criteria:  
● Surgically sterile (has had a hysterectomy and/or bilateral oophorectomy, or 
bilateral salpingectomy or tubal ligation for the purpose of contraception for at 
least 6 weeks with appropriate documentation of such surgery)  
● Postmenopausal (defined as older than 45 years of age with cessation of 
regular menstrual periods for 6 months and a follicle-stimulating hormone 
level of > 40 mIU/mL, or amenorrhea for at least 12 months) 
● 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 (IUD), or intrauterine 
hormone-releasing system (IUS) for the entire duration of the study 
● Of childbearing potential and practices abstinence as a preferred and usual 
lifestyle, and agrees to continue practicing abstinence from Screening and for 
the entire duration of the study 
● Of childbearing potential, whose sole heterosexual partner has been 
successfully vasectomized and agrees to not have other heterosexual partners 
for the entire duration of the study 
6. Patients meeting specific criteria for each infection site (See Section 4.4) 
4.3 
General Exclusion Criteria 
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 


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1. Patients who have a history of any moderate or severe hypersensitivity or allergic 
reaction to any β-lactam (Note: for β-lactams, a history of a mild rash followed by 
uneventful re-exposure is not a contraindication to enrollment) 
2. Patients who need more than 3 systemic antibiotics as part of BAT for the 
treatment of the Gram-negative infection (Patients with mixed Gram-positive or 
anaerobic infections may receive appropriate concomitant narrow-spectrum 
antibiotics [eg, vancomycin, linezolid, metronidazole, clindamycin]) 
3. Patients with coinfection caused by invasive aspergillosis, mucormycosis or other 
highly lethal mold 
4. Patients who have central nervous system infection (eg, meningitis, brain abscess, 
shunt infection) 
5. Patients with infection requiring > 3 weeks of antibiotic treatment (eg, bone and 
joint infection, endocarditis) 
6. Patients with cystic fibrosis or moderate to severe bronchiectasis 
7. Patients in refractory septic shock defined as persistent hypotension despite 
adequate fluid resuscitation or despite vasopressive therapy at the time of 
randomization 
8. Patients with severe neutropenia, ie, polymorphonuclear neutrophils 
(PMNs) < 100 cells/µL  
9. Female patients who have a positive pregnancy test at Screening or who are 
lactating  
10. Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) 
score > 30 
11. Patients who have received a potentially effective antibiotic regimen for the 
carbapenem-resistant, Gram-negative infection for a continuous duration of more 
than 24 hours in cUTI, or 36 hours in HAP/VAP/HCAP or BSI/sepsis during the 
72 hours leading to Randomization   
12. Patients with any condition or circumstance that, in the opinion of the 
investigator, would compromise the safety of the patient or the quality of the 
study data 
13. Patients who have received another investigational drug or device within 30 days 
prior to study entry 
14. Patients who have previously been randomized in this study or received S-649266 
15. Patients receiving peritoneal dialysis 
16. Patients meeting specific exclusion criteria for each infection site (See Diagnosis-
Specific Exclusion Criteria) 
4.4 
Diagnosis Specific Inclusion and Exclusion Criteria 
4.4.1 
HAP/VAP/HCAP Patients  
4.4.1.1 
HAP/VAP/HCAP Definitions  
The diagnosis of HAP, VAP, or HCAP will be specified and recorded in the eCRF.  HAP 
is defined as an acute bacterial pneumonia in a patient hospitalized for more than 


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48 hours or developing within 7 days after discharge from a hospital.  Patients may 
experience acute respiratory failure and require mechanical ventilation for HAP 
(ventilated-HAP). 
VAP is defined as an acute bacterial pneumonia in a patient receiving mechanical 
ventilation via an endotracheal (or nasotracheal) tube for a minimum of 48 hours. 
HCAP is defined as below when at least one of the criteria is met: 
• an acute bacterial pneumonia in a patient who was hospitalized in an acute care 
hospital for 2 or more days within 90 days of the infection;  
• resided in a nursing home or long-term care facility;  
• received intravenous antibiotic therapy, chemotherapy, or wound care; or attended 
a hemodialysis clinic within the past 30 days of the current infection.  
4.4.1.2 
HAP/VAP/HCAP Specific Inclusion Criteria 
Patients who fulfill the following criteria at Screening will be included in the study: 
1. All patients must have at least one of the following clinical features: 
a. New onset or worsening of pulmonary symptoms or signs, such as cough, 
dyspnea, tachypnea (eg, respiratory rate greater than 25 breaths/minute), 
expectorated sputum production, or requirement for mechanical ventilation 
b. Hypoxemia (eg, a partial pressure of oxygen less than 60 mmHg while the 
patient is breathing room air, as determined by arterial blood gas [ABG] or 
worsening of the ratio of the partial pressure of oxygen to the fraction of 
inspired oxygen [PaO2/FiO2]) 
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 
2. All patients must have at least one of the following signs: 
a. Documented fever (eg, core body temperature [tympanic, rectal, esophageal] 
greater than or equal to 38°C [100.4°F], oral temperature greater than or equal 
to 37.5°C or axillary temperature greater than or equal to 37°C)   
b. Hypothermia (eg, core body temperature [tympanic, rectal, esophageal] less 
than or equal to 35°C [95°F], oral temperature less than or equal to 35.5°C or 
axillary temperature less than or equal to 36°C)  
c. Leukocytosis with a total peripheral WBC count greater than or equal to 
10,000 cells/mm3 
d. Leukopenia with total peripheral WBC count less than or equal to 
4,500 cells/mm3 


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e. Greater than 15% immature neutrophils (bands) noted on peripheral blood 
smear  
3. All patients must have a chest radiograph or lung computed tomography (CT) 
scan within 48 hours of randomization showing the presence of new or 
progressive infiltrate(s) suggestive of bacterial pneumonia.  
4.4.1.3 
HAP/VAP/HCAP Specific Exclusion Criteria 
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Patients who have known or suspected community-acquired bacterial pneumonia, 
atypical pneumonia, viral pneumonia or chemical pneumonia (including 
aspiration of gastric contents, inhalation injury) 
2. Patients receiving concomitant aerosolized antibiotics with Gram-negative 
activity 
4.4.2 
cUTI Patients 
4.4.2.1 
cUTI Definition 
cUTI is defined as a clinical syndrome characterized by pyuria and a documented 
microbial pathogen on urine culture, accompanied by local and systemic signs and 
symptoms including fever, chills, malaise, flank pain, back pain, and/or costovertebral 
angle pain or tenderness that occur in the presence of a functional or anatomical 
abnormality of the urinary tract or in the presence of catheterization and who require 
hospitalization for the parenteral (intravenous) treatment of cUTI will be enrolled in the 
study.  
4.4.2.2 
cUTI Specific Inclusion Criteria 
Patients who have a clinical diagnosis of either cUTI with pyelonephritis or cUTI without 
pyelonephritis and fulfill the following criteria at Screening will be included in the study: 
1. All patients must have a cUTI with a history of at least one of the following: 
a. Indwelling urinary catheter or recent instrumentation of the urinary tract 
(within 14 days prior to Screening) 
b. Urinary retention caused by benign prostatic hypertrophy 
c. Urinary retention of at least 100 mL or more of residual urine after voiding 
(neurogenic bladder) 
d. Obstructive uropathy (nephrolithiasis, fibrosis, etc) 
e. Azotemia caused by intrinsic renal disease (BUN and creatinine values greater 
than normal clinical laboratory values) 
2. All patients must have at least 2 of the following signs or symptoms:  
a. Chills, rigors, or warmth associated with fever (body temperature greater than 
or equal to 38°C [100.4°F]) 
b. Flank pain (pyelonephritis) or suprapubic/pelvic pain (cUTI) 


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c. Nausea or vomiting 
d. Dysuria, urinary frequency, or urinary urgency 
e. Costovertebral angle tenderness on physical examination 
3. All patients must have evidence of pyuria on urinalysis demonstrated by either: 
a. Either dipstick analysis positive for leukocyte esterase  
OR 
b. ≥ 10 WBCs /μL in unspun urine, or ≥ 10 WBCs /high power field in spun 
urine 
4. Patients who had a positive urine culture within 48 hours prior to Randomization 
containing ≥ 105 colony forming unit (CFU)/mL of a carbapenem-resistant Gram-
negative uropathogen are eligible for this study (Note: patients may be 
randomized prior to the results of the urine culture if they have evidence of a 
carbapenem-resistant pathogen) 
5. Patients receiving antibiotic prophylaxis for cUTI who present with signs and 
symptoms consistent with an active new cUTI may be enrolled provided all other 
eligibility criteria are met including obtaining a pretreatment qualifying urine 
culture 
4.4.2.3 
cUTI Specific Exclusion Criteria 
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Patient’s urine culture at study entry isolates more than 2 uropathogens, regardless 
of colony count, or patient has a confirmed fungal cUTI 
2. Patients with asymptomatic bacteriuria, the presence of >105 CFU/mL of a 
uropathogen and pyuria but without local or systemic symptoms [30] 
3. Patients with an ileal loop for urine outflow (for patients with BSI/sepsis and an 
ileal loop are eligible) 
4. Patients with acute uncomplicated pyelonephritis, ie, absence of anatomic urinary 
tract abnormality 
5. Patients with vesico-ureteric reflux  
4.4.3 
Bloodstream Infections/Sepsis Patients 
4.4.3.1 
BSI/Sepsis Definitions 
The BSI/sepsis category includes bacteremia or sepsis caused by infections other than 
HAP/VAP/HCAP or cUTI. The diagnosis of BSI or sepsis and the causal infection will 
be specified and recorded in the eCRF.  Patients will be enrolled in the BSI/sepsis group 
with either: 
a. Documented BSI caused by a carbapenem-resistant Gram-negative pathogen   
OR 
b. Systemic response to infection, meeting the clinical criteria of SIRS [29] and an 


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identified infection source (eg, severe skin infection, intra-abdominal infection) 
caused by a carbapenem-resistant Gram-negative pathogen   
Note: The inclusion/exclusion criteria for BSI and sepsis are not the same.  It is 
possible to meet the criteria for one without the other.   
4.4.3.2 
Bloodstream Infection-specific Inclusion Criteria 
Patients who fulfill the following criteria at Screening will be included in the study: 
1. Patients who have one or more positive blood cultures identifying a carbapenem-
resistant Gram-negative pathogen that is consistent with the patient’s clinical 
condition  
2. Patients who have signs or symptoms associated with bacteremia 
4.4.3.3 
Bloodstream Infection-specific Exclusion Criteria 
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Patients who have a positive blood culture only obtained from an intravenous 
catheter.  If both peripheral venipuncture blood culture and intravenous catheter 
blood culture show the same organism, the patient is eligible  
2. Patients with BSI considered to be due to an endovascular source, eg, endocarditis, 
infected vascular graft, a permanent intravascular device that cannot be removed 
during the course of treatment   
4.4.3.4 
Sepsis-specific Inclusion Criteria  
Patients who fulfill the following criteria at Screening will be included in the study: 
1. Patients defined for SIRS (Appendix 2), indicated by having 2 or more of the 
following responses: 
a. Oral or tympanic body temperature greater than 38°C (100.4°F) or less than 
36°C (96.8°F) 
b. Tachycardia, heart rate greater than 90 beats/minute 
c. Tachypnea, manifested by a respiratory rate greater than 20 breaths/minute or 
hyperventilation, as indicated by an arterial partial pressure of carbon dioxide 
(PaCO2) of less than 32 mm Hg 
d. WBC greater than 12,000 cells/mm³, less than 4000 cells/mm³, or > 10% 
immature (band) forms 
2. Patients with an identified infection site from which a carbapenem-resistant 
Gram-negative pathogen has been isolated using an appropriate clinical specimen 
4.4.3.5 
Sepsis Specific Exclusion Criteria  
Patients who meet any of the following criteria at Screening will be excluded from the 
study: 


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1. Patient does not have an identified source of a bacterial infection and an identified 
carbapenem-resistant Gram-negative pathogen 
2. Patient has an alternative explanation for the physiologic parameters of SIRS, eg, 
cardiogenic shock, cardiac arrhythmia, or hyperthyroid storm 
3. Patients with infections where isolation of a Gram-negative pathogen is unlikely 
to be causing the infection such as that in the upper respiratory systems, head and 
neck, pelvic or genital organ, etc. 


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5. STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Test Drug 
S-649266 (1 g/vial) as a lyophilized powder for dilution for intravenous administration, 
manufactured by Shionogi & Co., Ltd., Japan.   
5.1.2 
Control Treatment Regimen 
The control population will be treated with BAT, locally sourced by study sites, within 
the local standard of care determined by the investigator for each infection diagnosis.  
This will usually involve 1 or 2 or possibly 3 antibiotic agents specifically for the 
carbapenem-resistant Gram-negative pathogen.   
One or 2 or possibly 3 antibiotic agents: Published clinical studies, usually retrospective 
or non-randomized observational studies, have not shown conclusively that combinations 
of antibiotics are superior to monotherapy.  Results of these studies are highly variable 
and often dependent on the type of infection or the specific causative pathogen [22-26]. 
5.2 
Treatments To Be Administered 
Each patient who is qualified for entry in the study will be randomized into 1 of 2 
treatment groups according to the method of treatment assignment as specified in  
Section 5.4.  The treatment groups are shown in Table 5-1.   
S-649266 will be administered intravenously over 3 hours q8h.  The adjunctive antibiotic 
to S-649266 and BAT will be administered according to the country specific package 
label and the discretion of the investigator.   
The treatment duration for S-649266 or BAT is anticipated to be 7 to 14 days which are 
consistent with published treatment guidelines for serious infections [27-29].  Only in 
cUTI is a minimum of 5 days permissible if in the opinion of the investigator, the 
patient’s infection has been cured and it is in the patient's best interest.  It is 
recommended that dosing does not exceed 14 calendar days or 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 patient.  The reason for the extension should be clearly 
documented.  All study treatments will be performed in the hospital. 
If a patient needs to be treated for longer than 21 days, an EOT visit should be performed 
as soon as possible after last dose (same calendar day) and the patient should be 
discontinued from the study treatment: 1) in the case of S-649266 (and the adjunctive 
antibiotic), treatment should then follow local clinical practice; 2) in the case of BAT, it 
should be continued or changed per local clinical practice.  These patients are still 
considered to be in the study and should be followed through to the completion of all 
study activities, ie, TOC, FUP, and EOS.  
 


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Table 5-1 
Study Treatment Administration 
Treatment 
Groups 
Study Treatment 
S-649266 
S-649266 2 g* administered intravenously every 8** hours as a 3-hour 
infusion with/without another single adjunctive Gram-negative 
antibiotic other than a polymyxin or a cephalosporin/carbapenem 
including combination with beta-lactamase inhibitor (eg, 
ceftazidime/avibactam or ceftolozane/tazobactam)  
BAT 
Standard of care with either a polymyxin-based or non-polymyxin-
based regimen as determined by the investigator and consisting of 1 to 
3 marketed antibacterial agent(s) 
BAT = best available care  
* 
0.75 g, 1 g, 1.5 g, or 2 g based on renal function see Table 5-2.  
** 6, 8, or 12 hours based on renal function see Table 5-2.  
5.2.1 
S-649266 Group 
The preparation of the dosing solutions for S-649266 is described in the study procedure 
manual.  The solution volume for infusion must be at least 100 mL.  Under no 
circumstances is S-649266 to be administered in a saline solution of less than 100 mL.  
Dilution volumes greater than 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. 
5.2.1.1 
Adjunctive Antibiotic Therapy 
Patients with cUTI should receive S-649266 monotherapy, ie, without combining with an 
additional Gram-negative antibiotic.   
Patients with HAP/VAP/HCAP or BSI/sepsis randomized to treatment with S-649266 
may receive a second (but not a third) Gram-negative antibiotic other than a polymyxin 
(colistin or polymyxin B) or a cephalosporin/carbapenem including combination with 
beta-lactamase inhibitor (eg, ceftazidime/avibactam or ceftolozane/tazobactam) at the 
initiation of study drug.  This decision should be based on the investigators consideration 
of the patient’s condition, the causative pathogen, and current best practices.   
If a second Gram-negative antibiotic is administered with S-649266 at the time of 
randomization, the investigator must reassess the need for the second Gram-negative 
antibiotic upon availability of susceptibility testing to S-649266 no later than EA visit.  
The adjunctive antibiotic therapy should be discontinued (de-escalated) accordingly. 
Examples of allowed adjuvant Gram-negative antibiotics for patients randomized to the 
S-649266 arm for HAP/VAP/HCAP or BSI/sepsis infections only are:  
Any aminoglycoside 
Any fluoroquinolone 


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Any macrolide 
Piperacillin/tazobactam 
Ampicillin/sulbactam, but not sulbactam alone 
Piperacillin 
Fosfomycin 
Tigecycline 
5.2.2 
BAT Group 
BAT is the standard of care as determined by the investigator based on his/her assessment 
of the patient’s clinical condition, the site of infection and the causative organism 
(including available susceptibility data) as well as the totality of evidence on available 
medicines and his/her best clinical judgment.  BAT consists of 1 to 3 antibiotics 
prescribed for the carbapenem-resistant, Gram-negative pathogen, without aerosolized 
antibiotics.  BAT can be a polymyxin-based or non-polymyxin-based regimen.  A second 
or third antibiotic could include but is not limited to an aminoglycoside, a carbapenem, a 
fluoroquinolones, or tigecycline.  The planned standard of care regimen needs to be 
recorded prior to randomization (refer to Section 5.4).   
If the investigator chooses to use a polymyxin (either polymyxin B or colistin 
[polymyxin E]), the investigator is encouraged to follow EMA’s dosing 
recommendations [Appendix 3].  Some formulations of colistin, eg, colistimethate and 
colistin methanesulfonate, are pro-drugs and are hydrolyzed to colistin in situ.  Since the 
availability of polymyxin B and colistin products vary from country to country, no 
standardized BAT is possible for this multinational study.  Careful attention to labelled 
dosing recommendations including adjustments for renal function is recommended [31].  
Combination therapy for BAT may include drugs to which the patient’s identified 
pathogenic organism is non-susceptible in vitro.  Various combinations of these 
antibiotics have been shown to be synergistic in vitro and in animal experiments [32, 33].   
De-escalation is defined as the discontinuation of unnecessary antibiotics consistent with 
best medical practices [34, 35].  BAT regimen may be modified by reducing the number 
of antibiotics used to treat the carbapenem-resistant Gram-negative infections at any time, 
but an assessment for de-escalation is required no later than EA.   
5.3 
Selection and Timing of Dose for Each Patient 
The proposed S-649266 dose regimen for the treatment of serious or life-threatening 
infections is 2 g q8h infusion over 3 hours.   
Table 5-2 provides the S-649266 dosing adjustments for patients with various degrees of 
renal function and ARC.  The dosages for S-649266 in Table 5-2 were derived from the 
results of the ascending dose Phase 1 study (Study R2111) and the renal impairment 
study (Study R2113) examining the PK characteristics of the S-649266 in normal healthy 
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The initial dosage for each patient will be adjusted based on eGFR calculated by MDRD 
equation [36] and CrCl by Cockcroft-Gault equation [37] as per Table 5-2.  Renal 
function for all patients will be assessed at EA to determine if there are changes in renal 
function as a result of treatment.  The main purpose for this is to insure that drug levels 
remain in a safe and therapeutic range.  If renal function is changed at EA from Screening, 
dose adjustment will be required as per Table 5-2.  During treatment period other than 
EA, dose adjustment will be required on review of renal function conducted per local 
clinical practice.  
A urinary measured CrCl will be calculated at EA for patients with eGFR 
≥ 90 mL/min/1.73 m2 at Screening in order to determine if an additional adjustment is 
required.    
The adequacy of the proposed S-649266 dose regimen will be evaluated using PK data of 
patients treated by S-649266, if necessary. 
Table 5-2 
S-649266 Dosing Adjustments for Various Degrees of 
Renal Function and Augmented Renal Clearance 
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)a 
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  
Patient 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; ESRD = end-stage 
renal disease; HD = hemodialysis; MDRD-eGFR = modification of diet in renal disease-estimated 
glomerular filtration rate calculated with the MDRD equation; q6h = every 6 hours; q8h = every 8 hours; 
q12h = every 12 hours. 
a 
A CrCl will be calculated by Cockcroft-Gault equation at Screening.  A urine measured CrCl will be 
calculated by using timed urine collections of 2-8 hours at EA.  
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 an excessive exposure and complexity of clinical operation.  
c 
The dose will be determined based on MDRD-eGFR on non-dialysis days. 


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The dosage of BAT and adjunctive antibiotic therapy is based on the country specific 
package insert(s) and the discretion of the investigator.  Adjustments for renal 
impairment will be made according to each product label.  
The administration schedule of study after initial administration may be adjusted 
gradually, within reason and based on the clinical judgement 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 patient identification numbers by the IXRS® 
provider in a 2:1 fashion, ie, to S-649266 and BAT, respectively.  An interactive web or 
voice response system (IWRS/IVRS) will be used to assign patients to identification 
numbers for which treatment has already been randomly assigned.  Randomization will 
be performed by the stochastic minimization method using their infection site 
(HAP/VAP/HCAP, cUTI, and BSI/sepsis), APACHE II score (≤ 15 and ≥ 16), and region 
(N. America, S. America, Europe, and Asia-Pacific) as allocation factors.  To avoid 
deterministic allocation based on the ongoing allocation results, probabilistic allocation 
will be incorporated [19]. 
The investigator or designee will record the planned Standard of Care drug(s), drug dose, 
and dosing regimens, which would have been given if the patient was not participating in 
this clinical study, for both treatment groups (S-649266 or BAT) at the time the patient is 
to be randomized.  Once the centralized IWRS/IVRS has accepted and randomized the 
patient to either treatment group, the dispensing pharmacist will prepare for 
administration of the allocated treatment.  If BAT is allocated, please refer to 
Sections 5.2.2, 5.6.2, and 6.2 of protocol to confirm appropriate treatment options 
allowed within protocol. 
The population with HAP/VAP/HCAP will be approximately 50% of randomized 
patients; cUTI is limited to no more than 30% of randomized patients, and the remainder 
of patients will be enrolled under the BSI/sepsis diagnosis.  The randomization ratio of 
patients between treatment groups based on clinical diagnosis will be maintained through 
the allocation factor of clinical diagnosis at the time of randomization.  The process for 
patient number assignment and treatment assignment is described in the study procedure 
manual. 
The person or organization responsible for randomization will prepare and complete the 
randomization procedures/processes.  
5.5 
Blinding 
This is an open-label study.   
The number of approved drugs for treating carbapenem-resistant Gram-negative bacterial 
infection is very limited.  Choice of treatment is determined by multiple factors.  Because 
BAT cannot be defined in the protocol, blinding of this study is not possible.   


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5.6 
Packaging and Labeling, Storage and Accountability 
The investigator/site pharmacist will ensure that S-649266 drug supply is stored and 
dispensed in accordance with local health regulations concerning the storage and 
administration of investigational drugs.  All S-649266 drug supplies must be kept in a 
secure area at specified refrigerated temperatures with access limited to those authorized 
by the investigator. 
The investigator or pharmacist will maintain accurate records on the following 
information: receipt and condition of S-649266 drug supplies, date of the receipt, when 
and how much S-649266 is dispensed and used by each patient in the study, and any 
reasons for departure from the protocol-dispensing regimen.  The drug accountability 
records and the spent dosage vials of S-649266 will be available for verification by the 
Shionogi monitor, contract research organization (CRO) or designee at each monitoring 
visit.  If 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 
S-649266 drugs will be performed.  S-649266 must not be used for any purpose other 
than the present study. 
5.6.1 
S-649266 
S-649266 will be supplied to the study sites in containers which identify the contents, ie, 
not blinded.  The pharmacist or qualified designee who will prepare the infusion solutions 
will also adjust the dosages as described in Section 5.3.  The individual vials for 
S-649266 will be labeled with the name of active ingredient, protocol number, lot number, 
dosage form, strength, dosing instructions, medication ID number, storage conditions, 
caution statements, name and address of the manufacturer or sponsor as appropriate for a 
given country labeling requirements. 
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.   
Adjunctive antibiotic therapy for HAP/VAP/HCAP or BSI/sepsis patients will be locally 
sourced by study sites and will include only marketed drug products available through the 
investigator’s site pharmacy.  Investigational agents, a polymyxin (colistin or polymyxin 
B), and a cephalosporin/carbapenem including combination with beta-lactamase inhibitor 
(eg, ceftazidime/avibactam or ceftolozane/tazobactam) are not permitted as part of 
Adjunctive antibiotic therapy.  Adjunctive antibiotic therapy will be stored as specified 
by the label.  
5.6.2 
BAT 
BAT will be locally sourced by study sites and will include only marketed drug products 
available through the investigator's site pharmacy.  Investigational agents, including 
S-649266 are not permitted as part of BAT.  BAT will be stored as specified by the label. 


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5.7 
Investigational Product Retention at Study Site 
All unused study drug supplies (S-649266 only) 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 the unused drug supplies must be 
returned to the sponsor (or designee) as per the sponsor’s written instructions or 
destroyed as per the CRO's or local standard operating procedures upon agreement and 
written approval of the sponsor. 
5.8 
Treatment Compliance 
Dose, start times, and end times of the administration of intravenous treatments, and the 
approximate extent of completion of all infusions of S-649266, antibacterial agents used 
as BAT, and adjunctive antibiotics will be recorded in the electronic case report form 
(eCRF).  Any interruption or adjustment of the rate of an infusion will be noted in the 
eCRF.  The reason for interruption or adjustment will also be noted in the eCRF. 
5.8.1 
Changes in Treatment Regimen 
After initial administration of S-649266 or BAT, patients who have their treatment 
regimen altered for reasons of either 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. 


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6. RESTRICTIONS 
6.1 
Prior Therapy 
Prior therapies are defined as therapies which were taken prior to randomization of the 
study.   
Systemic antibiotic treatment or prophylaxis for Gram-negative pathogens including 
aerosolized antibiotics in patients with HAP/VAP/HCAP must be stopped before 
administration of study drug.   
Prior antibiotic therapy (oral or intravenous) taken by patient during the current during 
the current hospitalization until randomization into the study will be recorded in the 
eCRF and the information will include the name of drug used or procedures done, start 
and end dates, route of administrations and reason.   
Similarly, any prior therapy other than systemic antibiotics (prescription drugs, over-the-
counter drugs, procedures [eg, surgical or non-surgical related to infection treatment or 
treatment-related complications such as dialysis] with or without any medication) taken 
by patient within 2 weeks prior to randomization of the study will be recorded in the 
eCRF. 
6.2 
Concomitant Therapy during the Study 
6.2.1 
Antibiotic Therapies 
Concomitant antibiotic therapies are defined as therapies taken after randomization in the 
study.   
Additional antibiotics may be added to both S-649266 and BAT groups for concomitant 
Gram-positive or anaerobic infection or for infection prevention (prophylaxis).  Only 
narrow-spectrum agents lacking substantial Gram-negative activity are permitted (eg, 
vancomycin, daptomycin, linezolid, metronidazole, or clindamycin).  Topical antibiotics 
excluding aerosolized antibiotics will be permitted. 
The investigator, sub-investigator, or designee will record the following information for 
all therapies (prescription drugs, over-the-counter drugs, herbal preparation, and 
procedures without any medication) used during the study (from randomization 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 


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6.2.2 
Nonantibiotic Therapies and Procedures  
Concomitant therapies are defined as therapies including concomitant drugs to support 
blood pressure or renal output, antiviral agents, or antifungal therapy which 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, sub-investigator, or designee will record the following information for 
all therapies (prescription drugs, over-the-counter drugs, herbal preparation, and 
procedures without any medication) used during the study (from randomization 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 
6.2.3 
Prohibited Therapy 
For patients randomized to S-649266 
● Systemic antibiotics with Gram-negative activity, other than a single adjunctive 
Gram-negative antibiotic therapy for HAP/VAP/HCAP or BSI/sepsis patients 
initiated with the study drug, are not permitted until TOC 
● Aerosolized antibiotics are not permitted until TOC 
● Refer to the label of any adjunctive antibiotic therapy being used in combination 
with S-649266 for information about contraindicated therapies to those adjunctive 
antibiotic therapies 
For patients randomized to BAT 
● More than 3 systemic antibiotics with Gram-negative activity are not permitted 
until TOC 
● Aerosolized antibiotics are not permitted until TOC 
● Refer to label of BAT drugs for contraindicated therapies 
6.2.4 
Rescue Therapy 
There is no identified rescue treatment regimen.  No addition or substitution of any 
antibiotic after randomization is allowed unless the patient is assessed as a microbiologic 
or clinical failure in which case an EOT assessment should occur.  If a patient needs to be 
treated for longer than 21 days, an EOT visit should be performed as soon as possible 
after last dose (same calendar day) and the patient should be discontinued from the study 
treatment: 1) in the case of S-649266 (and the adjunctive antibiotic), treatment should 


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follow local clinical practice; 2) in the case of BAT, it should be continued or changed 
per local clinical practice.  All antibiotics will continue to be recorded in the eCRF until 
the completion of the EOS assessment. 


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7. STUDY PROCEDURES AND METHODS OF ASSESSMENTS 
In the case that a patient is screened and enrolled on the same day, the information 
requirements for the Screening (Day −2 to Day 1) and for Randomization (Day 1) are to 
be completed.  The requirements for the complete physical examination, vital signs, and 
clinical laboratory tests will be limited to only one set of tests. 
7.1 
Informed Consent 
The investigator or sub-investigator will fully explain the nature of the study to a patient 
or if unable to give consent him/herself, his/her legal guardian using the Institutional 
Review Board (IRB)/Institutional Ethics Committee (IEC)-approved informed consent 
document.  When the patient or his/her legal guardian agrees that he/she can participate 
in the study, the patient or his/her legal guardian 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 patient.  The signed and dated original consent 
form will be retained by the investigator.  Informed consent will be obtained from all 
patients.  A patient 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 patient who can only be enrolled with the consent of his/her legal guardian should be 
informed about the study when the patient is able to sign a consent during the study and, 
if capable, the patient should sign and personally date the written informed consent.  
(Note: Country specific rules and local Ethics Committee approval for legal guardian 
informed consent will determine whether or not a patient unable to comprehend or sign 
the informed consent is allowed to be enrolled in the study). 
The investigator or sub-investigator is responsible for ensuring that the patient 
understands the risks and benefits of participating in the study, including answering any 
questions the patient may have throughout the study and sharing any new information in 
a timely manner that may be relevant to the patient’s willingness to continue his/her 
participation in the study. 
Patient’s eligibility for the study may be determined through the use of diagnostics, some 
of which are investigational in the country where the protocol will be used. The use of 
investigational diagnostics or diagnostics that are not the local standard of care for 
determination of carbapenem resistance will require that the investigational diagnostics 
section of the informed consent be signed by the patient or legal guardian. 
7.2 
Baseline Patient Characteristics and Medical History 
The following baseline patient characteristics will be obtained upon entrance into the 
study and entered in the eCRF: age, sex, ethnicity, race, onset of infection, severity of 
infection, prior therapy, and medical history.  Medical history will include the following: 
• The detailed reason for current hospitalization 
• History of study qualifying infection and the cause of the infection if known at 
the time of enrollment (eg, recurrent pneumonia, BSI, cUTI, etc) with 


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microbiological information 
• Any previous, concurrent, or concomitant medical conditions meaningful to the 
current infection (eg, cancer, stroke, and myocardial infarction) 
• Conditions that required antibiotic treatment during current hospitalization, and 
the name and duration (calendar dates) of antibiotic treatment as well as relevant 
microbiological information 
• Tracheostomy during the hospitalization  
• History of other relevant surgical procedures that relate to the patient’s study 
infection 
• History of other major, clinically important infections (not same as study 
infection)  during the current hospitalization, including fungal or viral infections, 
with relevant microbiological information 
All patients must receive a clinical diagnosis of serious bacterial infection (cUTI, 
HAP/VAP/HCAP, or BSI/sepsis) presumably caused by a carbapenem-resistant Gram-
negative pathogen at the time of randomization.   
Screening/baseline assessments as part of the standard of care, eg, chest radiographs 
performed within 48 hours prior to randomization and safety laboratory tests obtained 
within 24 hours prior to randomization may be accepted for Screening/baseline. 
7.3 
Hospitalization 
Additional information to be entered into the eCRF to assist in the pharmacoeconomics 
evaluation are the date of hospitalization from 90 days prior to enrollment or current 
hospitalization date if the date of hospitalization is before 90 days of enrollment, 
throughout 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 ICU admission or isolation, initial/end date of treatment with 
ventilator, and status at EOS. 
7.4 
Physical Examination 
A complete physical examination will be performed at Screening.  A limited physical 
examination relevant to the patient’s current condition will be performed at the specified 
evaluation points (See Section 8 or Appendix 1).  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 
sub-investigator.  Clinically significant findings on physical examination will be recorded 
as an AE.  Weight and height will be entered in the eCRF.   
7.4.1 
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 Glasgow 
Coma Scale (GCS) according to Appendix 5, record it in the source document and use it 


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to complete the APACHE II and SOFA scores in the eCRF at the specified evaluation 
points.  In ventilated and sedated patients, the GCS cannot be properly assessed, and a 
normal score of 15 could be used to complete the APACHE II and SOFA scores.  
7.4.2 
APACHE II 
The components measurements, observations, and calculation of APACHE II system will 
be collected and used as a method to establish the severity of disease for a given patient.  
The APACHE II score will be collected and entered in the eCRF at Screening by the 
investigator or qualified designee based on Appendix 6.  If APACHE II components are 
measured multiple times, the highest APACHE II score recorded during the Screening 
period will be entered in the record.  If core temperature measurement is not available (ie, 
tympanic, rectal, esophageal), oral and axillary temperatures could be adjusted by adding 
0.5 °C or 1 °C, respectively.  
7.5 
Vital Signs 
Blood pressure (systolic/diastolic pressures), 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 the 24-hour day starting on Day 1 (calendar 
date) of the infusions and continuing while the patient is hospitalized and receiving 
treatment.  
For patients 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 sub-investigator will consider whether changes from baseline are 
clinically significant (See also Section 7.12.6).  Results of blood pressure, temperature, 
pulse rate, and respiratory rate will be entered in the eCRF. 
7.6 
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 patient has been in a supine or 
semi-recumbent position for several minutes.  Electrocardiograms obtained by the site 
within the 48 hours prior to signing 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.  QTc interval data will be 
calculated using Fridericia's correction (QTcF) by the electronic data capture system once 
the basic ECG data are entered therein. 


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The investigator or sub-investigator will assess whether the ECG is normal or abnormal, 
the investigator or sub-investigator will consider further whether the abnormal ECG is 
clinically significant (See also Section 7.12.6).  Results of the ECG 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 be reported as an AE. 
7.7 
Clinical Laboratory Tests 
7.7.1 
Microbiologic Cultures  
Appropriate clinical specimens will be obtained from all patients within 48 hours prior to 
the start of the infusion of the first dose of study treatment or clinical specimens obtained 
by the site within the 48 hours prior to signing ICF could be acceptable as 
screening/baseline cultures for this study.   
For patients who failed empiric treatment (as defined in general inclusion No. 4), clinical 
specimens obtained within 72 hours of randomization in this study could be used as 
screening/baseline cultures.  A culture should be done again upon randomization and the 
pathogen isolated sent to central lab. 
Biologic tissue or fluids for microbiologic cultures will be sent to the local laboratory for 
identification of all pathogens causing the infection.  After initiation of study treatment, 
appropriate clinical specimens will be obtained at the specified assessment time points 
(EA, EOT, TOC, FUP.  If it is not possible to obtain an appropriate clinical specimen 
after randomization, the reason (eg, no material available to culture) must be documented 
in the eCRF.  
In addition, 2 blood samples from separate venipunctures will be obtained from all 
patients regardless of the site of infection, within 48 hours prior to the start of study 
treatment and sent to the local laboratory.  Subsequent blood cultures are to be repeated 
only if the baseline blood culture is positive.  
Culture results should be recorded in the eCRF with the date of sampling and the 
reporting date and identified isolates sent to the central lab. 
In general, all specimens should also have Gram stain of infected material (not swab).  A 
report of both inflammatory cells and bacteria is necessary.   
Inappropriate clinical specimens should not be used for confirmatory culture 
identification of causative pathogens.   
Detailed procedures (Gram stain, quantitative or semi-quantitative cultures) per infection 
type are provided in Appendix 4.   
All isolated pathogens (Gram-positives, Gram-negatives, fungi and yeast) will be frozen 
and stored for later shipping to the central laboratory.  Detailed procedures for sample 


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collection, handling, labeling, storage, and shipping will be provided in the separate study 
procedure manual.  Shipping labels, instructions for shipping, and courier service will be 
provided from the sponsor or CRO. 
7.7.1.1 
Diagnostics for Initial Patient Qualification 
Patients are eligible for randomization only if there is documented evidence of a 
carbapenem-resistant Gram-negative pathogen from a suitable infection source.  Routine 
culture methods with susceptibility phenotype determination (MIC, Etest, or disc 
diffusion) using standard determination of susceptibility (breakpoints) based on local 
regulations would meet eligibility criteria.  Isolates considered intermediate, but not fully 
susceptible, will be considered carbapenem-resistant. 
In order to expedite appropriate treatment for the patient before the availability of 
standard susceptibility results, rapid diagnostic methods, or selective chromogenic media 
may be used to identify patients with carbapenem-resistant pathogens.  These may 
include marketed tests to determine the presence of carbapenem hydrolyzing enzymes 
(carbapenemases) or tests to determine the presence of genes indicating the presence of 
carbapenemases (polymerase chain reaction [PCR]) (Figure 7-1).  Tests available to the 
investigator through their local microbiology laboratory may be used.  Investigational 
rapid diagnostics may be provided and can be used to determine a patient’s eligibility for 
inclusion into this study.  A manual with details on investigational rapid diagnostics that 
may be provided along with instructions for use will be provided separately.  Rapid 
diagnostic result should be recorded in the eCRF. 
Although the rapid diagnostic tests may provide evidence of eligibility of patients for this 
study, all patients will require subsequent confirmation through microbiologic isolation 
and susceptibility testing of isolates obtained from appropriate clinical specimens.  The 
final study analysis will use the pathogen identification and susceptibility data provided 
by the central microbiology laboratory. 


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Figure 7-1 
Schematic of Clinical Specimen Handling 
 
CR-GNB = carbapenem-resistant Gram-negative bacilli; CR Micro-ITT = Carbapenem-
resistant Microbiological Intent-to-treat; lab = laboratory; PCR = polymerase chain 
reaction; RT = respiratory specimen   


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7.7.2 
Clinical Laboratory Parameters 
7.7.2.1 
Clinical Laboratory Tests 
Clinical laboratory tests are shown in Table 7-1.   
Table 7-1 
Clinical Laboratory Tests 
Category 
Evaluation Items 
Hematology Tests 
Hematocrit, Hemoglobin, Platelet count, RBC count, WBC count 
with differential and morphology indices 
INR and PTT 
Blood Chemistry 
Tests 
ALP, ALT, AST, GGT, LDH, CPK, CRP, and Amylase 
BUN, Creatinine, TBL 
Sodium (Na), Potassium (K), Bicarbonate (HCO3), Chloride (Cl), 
Calcium (Ca), Magnesium (Mg) 
Glucose, Total protein, Albumin, Uric acid, Total cholesterol 
Urinalysis 
Glucose, Blood, Protein, Ketones, Bilirubin, Urobilinogen, 
Leukocyte esterase, Microscopica (WBC, RBC, Crystal and casts) 
Specialized Tests  
Iron, TIBC, Transferrin iron saturation, and Hepcidin at Screening 
and TOC 
Others 
Serum or urine pregnancy: at Screening  
CrCl and eGFR at Screening and EA  
CrCl determined from a timed urine collection at EAb 
RBC = red blood cell; WBC = white blood cell; INR = international normalized ratio; PTT = partial 
thromboplastin time; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; GGT = gamma glutamyl transferase; LDH = lactate dehydrogenase; CPK = creatine 
phosphokinase; CRP = C-reactive protein; BUN = blood urea nitrogen; TBL = total bilirubin; TIBC = total 
iron-binding capacity; TOC = test of cure; CrCl = creatinine clearance; eGFR = estimated glomerular 
filtration rate; EA = early assessment   
a 
If sediment is present 
b 
For patient with eGFR ≥ 90 mL/min/1.73 m2 at Screening 
Blood and urine samples for clinical laboratory tests will be collected at specified times.  
Blood samples for all clinical laboratory tests will be collected in the fasted state, if 
possible.   
The samples other than some specialized tests will be measured at a local laboratory and 
results will be entered in the eCRF.  The samples for serum iron, TIBC, transferrin iron 
saturation, and hepcidin will be shipped to a central laboratory.  Details procedures for 
sample collection, handling, labeling, storage, and shipping will be provided in the 
separate study procedure manual.  Shipping labels, instructions for shipping and courier 
service will be provided from the sponsor or CRO. 
The investigator or sub-investigator will assess whether any abnormal changes from 
baseline are clinically significant (See also Section 7.12.6). 


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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.  
7.7.2.2 
Pregnancy Tests 
A serum or urine pregnancy test for females who are not postmenopausal or surgically 
sterile will be performed at Screening.  
7.7.2.3 
Creatinine Clearance 
Renal function measured by urinary clearance of creatinine may be monitored per local 
clinical practice and study drug dose adjustments made accordingly and recorded in the 
eCRF.  
7.7.2.3.1 
Creatinine Clearance Estimate 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 patients at Screening and EA and serum 
creatinine will be recorded in the eCRF.  If renal function has changed at EA from 
Screening, dose adjustment will be required as per Table 5-2.  The MDRD equation and 
the Cockcroft-Gault equation are as follows [36-38]: 
● 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 American) 
● Cockcroft-Gault equation 
Creatinine clearance (mL/min) = Weight × (140 − age in years)/(72 × sCr) × (0.85 
if female) 
where sCr is serum creatinine concentration (mg/dL) and Weight is body weight 
(kg). 
7.7.2.3.2 
Urine-Measured Creatinine Clearance 
For patients with eGFR ≥ 90 mL/min/1.73 m2 at baseline, urine samples will be collected 
for a time interval as short as 2 hours or up to 8 hours at EA.  Total volume of urine and 
urinary creatinine concentration or CrCl, which will be derived from the following 
calculation formula, will be measured and will be recorded in the eCRF. 
The CrCl calculated using timed urine collections, which is given by the following 
equation, will be performed for the patients suspected to have ARC (ie, eGFR ≥ 
90 mL/min/1.73 m2 at baseline) to confirm the presence of ARC. 


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Creatinine clearance (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 (hour). 
7.8 
Efficacy, and Safety Evaluations 
7.8.1 
General Evaluations 
7.8.1.1 
Vital Status 
The investigator or qualified designee will enter the date and cause of death in the eCRF 
if the patient dies during this study. 
The investigator or qualified designee will enter vital status (survival or death) in the 
eCRF at EOS. 
7.8.1.2 
SOFA 
The SOFA score is a scoring system to determine the extent of a patient's organ function 
or rate of failure.  The score is based on six different scores, one each for the respiratory, 
cardiovascular, hepatic, coagulation, renal and neurological systems.  The investigator or 
qualified designee will collect and enter the SOFA scores in the eCRF at the specified 
evaluation points based on Appendix 7.  In non-ventilated patients, a respiration score of 
zero may be assigned.   
7.8.1.3 
Oxygenation Status 
For patients receiving an oxygen inhalation treatment, the patient’s oxygenation status 
including PaO2, PaCO2, FiO2 and O2 saturation, will be determined by either pulse 
oximetry or by arterial blood gas measurements as relevant at the specified evaluation 
points and entered in the eCRF. 
7.8.1.4 
Ventilator Parameters 
For ventilated patients treated with S-649266, specified ventilator parameters (FiO2, 
PEEP, and pressure support [PS]) will be captured at the start of the infusion during 
which PK sampling will be taken (acceptable time window: 0 hours to end of infusion).  
The results will be entered in the eCRF. 
7.8.1.5 
Clinical Assessment of Signs and/or Symptoms 
General signs and/or symptoms of infection, including fatigue, chills/rigors, malaise, 
nausea, vomiting 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 patient during the course of the study will also 
be assessed.  The results will be entered in the eCRF. 


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7.8.2 
HAP/VAP/HCAP Specific Evaluations 
7.8.2.1 
Clinical Assessment of Signs and/or Symptoms 
Signs and symptoms specific to HAP/VAP/HCAP 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 patient during the course of the study will also be 
assessed.  The results will be entered in the eCRF. 
7.8.2.2 
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 
including body temperature, WBC, tracheal secretion, PaO2/FiO2 and chest radiograph.  
For non-ventilated patients who, based on local practice, do not have blood gasses done, 
a CPIS point value of zero may be assigned for the PaO2/FiO2 evaluation.  The total score 
will be entered in the eCRF at the specified evaluation points based on Appendix 8.  
7.8.2.3 
Chest Radiographs 
A chest x-ray (lateral and posterior/anterior [PA], or portable [when the patient’s 
condition does not permit transport to the radiology department]) will be performed at the 
specified evaluation points 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, preferably by a certified radiologist, will be 
entered in the eCRF. 
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. 
7.8.3 
Complicated Urinary Tract Infection Specific Evaluation 
7.8.3.1 
Clinical Assessment of Signs and/or Symptoms 
Specific signs and/or symptoms of infection, including dysuria, frequency, suprapubic 
pain, urgency, or flank pain/costovertebral angle tenderness, 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 patient during the 
course of the study will also be assessed.  The results will be entered in the eCRF. 


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7.8.4 
Blood Stream Infection/Sepsis Specific Evaluations 
7.8.4.1 
Clinical Assessment of Signs and/or Symptoms 
Clinical signs and/or symptoms of the infection which caused the BSI/sepsis 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 
patient during the course of the study will also be assessed.  The results including 
negative blood culture at Screening will be entered in the eCRF with the relevant 
sampling and reporting dates. 
7.9 
Pharmacokinetic Sample Collection, Storage, and Shipping 
7.9.1 
Pharmacokinetic Blood Sampling 
All patients treated with S-649266 will have blood drawn for sparse PK sampling of 
plasma concentrations of study drug.  The actual sampling date and time will be recorded.  
PK blood sampling will occur on Day 3 (after at least 6 doses of drug) at 4 timepoints: (1) 
just prior to the start of infusion, (2) 1 hour after start of infusion, (3) at the end of 
infusion, and (4) 1 hour after the end of the infusion.   
The date, actual time, and site of the PK sampling will be recorded in the eCRF. 
Patients with nonstable renal function resulting in a dosage adjustment (dose or interval) 
at EA will undergo another blood PK sampling (4 samples at the above specified 
timepoints) within 24 to 72 hours after their dosing adjustment.  The timing for PK blood 
draws is the same as timing on Day 3. 
If possible, a single blood sampling should be performed as soon as possible at EOT in 
the case of premature EOT (within 24 hours of last dose). 
Blood 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 study procedure manual.  Shipping labels, 
instructions for shipping and courier service will be provided from the sponsor or CRO. 
7.9.2 
Other Tissue or Body Fluid Sampling for Pharmacokinetics 
A sub-study may be developed to determine drug concentrations in ELF in patients with 
VAP receiving S-649266.  In addition, the sponsor may choose to initiate a sub-study to 
determine S-649266 tissue concentrations in body sites other than lung, eg, peritoneal 
fluid.  Any sub-study designed to determine drug concentrations of S-649266 would 
require a separate written informed consent by the patient or representative. 
7.10 Enrollment in the Study and Dispensing Study Drug 
After a patient is determined to be eligible according to the inclusion/exclusion criteria, 
the investigator, designee or study site pharmacist will contact the IWRS/IVRS for an 
identification number and specify the: 


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● Clinical diagnosis (HAP/VAP/HCAP, cUTI, or BSI/sepsis) 
● Calculated APACHE II score (≤ 15 and ≥ 16) 
● Region (North America, South America, Europe, and Asia-Pacific; automatically 
added by the IXRS system according to the site number) 
If the registration is accepted, the patient will be randomized to either treatment group. 
7.11 Efficacy Assessments 
7.11.1 
Efficacy Criteria for Infection Site Specific Clinical Outcomes for 
EA, EOT, and TOC 
The clinical outcomes will be assessed by the investigator according to the following 
criteria established for each infection site 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. 
7.11.1.1 
HAP/VAP/HCAP 
● 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 antibacterial therapy is required for the treatment of the current infection.  
● 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. 
Applicable only to Germany due to local requirements:  If a chest X-ray is not 
performed because of standard of care at the site, clinical assessment will be done 
without chest X-ray.   
7.11.1.2 
cUTI  
● Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms of cUTI, or return to pre-infection baseline if known, such that no 
antibacterial therapy is required for the treatment of the current infection. 
● Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms of cUTI; or reappearance of signs and/or 
symptoms of cUTI; development of new signs and/or symptoms of cUTI 
requiring antibiotic therapy other than, or in addition to, study treatment therapy; 
or death due to cUTI.  


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● Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 
7.11.1.3 
BSI/Sepsis  
● Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms including a reduction in SOFA score, such that no antibacterial therapy 
is required for the treatment of BSI/sepsis.  Patients with bacteremia must have 
eradication of bacteremia caused by the Gram-negative pathogen. 
● Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms, reappearance of signs and/or symptoms; 
development of new signs and/or symptoms requiring antibiotic therapy other 
than, or in addition to, study treatment therapy; or death due to BSI/sepsis. 
● Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 
7.11.2 
Clinical Outcomes for FUP 
The clinical outcomes will be assessed by the investigator according to the following 
criteria established for each infection site at FUP.  The clinical outcomes will be entered 
in the eCRF. 
7.11.2.1 
HAP/VAP/HCAP 
● Sustained Clinical Cure: Continued resolution or substantial improvement of 
baseline signs and symptoms of pneumonia, such that no antibacterial therapy is 
required for the treatment of pneumonia in a patient assessed as cured at TOC.  
● Relapse: Recurrence of signs and/or symptoms of pneumonia, appearance of new 
signs and/or symptoms of pneumonia, new chest radiographic evidence of 
pneumonia, or death due to pneumonia in a patient assessed as cured at TOC. 
● Indeterminate: Lost to follow-up such that a determination of clinical sustained 
cure/relapse cannot be made, or patient received additional antibacterial therapy 
for the treatment of the current infection. 
7.11.2.2 
cUTI  
● Sustained Clinical Cure: Continued resolution or improvement of baseline signs 
and symptoms of cUTI, or return to pre-infection baseline if known, in a patient 
assessed as cured at TOC. 
● Relapse: Recurrence of signs and/or symptoms of cUTI, or appearance of new 
signs and/or symptoms of cUTI in a patient assessed as cured at TOC.  
● Indeterminate: Lost to follow-up such that a determination of clinical sustained 
cure/relapse cannot be made, or patient received additional antibacterial therapy 
for the treatment of the current infection. 


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7.11.2.3 
BSI/Sepsis  
● Sustained Clinical Cure: Continued resolution or substantial improvement of 
baseline signs and symptoms associated with reduction in SOFA score, such that 
no antibacterial therapy is required for the treatment of the patients original 
BSI/sepsis in a patient assessed as cured at TOC.  
● Relapse: Recurrence of signs and/or symptoms of BSI/sepsis, appearance of new 
signs and/or symptoms of the patients original BSI/sepsis, or death due to 
BSI/sepsis in a patient assessed as cured at TOC. 
● Indeterminate: Lost to follow-up such that a determination of clinical sustained 
cure/relapse cannot be made, or patient received additional antibacterial therapy 
for the treatment of the current infection. 
7.11.3 
Microbiological Outcomes for EA, EOT, and TOC 
An overall per-patient microbiological outcome will be determined based on the 
individual microbiological outcomes for each baseline pathogen.  The microbiological 
outcomes determined by investigator will also be entered in the eCRF. Emergent (ie, non-
baseline) pathogens are considered separately, and do not affect the per-patient 
microbiological outcome.  
Separately, the microbiological outcomes by baseline pathogen will be determined by the 
sponsor according to the following criteria established for each infection site at EA, EOT, 
and TOC.  In case treatment duration is extended beyond 14 days, an additional 
microbiological outcome will be assessed on Day 14.   
7.11.3.1 
HAP/VAP/HCAP 
● Eradication: Absence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen.  If it is not possible to obtain an appropriate clinical 
culture and the patient has a successful clinical outcome, the response will be 
presumed to be eradication. 
● Persistence: Continued presence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen.  
● Indeterminate: No culture obtained from an appropriate clinical specimen or 
additional antibacterial therapy for the treatment of the current infection including 
missed sampling.  
7.11.3.2 
cUTI 
● Eradication: A urine culture shows the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFU/mL are reduced to < 103 CFU/mL. 
● Persistence: A urine culture shows that the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFU/mL grows ≥ 103 CFU/mL.  
● Indeterminate: No urine culture obtained or additional antibacterial therapy for 
the treatment of the current infection including missed sampling.  


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7.11.3.3 
BSI/Sepsis 
● Eradication: Absence of the baseline Gram-negative pathogen from a blood 
culture and/or other primary source as applicable.  In the case of sepsis, if the 
patient has a successful clinical outcome and it is not possible to obtain an 
appropriate clinical culture, the response will be presumed to be eradication. 
● Persistence: Continued presence of the baseline Gram-negative pathogen from a 
blood culture or other primary source. 
● Indeterminate: No culture obtained or additional antibacterial therapy for the 
treatment of the current infection including missed sampling.  
7.11.4 
Microbiological Outcomes for FUP 
An overall per-patient microbiological outcome will be determined based on the 
individual microbiological outcomes for each baseline pathogen.  The microbiological 
outcomes determined by investigator will also be entered in the eCRF.  
Separately, the microbiological outcomes by baseline pathogen will be determined by the 
sponsor according to the following criteria established for each infection site at FUP.   
7.11.4.1 
HAP/VAP/HCAP 
● Sustained Eradication: Absence of the baseline Gram-negative pathogen from 
an appropriate clinical specimen after TOC.  If it is not possible to obtain an 
appropriate clinical culture and the patient 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 is negative.   
● Indeterminate: No culture obtained from an appropriate clinical specimen or 
patient received additional antibacterial therapy for the treatment of the current 
infection including missed sampling. 
7.11.4.2 
cUTI 
● Sustained Eradication: A culture taken any time after documented eradication at 
TOC, and a urine culture obtained at FUP shows that the baseline uropathogen 
found at entry at ≥105 CFU/mL remains < 103 CFU/mL. 
● Recurrence: A culture taken any time after documented eradication at TOC, up 
to and including FUP that grows the baseline uropathogen ≥ 103 CFU/mL  
● Indeterminate: No urine culture or patient received additional antibacterial 
therapy for the treatment of the current infection including missed sampling. 
7.11.4.3 
BSI/Sepsis 
● Sustained Eradication: Absence of the baseline Gram-negative pathogen from a 
blood culture or other primary source after TOC as applicable.  In the case of 
sepsis, if the patient has a successful clinical outcome after TOC and it is not 


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possible to obtain an appropriate clinical culture, the response will be presumed to 
be sustained eradication. 
● Recurrence: Recurrence of the baseline Gram-negative pathogen from a blood 
culture or other primary source after TOC, and the TOC culture is negative.   
● Indeterminate: No culture or patient received additional antibacterial therapy for 
the treatment of the current infection including missed sampling. 
7.11.5 
New Pathogens 
New pathogens that emerge after study therapy is started will be categorized as either 
superinfection or new infection as follows: 
● Superinfection: The identification from an appropriate clinical specimen of a 
new pathogen from the original infection site.  This new pathogen must be 
associated with new or persisting signs and symptoms of infection. 
● New Infection: The identification from an appropriate clinical specimen of a new 
pathogen from an infection site different from the original infection site.  This 
new pathogen must be associated with new or persisting signs and symptoms of 
infection.   
7.12 Adverse Events Assessments 
7.12.1 
Performing Adverse Events Assessments 
An AE is defined as any untoward medical occurrence in a patient 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.  
Adverse events will be found by the patient's spontaneous complaint, patient comment 
cards, or as a result of nonleading questions, physical examination, vital signs, or 
laboratory tests.  AEs 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 which are reported at the baseline and worsen will be considered as AEs.  Lack 
of efficacy, aggravation, or relapse of current infection are not an AE in the study and 
therefore also not an SAE (except death).   
The investigator or sub-investigator is responsible for assessing AEs.  AEs should be 
fully investigated and recorded in detail including 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. 


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7.12.2 
Timing 
AEs will be collected from the time of having signed informed consent through 28 days 
after the last dose of the study treatment for randomized patients.  If a patient withdraws 
early from the study, the investigator or sub-investigator will make an effort to collect 
AEs for 28 days after the last dose of the study treatment.  Any ongoing AE 28 days after 
the last dose of study treatment will be followed until resolution, stabilization, the 
condition becomes chronic, or the patient is lost to follow-up.   
7.12.3 
Severity 
The severity of an event will be graded by the investigator or sub-investigator according 
to the following definitions: 
● Mild: A finding or symptom is minor and does not interfere with usual daily 
activities. 
● Moderate: The event causes discomfort and interferes with usual daily activity or 
affects clinical status. 
● Severe: The event causes interruption of the patient'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. 
7.12.4 
Relationship 
The relationship of an event to the study treatment will be determined by the investigator 
or sub-investigator according to the following criteria: 
● Related: An AE which can be reasonably explained as having been caused by the 
study treatment.  
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 which cannot be reasonably explained as having been 
caused by the study treatment.  
7.12.5 
Expectedness 
Expected AEs for S-649266 are listed under Expected Adverse Reactions in Section 
“Undesirable Effects” of the “Summary of Data and Guidance for Investigators” in the 
current Investigator's Brochure for S-649266.  The expected AEs for the drugs that are a 
part of the BAT will be those found in the EMA Summary of Product Characteristics 


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(SmPCs) for those products.  The US Package Insert will be used if the SmPC is not 
available.  Expectedness will be assessed by the sponsor.   
7.12.6 
Clinical Laboratory Adverse Events 
For any abnormal laboratory test results (hematology, blood chemistry, or urinalysis) or 
other safety assessments (eg, physical examination, vital signs, ECG) that are worsening 
from baseline or occur thereafter in the course of the study, the investigator or 
sub-investigator will consider whether these results are clinically significant.  Abnormal 
laboratory test results are defined as values outside the reference range.  Any test results 
which are considered to be clinically significant by the investigator or sub-investigator 
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 sub-investigator will consider test results to be clinically significant in 
the following circumstances: 
● 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 drug 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 Appendix 9. 
7.12.6.1 
Liver Abnormalities 
Management and Discontinuation Criteria for Abnormal Liver Function tests have been 
designed to ensure patient safety and evaluate liver event etiology.  The investigator or 
sub-investigator must review study patient laboratory results as they become available to 
identify if any values meet the criteria in Appendix 9.  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. 
7.12.7 
Serious Adverse Events 
7.12.7.1 
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  
● Persistent or significant disability/incapacity 
● Congenital anomaly/birth defect 


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● 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 patient and may require medical intervention to prevent one 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 inpatient hospitalization, or the 
development of drug dependency or drug abuse.  Test results that meet the criteria of 
Hy’s law are considered SAEs (Appendix 9).  The investigator or sub-investigator 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 is met).  A hospitalization or prolongation of hospitalization for reasons other 
than an AE would not be considered an SAE.   
7.12.7.2 
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 of 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 (EDC) or by phone or fax if 
EDC is not available. 
CRO SAE hotline – North America and South America: 
Telephone: 
 
Fax: 
 or 
 
 
OR  
CRO SAE hotline – Europe and Asia-Pacific: 
Telephone: 
 


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Fax: 
 
 
If the sponsor requires a follow-up assessment, the investigator should provide new 
information as it becomes available and then report to CRO or the sponsor.  Discharge 
summaries, consultant reports, autopsy reports, or other relevant documents must be 
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 patient’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 AE assessment period specified in Section 7.12.2, that is 
considered to be related to study drug by the investigator must be reported to CRO or the 
sponsor. 
The investigator will be responsible for reporting all SAEs to the IRB or IEC and CRO or 
the sponsor.  The sponsor will be responsible for reporting SAEs to the regulatory 
authorities as required by the applicable regulatory requirements. 
7.12.8 
Special Situations-Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication errors (as defined below) in patients treated with 
S-649266 must be reported by the investigator to CRO or sponsor via fax using a Special 
Situations Report Form within 24 hours of becoming aware (Refer to Section 7.12.7.2 for 
reporting destination).  If there are associated SAEs, the investigator will report an SAE 
as well. 
● Abuse: Persistent or sporadic, intentional excessive use of an investigational 
product(s), which is accompanied by harmful physical or psychological effects. 
● Misuse: Intentional and inappropriate use of an investigational product(s) other 
than as directed or indicated at any dose.   
● Overdose: Intentional or unintentional intake of a dose of investigational 
product(s) 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(s).  Medication errors are reportable 
only as defined below.   
The administration or consumption of the unassigned treatment is always 
reportable as a medication error.   
Administration of an expired product should be considered as a reportable 
medication error.   


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7.12.9 
Pregnancy 
Women of child bearing potential will be screened for pregnancy at the time of study 
enrollment.  A positive test is reason for exclusion.  Patients will be instructed to avoid 
conception until 28 days (EOS) following treatment (EOT) or according to country 
specific requirements, whichever is longer.   
If a female patient in S-649266 group becomes pregnant during the study, investigator or 
sub-investigator will immediately discontinue study drug.  All pregnancies that occur 
after the first dose of the study treatment through the follow-up period (EOS) must be 
reported within 24 hours of becoming aware of the pregnancy and the Pregnancy Form 
will be reported to CRO or the sponsor by the investigator (Refer to Section 7.12.7.2 for 
reporting destination).  Pregnancy complications and elective terminations for medical 
reasons must be reported as an AE or SAE 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, to 
CRO or the sponsor.   
7.12.10 Treatment-Emergent Adverse Events 
AEs reported after the initial dose of randomized study or control treatment will be 
considered treatment-emergent adverse events (TEAE). 
7.13 Withdrawal or Discontinuation of Patients from the Study or 
Study Treatment 
The investigator will make every reasonable attempt to complete the study for each 
enrolled patient.  A patient 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 
patient from the study by using the IWRS/IVRS. 
The investigator or sub-investigator will discontinue a patient from the study treatment 
for any of the following reasons.  Please note that unless the patient withdraws consent to 
participate in the study, all randomized patients should be followed for the entire duration 
of the study: 
● A serious or intolerable AE occurs and the investigator considers that the patient 
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 patient should be withdrawn.  
● The patient requests to be withdrawn from the study. 
● The patient is lost to follow-up. 
● The investigator determines that the patient should be withdrawn because of other 
reasons. 
For patients who withdraw or are discontinued by the investigator or sub-investigator at 
any time after the start of treatment, they are still considered to be in the study, and they 


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should still be followed through to the completion of all study activities, ie, EOT, TOC, 
FUP, and EOS, if at all possible.  All withdrawn or discontinued patients will remain in 
the study for safety and clinical outcome purposes. 
All patients 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 patient is lost 
to follow-up. 
Patients who withdraw or are 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). 
7.14 Appropriateness of Measurements 
The measures of efficacy selected in the study differ for each of the 3 groups of infection, 
but in general includes both clinical and microbiologic outcome.  The specific endpoints 
based on the EMA guidance [17] have been discussed with regulatory agencies.   
The safety evaluations selected for the study are typical of those for this patient 
population and type of investigation, and utilize widely accepted measures.   
7.15 Acceptable Time Windows 
Measurements for efficacy or safety endpoints will be performed according to the 
schedule of assessments as shown in Appendix 1.  The following time window, as 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 Blood PK 
Sampling  
Day 3 
+ 2 days 
Day 3 Blood PK 
Sampling   
(This sample 
should be drawn 
after the patient 
had at least 6 
infusions) 
Just prior to the next infusion 
–1 to 0 hours 
One (1) hour into the infusion 
± 15 minutes  
At the end of infusion  
–15 minutes to end of 
infusion 
One (1) hour after end of infusion 
(four [4] hours after the start of 
infusion) 
± 0.5 hours 
EA 
Day 3 to 4  
+ 1 day 
EOT 
Last day of study treatment 
As soon as possible after last 
dose (within 24 hours after 
the last dose) 
TOC 
EOT + 7 
 2 days 
FUP 
EOT +14  
 3 days 
EOS 
EOT +28 
 3 days 


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8. STUDY ACTIVITIES 
The overall schedule of events for the study is presented in Appendix 1. 
8.1 
Screening (Day –2 to Randomization)  
● Informed consent 
● Appropriate clinical specimens will be obtained from all patients within 48 hours 
prior to the start of the infusion of the first dose of study treatment including 
blood for culture.  Clinical specimens obtained by the site within the 48 hours 
prior to signing ICF could be acceptable as screening/baseline cultures for this 
study. 
● Rapid diagnostics for the presence of a carbapenemase (if necessary) 
If any diagnostics provided by the sponsor are considered investigational in the 
country where the protocol is implemented are to be used, or diagnostics that are 
not the local standard of care for determination of carbapenem resistance are to be 
used, the investigational diagnostics section of the informed consent form will be 
required. (See Section 7.1) 
● Inclusion and exclusion criteria assessments 
● Baseline patient characteristics 
● Medical history 
● Physical examination including height and body weight 
● Vital signs (including blood pressure, body temperature, pulse rate, and 
respiratory rate) 
● 12-lead ECG 
● Pregnancy test if applicable 
● Clinical laboratory tests (hematology, blood chemistry, urinalysis, specialized 
tests and others; see Table 7-1) 
● Glasgow Coma Scale 
● Calculate APACHE II score 
● Calculate SOFA score 
● Provide parameters for CPIS score (HAP/VAP/HCAP patients) 
● Clinical assessment of signs and/or symptoms 
● Oxygenation status (patients receiving an oxygen inhalation treatment) 
● Chest radiographs (HAP/VAP/HCAP patients) 
● Biologic tissue or fluids (including blood) for microbiological culture 
● AE assessment (begins with the signing of the informed consent form and 
continues through to the EOS)  
● Prior and concomitant therapies 
● Hospitalization 


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8.2 
Treatment Period (Day 1 to up through Day 14) 
8.2.1 
Randomization and Treatment Initiation Day 1 
● Randomize patient via IWRS or IVRS 
● Initiate treatment based on eGFR and CrCl by Cockcroft-Gault equation 
8.2.2 
All Treatment Days  
● Continue randomized treatment  
● Vital signs including body temperature 
● Concomitant therapy 
● AE assessment 
● Hospitalization 
● Vital status (survival) 
● Dose adjustment considered on review of renal function conducted per local 
clinical practice (If necessary) 
8.2.3 
Treatment Day 3 
● Activities for all treatment days (See Section 8.2.2) 
● Blood PK samples (after at least 6 infusions) for patients receiving S-649266 
● Ventilator parameters at the timing of blood PK sampling for ventilated patients 
(See Section 7.8.1.4) 
8.2.4 
Early Assessment (EA) (Occurs once at investigator’s discretion 
during Days 3 to 4) 
● Activities for all treatment days (See Section 8.2.2) 
● Limited physical examination relevant to the patient’s current condition 
● Clinical laboratory tests (hematology, blood chemistry, urinalysis, and others;  
see Table 7-1) 
● Glasgow Coma Scale 
● Calculate SOFA score 
● Provide parameters for CPIS score (HAP/VAP/HCAP patients) 
● Clinical assessment of signs and/or symptoms 
● Oxygenation status (patients receiving an oxygen inhalation treatment) 
● Chest radiographs (HAP/VAP/HCAP patients) 
● Biologic tissue or fluids (including blood until result is negative) for 
microbiological culture 
● Assess clinical outcome 
● Assess microbiological outcome 
● Dosing adjustment if renal function is changed 
● Blood PK samples for patients with nonstable renal function resulting in a dosing 


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adjustment at EA (S-649266 group only) (See Section 7.9.1) 
● Ventilator parameters at the timing of blood PK sampling for ventilated patients 
(See Section 7.8.1.4) 
8.2.5 
Treatment Day 14 
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 patient’s current condition 
● Clinical laboratory tests (hematology, blood chemistry, and urinalysis;  
see Table 7-1) 
● Glasgow Coma Scale 
● Calculate SOFA score 
● Provide parameters for CPIS score (HAP/VAP/HCAP patients) 
● Clinical assessment of signs and/or symptoms 
● Oxygenation status (patients receiving an oxygen inhalation treatment) 
● Chest radiographs (HAP/VAP/HCAP patients) 
● Biologic tissue or fluids (including blood until result is negative) for 
microbiological culture 
● Assess clinical outcome 
● Assess microbiological outcome 
8.2.6 
Last Day of Study Treatment (EOT)  
● Activities for all treatment days (See Section 8.2.2) 
● Limited physical examination relevant to the patient’s current condition 
● Clinical laboratory tests (hematology, blood chemistry, and urinalysis;  
see Table 7-1) 
● Glasgow Coma Scale 
● Calculate SOFA score 
● Provide parameters for CPIS score (HAP/VAP/HCAP patients) 
● Clinical assessment of signs and/or symptoms 
● Oxygenation status (patients receiving an oxygen inhalation treatment) 
● Chest radiographs (HAP/VAP/HCAP patients) 
● Biologic tissue or fluids (including blood until result is negative) for 
microbiological culture 
● Assess clinical outcome 
● Assess microbiological outcome 


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8.3 
Test of Cure (TOC [EOT + 7 days])  
● Limited physical examination relevant to the patient’s current condition 
● Vital signs (including blood pressure, body temperature, pulse rate, and 
respiratory rate)  
● Clinical laboratory tests (hematology, blood chemistry, urinalysis, and specialized 
tests; see Table 7-1) 
● Clinical assessment of signs and/or symptoms 
● Oxygenation status (patients receiving an oxygen inhalation treatment) 
● Chest radiographs (HAP/VAP/HCAP patients) (if indicated) 
● Biologic tissue or fluids (including blood until result is negative) for 
microbiological culture 
● Glasgow Coma Scale 
● Calculate SOFA score 
● Provide parameters for CPIS score (HAP/VAP/HCAP patients) 
● AE assessment 
● Concomitant therapy 
● Assess clinical outcome 
● Assess microbiological outcome 
● Hospitalization 
8.4 
Follow-up (FUP [EOT + 14 days]) 
● Limited physical examination relevant to the patient’s current condition 
● Vital signs (including blood pressure, body temperature, pulse rate, and 
respiratory rate)   
● Clinical laboratory tests (hematology, blood chemistry, and urinalysis;  
see Table 7-1)  
● Clinical assessment of signs and/or symptoms 
● Oxygenation status (patients receiving an oxygen inhalation treatment) 
● Chest radiographs (HAP/VAP/HCAP patients) (if indicated) 
● Biologic tissue or fluids (including blood until result is negative) for 
microbiological culture (if indicated) 
● Glasgow Coma Scale 
● Calculate SOFA score 
● Provide parameters for CPIS score (HAP/VAP/HCAP patients) 
● AE assessment 
● Concomitant therapy 
● Assess clinical outcome 
● Assess microbiological outcome 
● Hospitalization 


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8.5 
End of Study (EOS [EOT + 28 days]) 
● Limited physical examination relevant to the patient’s current condition 
● Vital signs (including blood pressure, body temperature, pulse rate, and 
respiratory rate)  
● Clinical laboratory tests (hematology, blood chemistry, and urinalysis;  
see Table 7-1) if required to follow abnormal safety test results 
● AE assessment 
● Concomitant therapy 
● Hospitalization 
● Vital status (survival or death)  
EOS assessments may be performed by phone to document current patient status, in 
which case, the physical examination, vital signs, and laboratory tests will not be 
performed.  Any AEs ongoing at EOS (28 days after the last dose of study treatment) will 
be followed as specified in Section 7.12.2.  Continuing laboratory changes that are 
considered significant and symptoms related to AEs should be followed until resolution, 
AEs are judged by the investigator to have stabilized, or the patient is lost to follow-up.  
Pregnancies should be followed as specified in Section 7.12.9. 


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9. PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The statistical efficacy analysis and PK analyses will be performed by the sponsor or 
designee.  The detailed statistical analysis methods will be specified in a statistical 
analysis plan (SAP).  Deviations from analyses outlined in the protocol will be detailed 
and justified in the SAP.  The SAP will be finalized before scheduled database lock.  A 
separate detailed PK/PD analyses plan will also be prepared.   
Unless otherwise noted, continuous variables will be summarized by using the number of 
non-missing observations, arithmetic mean, standard deviation (SD), median, minimum, 
and maximum values as descriptive statistics; categorical variables will be summarized 
by using the frequency count and the percentage of patients in each category as 
descriptive statistics.   
All patient study data, including data not appearing in tables, will be presented in by-
patient data listings.  In general, all tables and associated graphics will be presented by 
treatment group.  Individual patient data, PK data, and any derived data will be presented 
by treatment and patient.  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. 
If statistical tests are performed, they will be performed at the 0.05 significance level 
using 2-sided tests, except where otherwise noted.  No multiplicity adjustment of 
statistical tests will be applied in this study. 
9.2 
Determination of Sample Size  
Given the challenges involved in recruiting patients meeting the criteria for inclusion in 
this study, and, after discussions with the EMA, it was agreed that approximately 
150 patients will be enrolled and randomized 2:1 to S-649266 and BAT, respectively.  
This sample size will ensure that approximately 100 patients are treated with S-649266. 
9.3 
Analysis Populations 
The following analysis populations will be examined in this study:  
● Intent to Treat (ITT) population: All randomized patients who received at least 1 
dose of the study treatment.  
● Microbiological Intent to Treat Population (Micro-ITT): All ITT patients who 
have a baseline Gram-negative pathogen from an appropriate clinical specimen.  
Patients should not be excluded from this population based upon events that 
occurred post randomization (eg, loss to follow-up).  
● Carbapenem-Resistant Microbiological Intent to Treat Population (CR Micro-
ITT): All Micro-ITT patients whose baseline Gram-negative pathogen is 
carbapenem-resistant. 


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● Carbapenem-Resistant Microbiologically Evaluable Population (CR-ME): 
includes all CR Micro-ITT patients who follow important components of the 
study as specified in the protocol with no major protocol violations.   
Criteria for inclusion are:   
▪ ≥ 5 days of intravenous (IV) study treatment unless treatment was a failure 
▪ Underwent TOC assessment 
▪ Patients without any major protocol inclusion or exclusion violations 
▪ Patients with no violations of restrictions for concomitant therapy including 
concomitant antibiotic(s) effective against Gram-negative bacteria  
● Safety population includes all randomized patients who receive at least 1 actual 
dose of the study treatment (ITT population).  The population will be analyzed 
according to the treatment that the patients actually received, rather than the 
treatment to which the patients were randomized. 
● The PK concentration population includes all patients who undergo plasma 
sampling and have at least one evaluable PK assay result for S-649266.  This 
population will be used for the concentration listing, plotting of the concentration-
time data and the concentration summary. 
9.4 
Handling of Missing Data 
Missing data will not be replaced. Details will be defined in SAP. 
9.5 
Patient Disposition 
Among the randomized patients in the safety population, and the ITT population, and the 
Micro-ITT population, the number and percentage of patients who complete the study 
and those of patients who prematurely discontinue 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 patients for the randomized patients included in 
each analysis population will also be presented. 
9.6 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized with descriptive statistics 
for the ITT population, the CR Micro-ITT population. 
9.7 
Prior Therapies 
Prior therapies for drugs will be coded using the World Health Organization Drug 
Dictionary (WHO-DD).  Patients who received prior therapy(ies) will be listed and 
summarized for the safety population and the CR Micro-ITT population.   
9.8 
Concomitant Therapies 
Concomitant therapies for drugs will be coded using WHO-DD.  Patients who received 
concomitant therapy(ies) will be listed and summarized for the safety population and the 
CR Micro-ITT population.   


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9.9 
Efficacy Analyses 
The CR Micro-ITT population will be the primary population for efficacy analyses 
(primary and secondary efficacy analyses).  The CR-ME population and the Micro-ITT 
population will be used for assessing the robustness of the conclusions.   
9.9.1 
Primary Efficacy Endpoint 
● Clinical outcome per patient at TOC in patients with HAP/VAP/HCAP or 
BSI/sepsis 
● Microbiologic outcome (for Gram-negative pathogen) per patient at TOC in 
patients with cUTI 
9.9.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the following variables:  
● Clinical outcome per patient at EOT and FUP (HAP/VAP/HCAP or BSI/sepsis) 
● Clinical outcome per pathogen at EOT, TOC, and FUP (HAP/VAP/HCAP or 
BSI/sepsis) 
● Clinical outcome per patient/pathogen at EOT, TOC, and FUP (cUTI) 
● Microbiologic outcome (for Gram-negative pathogen) per patient/pathogen at 
EOT, TOC, and FUP (HAP/VAP/HCAP or BSI/sepsis) 
● Microbiologic outcome (for Gram-negative pathogen) per patient at EOT, and 
FUP (cUTI) 
● Microbiologic outcome (for Gram-negative pathogen) per pathogen at EOT, TOC, 
and FUP (cUTI) 
● Microbiologic outcome with documented carbapenem-resistant Gram-negative 
bacteremia (regardless of primary infection diagnosis) at EOT, TOC, and FUP 
● Composite clinical and microbiologic outcome at EOT, TOC, and FUP  
● All-cause mortality at Day 14 and Day 28 for HAP/VAP/HCAP and BSI/sepsis  
● Composite endpoint of survival and no change in antibiotic treatment due to either 
lack of therapeutic benefit or drug-related toxicity at TOC 
● Survival time (HAP/VAP/HCAP, BSI/sepsis) 
● CPIS parameters at EOT and TOC (HAP/VAP/HCAP only) 
● SOFA Score at EOT, and TOC 
9.9.2.1 
Composite Clinical and Microbiologic Outcome for cUTI 
The composite clinical and microbiologic outcome for cUTI will be determined by the 
sponsor based on both the clinical and microbiologic outcomes:  
Clinical and microbiologic response: Clinical cure/Sustained clinical cure in clinical 
outcomes (resolution or improvement of the signs and symptoms of cUTI or return to 
pre-infection baseline if known) and Eradication/Sustained eradication in 
microbiological outcomes (microbiological success) at each scheduled timepoint. 


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Clinical or microbiologic failure: Clinical failure/Relapse in clinical outcomes, or 
Persistence/Recurrence in microbiological outcomes.  
9.9.2.2 
Per Patient Microbiological Outcome 
A per-patient microbiological outcome is determined based on individual microbiological 
outcomes for each baseline pathogen.  For the patient to have a favorable microbiological 
outcome (ie, eradication), the outcome for each baseline pathogen has to be favorable (ie, 
all baseline pathogens are eradicated at the specified timepoint).  If the microbiological 
outcome for any pathogen is unfavorable, the patient is considered to have an unfavorable 
overall (per-patient) microbiological outcome. 
9.9.3 
Primary Efficacy Analyses 
Descriptive statistics will be provided.  For patients with HAP/VAP/HCAP or BSI/sepsis, 
the clinical response rates by treatment group and the 95% CIs will be calculated.  Also 
for the patients with cUTI, microbiological response rates by treatment group and the 
95% CIs will be calculated. 
Details for the primary efficacy analyses will be discussed in the SAP. 
9.9.4 
Secondary Efficacy Analyses 
The secondary endpoint of clinical response rates and microbiological response rates by 
treatment group and the 95% CIs will be calculated.   
Composite clinical and microbiologic response rates by treatment group and the 95% CIs 
will be calculated.   
Survival analysis of all-cause mortality will be performed. 
The response rate of a composite endpoint of survival and no change in antibiotic 
treatment due to either lack of therapeutic benefit or drug-related will be compared 
between treatment groups by infection site (HAP/VAP/HCAP, cUTI, or BSI/sepsis) at 
TOC.  
SOFA and CPIS (ventilated only) scores by infection site as relevant will be summarized 
by timepoint.   
Descriptive statistics for all efficacy parameters will be provided. 
Details for the secondary efficacy analyses will be discussed in the SAP. 
9.10 Safety Analyses 
Safety assessments include AEs, mortality for up to EOS, clinical laboratory tests 
(hematology, chemistry, and urinalysis), and vital signs.  Safety analyses will be 
performed for the safety population. 


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9.10.1 
Adverse Events 
AEs will be classified by system organ class and preferred term using Medical Dictionary 
for Regulatory Activities (MedDRA).  Of reported AEs on the eCRF, TEAEs will be 
used for safety analyses.  The definition of TEAE is described in Section 7.12.10.   
The number and the percentage of patients who experienced TEAEs will be summarized 
by treatment group.  Treatment-emergent SAEs and AEs related to study treatment 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 TEAE by system organ class and preferred term, the number of 
patients who experienced AEs will be presented for each treatment group with the 
percentage of patients.  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. 
9.10.2 
Vital Signs 
Vital signs measured at the time when highest body temperature is observed will be 
included in the analysis.  Summary statistics for vital signs will be presented for EOT, 
TOC and for the change from baseline to each timepoint.  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 timepoint 
and for the change from baseline to each timepoint.  Baseline will be the last value 
obtained before randomization. 
9.11 Pharmacokinetic Analysis 
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 PK analyses will be planned and reported separately by the Clinical 
Pharmacology & Pharmacokinetics of Shionogi & Co., Ltd. 
Individual plasma concentrations, if deemed to be anomalous, may be excluded from the 
analysis at the discretion of the study PK director.  Any such exclusion will be clearly 
listed in the study report along with justification for exclusion. 
9.12 Pharmacokinetic/Pharmacodynamic Analysis 
The PK/PD analyses will be planned and reported separately by the Clinical 
Pharmacology & Pharmacokinetics of Shionogi & Co., Ltd. 


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For each patient 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 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 Stay (LOS) attributable to the infection 
● Days in ICU 
● Hours on assisted mechanical ventilation 
● Days in isolation for infection control (ICU or ward) 
● Discharge status, eg, to home, hospice, or general ward 
● Monitoring for renal toxicity or renal replacement therapy utilization 
9.14 Interim Analysis 
No interim analysis is planned.  The study is open-label, and monitoring of patient safety 
and efficacy by the sponsor will be continuous.  In addition, a data safety monitoring 
board (DSMB) will periodically review the efficacy and safety.  The sponsor reserves the 
option to submit preliminary data to competent regulatory authorities.   


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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: 
Shionogi Ltd. 
33 Kingsway, Holborn, London 
WC2B 6UF, United Kingdom 
Sponsor for Asia-pacific: 
Shionogi & Co., Ltd. 
(Head Office) 3-1-8 Doshomachi, 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 
Tel: 
 
 
  
Shionogi Ltd. 
33 Kingsway, Holborn, London 
WC2B 6UF, United Kingdom 
Tel: 
 
 
 
Clinical Research Department,  
Shionogi & Co., Ltd. 
1-1-4, Shibata, Kita-ku, Osaka 530-0012, Japan 
Tel: 
 
: 
 
 
: 
 
 
: 
 
Shionogi Inc. 
300 Campus Drive, Florham Park, NJ 07932 USA 
Tel: 
 
E-mail:
 
Medical Monitor 
 – 
North America and South 
America: 
 Medical Monitor 
 
North America - Tel: 
 
North America - Fax: 
 
South America - Tel: 
  


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South America - Fax: 
 
Medical Monitor 
  
Europe and Asia-Pacific: 
  
 
Tel: 
 
Fax: 
  
Investigator and Study Center: 
Multicenter 
Study Monitoring: 
 
 
Tel: 
 
Fax: 
 
 
 
 
 
Tel: 
 
Fax: 
 
Clinical Laboratory for North 
America and South America: 
 
 
 
Tel: 
 
Fax: 
 
 
Clinical Laboratory for Europe: 
 
 
 
 
Tel: 
 
Fax: 
 
Clinical Laboratory for Asia-
Pacific: 
 
 
 
 
Tel: 
 
Fax: 
 
Bioanalytical Laboratory: 
  
  
  
Tel: 
  
Fax: 
 
Microbiological Laboratory: 
 
 
Tel: 
 
Fax: 
 


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10.2 Institutional Review Board or Institutional Ethics Committee 
Approval 
Relevant IRBs/IECs will safeguard the rights, safety, and well-being of the patients by 
reviewing the following study documents: the protocol, informed consent form, written 
information on patient recruitment procedures (if applicable), other written information 
given to the patients, 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 International Council for Harmonisation 
(ICH) good clinical practice (GCP), and local requirements, as applicable.  The study will 
be undertaken only after 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 protocol approved by an IRB/IEC.  The study will be conducted in accordance 
with current ICH GCP, all appropriate patient privacy requirements, and the ethical 
principles that are outlined in the Declaration of Helsinki.   
10.4 Patient 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 sub-investigator will explain the nature, purpose 
and methods, reasonable anticipated benefits and potential hazards of the study to the 
patient or his/her legally qualified representative if incapacitated in simple terms by using 
the consent form before the patient is entered into the study.  The method of obtaining 
and documenting informed consent will comply with ICH GCP and all applicable 
regulatory requirement(s). 
10.5 Patient Confidentiality 
Procedures for protecting patient privacy must adhere to applicable data privacy laws and 
regulations.  In order to maintain patient privacy, all eCRFs, study drug accountability 
records, study reports, and communications will identify the patient by the patient 


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number.  The investigator will grant site monitor(s) and auditor(s) of the sponsor or 
designee and regulatory authority(ies) access to all source documents for verification of 
data collected on the eCRFs and for verification of the data collection process.  The 
patient’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 
requirements (eg, Health Insurance Portability and Accountability Act [HIPAA]).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if 
applicable) of protected information must be obtained. 
Data on patients collected on eCRFs during the study will be documented in an 
anonymous fashion and the patient will only be identified by the patient number.  In the 
emergent or rare event that for safety or regulatory reasons it is necessary to identify a 
patient, 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 frequent communications (e-mail, letter, telephone, 
and fax).  The site monitor will review data recorded on the eCRFs, verify the eCRF 
entries with direct access to source documents, collect any safety/efficacy information on 
patients, verify that amounts of unused study drug 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 sponsor or designee will supply eCRFs.  The eCRFs for each patient signed informed 
consent will be provided and historical information and study data, which are specified 
by the protocol, will be recorded on eCRFs by the investigator.  All patient data from the 
study evaluations must be collected on source documents and are promptly entered in the 
eCRFs in accordance with the specific instructions.  The eCRF entries will be performed 
by an investigator, sub-investigator, 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 is 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 


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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 patient’s 
participation in the study and should document the dates and details of study procedures, 
AEs, and patient status.  However, the following data will be allowed as data which can 
be directly recorded on eCRF:  
● 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 
● Automatically-calculated data in eCRF (eg, QTc) 
The investigator must maintain source documents such as laboratory reports, and 
complete medical history and physical examination reports.  All the source documents 
are accessible for verification by the site monitor, auditor, IRB/IEC, and inspectors form 
regulatory authorities.  Direct access to these documents must be guaranteed by the 
investigator, sub-investigator, 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 document within the medical institution.   
10.7.3 
External Data 
The following data will be reported in documents that are separate from the eCRFs.   
● Drug concentration of S-649266 determined by bioanalytical laboratory, 
according to procedures specified in a separate document 
● Pharmacokinetic parameter data 
● Microbiological results from central laboratory 
● Clinical laboratory results from central laboratory 
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, responsibilities, and processes will be documented in a separate 
DSMB charter. The DSMB will review patient information periodically and immediately 
in the event of a death.  However, the timing and the frequency of DSMB reviews and 
meetings will be adjusted as needed, as decided by the DSMB members.  


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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 patient safety becomes difficult due to safety concerns (eg, occurrence 
of many serious treatment-related AEs) 
● Achieving the purpose of the study is considered impossible (eg, data suggests 
lack of efficacy/safety, inadequate recruitment of patients) 
If the study is prematurely terminated or suspended, the sponsor should promptly inform 
the investigators.  The investigator or sub-investigator should promptly inform the 
participating patients and change the study treatment to other appropriate therapy(ies).   
For withdrawal criteria for individual patients, see Section 7.13. 
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, 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 protocol, 
other procedures, and ICH GCP guidelines. 
If the study is prematurely terminated or suspended, the investigator or sub-investigator 
should promptly inform the corresponding IRB/IEC and participating patients and change 
the study treatment to other appropriate therapy(ies).   
10.10 Protocol Deviations and Modifications 
The investigator will conduct the study in compliance with the protocol provided by the 
sponsor and approval/favorable opinion given by the IRB/IEC and the regulatory 
authority(ies).  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(s) to patients.   
The investigator or sub-investigator 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(s) to patients, 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. 


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When deviation from the protocol is required to eliminate immediate hazard(s) to patients, 
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. 
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 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 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 
● Two years after formal discontinuation of the clinical development of the 
investigational product 
● Other period according to applicable country regulatory requirement(s), 
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 the 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. 


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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 
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 authority(ies), 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 (JAPIC CTI).   
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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11. REFERENCE LIST 
1. Diene SM, Rolain JM. Carbapenemase genes and genetic platforms in Gram-negative 
bacilli: Enterobacteriaceae, Pseudomonas and Acinetobacter species. Clin Microbiol 
Infect. 2014;20(9):831-8. 
2. Livermore DM. Current epidemiology and growing resistance of Gram-negative 
Pathogens. Korean J Intern Med. 2012;27: 28-42. 
3. Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in 
Gram-negative bacteria. Clin Microbiol Rev. 2015;28(2):337-418. 
4. Nordmann P, Naas T, Poirel L.  Global Spread of Carbapenemase-producing 
Enterobacteriaceae.  Emerg Infect Dis. 2011;17(10):1791-8.  
5. Falagas WE, Tansarli GS, Karageorgopoulos DE, Vardakas KS. Deaths Attributable 
to Carbapenem-Resistant Enterobacteriaceae Infections. Emerging Infectious 
Diseases. 2014;20(7):1170-5.   
6. Bullen JJ. The significance of iron in infection. Rev Infect Dis. 1981;3:1127-38. 
7. Buchanan SK. Bacterial metal detectors. Mol Microbiol. 2005;58(5):1205-9. 
8. Curtis NA, Eisenstadt RL, East SJ, Cornford RJ, Walker LA, White AJ. Iron-
Regulated Outer Membrane Proteins of Escherichia coli K-12 and Mechanism and 
Action of Catechol-Substituted Cephalosporins. Antimicrobial Agents and 
Chemotherapy. 1988;32(12):1879-86. 
9. Krewulak KD, Vogel HJ. Structural biology of bacterial iron uptake. Biochimica et 
Biophysica Acta. 2008;1778(9): 781-804. 
10. Morrissey I, Hackel M, Badal R, et al. A Review of Ten Years of the Study for 
Monitoring Antimicrobial Resistance Trends (SMART) from 2002 to 2011. 
Pharmaceuticals (Basel. 2013; 6:1335-46. 
11. Colpan A, Johnston B, Porter S, et al. Escherichia coli Sequence Type 131 (ST131) 
Subclone H30 as an Emergent Multidrug-Resistant Pathogen among US Veterans. 
Clinical Infectious Diseases. 2013;57(9):1256–65. 
12. Gupta N, Limbago BM, Patel JB, Kallen AJ. Carbapenem-Resistant 
Enterobacteriaceae: Epidemiology and Prevention. Clinical Infectious Diseases. 
2011;53(1):60–7.  
13. Munoz-Price LS, Poirel L, Bonomo RA, et al. Clinical epidemiology and global 
expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis. 
2013;3(9):785-96.   
14. Cantón R, Akóva M, Carmeli Y, et al. Rapid evolution and spread of carbapenemases 
among Enterobacteriaceae in Europe. Clin Microbiol Infect. 2012;18(5):413-31. 
15. Marchaim D, Chopra T, Pogue JM, et al. Outbreak of colistin-resistant, carbapenem-
resistant Klebsiella pneumoniae in metropolitan Detroit, Michigan. Antimicrobial 
Agents and Chemotherapy. 2011;55(2):593–9. 


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16. Guidance for Industry Antibacterial Therapies for Patients with Unmet Medical Need 
for the Treatment of Serious Bacterial Diseases. Department of Health and Human 
Services Food and Drug Administration Center for Drug Evaluation and Research 
(CDER). July 2013.  
17. Addendum to the guideline on the evaluation of medicinal products indicated for 
treatment of bacterial infections. European Medicine Agency, Committee for Human 
Medicinal Products (CHMP). 24 October 2013 EMA/CHMP/351889/2013. 
18. 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). February 2014. 
19. Bhattacharya S. Early diagnosis of resistant pathogens. How can it improve 
antimicrobial treatment? Virulence. 2013;4(2):172–184.  
20. Tuite N, Reddington K. Barry T, Zumla A. and Enne V. Rapid nucleic acid 
diagnostics for the detection of antimicrobial resistance in Gram-negative bacteria: is 
it time for a paradigm shift? J Antimicrob Therapy. 2014;69(7):1729-33. 
21. Pocock SJ, Simon R. Sequential Treatment Assignment with Balancing for 
Prognostic Factors in the Controlled Clinical Trial. Biometrics. 1975;31:103-15. 
22. Daikos GL, Tsaousi S,Tzouvelekis LS, et al. Carbapenemase-Producing Klebsiella 
pneumoniae Bloodstream Infections: Lowering Mortality by Antibiotic Combination 
Schemes and the Role of Carbapenems. Antimicrobial Agents and Chemotherapy. 
2014;58(4):2322-8. 
23. López-Cortés LE, Cisneros JM, Fernández-Cuenca F, et al. Monotherapy versus 
combination therapy for sepsis due to multidrug-resistant Acinetobacter baumannii: 
analysis of a multicentre prospective cohort. J Antimicrob Chemother. 
2014;69:3119-26. 
24. Qureshi ZA, Paterson DL, Potoski BS, et al. Treatment Outcome of Bacteremia Due 
to KPC-Producing Klebsiella pneumoniae: Superiority of Combination Antimicrobial 
Regimens. Antimicrobial Agents and Chemotherapy. 2012;56:2108-13. 
25. Petrosillo N, Giannella M, Lewis R, Viale P. Treatment of carbapenem-resistant 
Klebsiella pneumoniae: the state of the art. Expert Rev Anti Infect Ther. 
2013;11(2):159–77. 
26. Dudley MN, Ambrose PG, Bhavnani SN, et al. Background and Rationale for 
Revised Clinical Laboratory and Standards Institute Interpretive Criteria 
(Breakpoints) for Enterobacteriaceae and Pseudomonas aeruginosa: I. 
Cephalosporins and Aztreonam. Clinical Infectious Diseases. 2013;56(9):1301-9. 
27. Nicolle LE, AMMI Canada Guidelines Committee. Complicated urinary tract 
infection in adults. Can J Infect Dis Med Microbiol. 2005;16(6):349-60. 
28. American Thoracic Society. Guidelines for the Management of Adults With Hospital 
Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia. Am J Respir 
Crit Care Med. 2005;171:88-416. 


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29. Bone RC, Balk RA, Cerra FB, et al. The American College of Chest 
Physicians/Society of Critical Care Medicine Consensus Conference Committee. 
Definitions for sepsis and organ failure and guidelines for the use of innovative 
therapies in sepsis. Chest. 1992;101:1644-55.  
30. Nicolle LE, Bradley S, Colgan R, et al. Infectious Diseases Society of America 
Guideline for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults. 
Clinical Infectious Disease. 2005;40:643-54. 
31. Nation RL, Velkov T, Li J. Colistin and Polymyxin B: Peas in a Pod, or Chalk and 
Cheese? Clinical Infectious Diseases. 2014;59:88-94. 
32. Tängdén T, Hickman RA, Forsberg P, Lagerbäck P, Giske CG, Cars O. Evaluation of 
double- and triple-antibiotic combinations for VIM- and NDM-producing Klebsiella 
pneumoniae by in vitro time-kill experiments. Antimicrobial Agents and 
Chemotherapy. 2014;58(3):1757-62. 
33. Zusman O, Avni T, Leibovici L, et al. Systematic Review and Meta-Analysis of In 
Vitro Synergy of Polymyxins and Carbapenems. Antimicrobial Agents and 
Chemotherapy. 2013;57(10):5104-11.   
34. Kollef MH, Micek ST. Antimicrobial stewardship programs: mandatory for all ICUs. 
Critical Care. 2012;16:179-80.  
35. Dellit TH, Owens RC, McGowan GE Jr, et al. Infectious Diseases Society of America 
and the Society for Healthcare Epidemiology of America Guidelines for Developing 
an Institutional Program to Enhance Antimicrobial Stewardship. Clinical Infectious 
Diseases. 2007;44:159-77. 
36. 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. 
37. Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41. 
38. 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.  
39. Guidance for Industry Complicated Urinary Tract Infections: Developing Drugs for 
Treatment. Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER), February 2012 (revision 1). 
 
 


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Appendix 1 
Time and Events Schedule  
Evaluation 
Screening\Baseline 
Randomization 
Treatment 
Test of 
Cure 
(TOC) 
Follow-Up 
(FUP) 
End of 
Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
Day 1 
Day 3 
 
Early 
Asses. 
(EA)  
Day 
3 to 4 
(Day 14)b 
End of 
Treat. 
(EOT)c 
EOT + 7 
(± 2) 
EOT + 14 
(± 3)  
 
EOT + 28  
(± 3) 
 
Rapid Diagnostic for the 
Presence of a Carbapenemase  
Xd 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical Historye 
X 
 
 
 
 
 
 
 
 
Physical Examination 
Xf 
 
 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg,h 
Glasgow Coma Scale 
X 
 
 
X 
X 
X 
X 
X 
 
APACHE II 
X 
 
 
 
 
 
 
 
 
SOFA Score 
X 
 
 
X 
X 
X 
X 
X 
 
Clinical Assessment of Signs 
and/or Symptoms 
X 
 
 
X 
X 
X 
X 
X 
 
Oxygenation Statusi  
X 
 
 
X 
X 
X 
X 
X 
 
Ventilator Parameters 
(Ventilated Patients Treated 
with S-649266) 
 
 
Xj 
Xj 
 
 
 
 
 
Chest Radiographsk 
(HAP/VAP/HCAP) 
X 
 
 
X 
X 
X 
X 
X 
 
CPIS Parameters 
(HAP/VAP/HCAP) 
X 
 
 
X 
X 
X 
X 
X 
 
Pregnancy Testl   
X 
 
 
 
 
 
 
 
 


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Evaluation 
Screening\Baseline 
Randomization 
Treatment 
Test of 
Cure 
(TOC) 
Follow-Up 
(FUP) 
End of 
Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
Day 1 
Day 3 
 
Early 
Asses. 
(EA)  
Day 
3 to 4 
(Day 14)b 
End of 
Treat. 
(EOT)c 
EOT + 7 
(± 2) 
EOT + 14 
(± 3)  
 
EOT + 28  
(± 3) 
 
Hematology Tests, Blood 
Chemistry Tests, and 
Urinalysis (Table 7-1) 
X 
 
 
X 
X 
X 
X 
X 
X h 
TIBC, Transferrin Iron 
Saturation, Hepcidin 
X 
 
 
 
 
 
X 
 
 
CrCl from Serum Creatininem 
X 
Randomization 
 
 
X 
 
 
 
 
 
CrCl from Urinary 
Creatinine1  
 
 
 
X 
 
 
 
 
 
Vital Signsn 
X 
X 
 
 
 
X 
X 
X 
X h 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
Drug Administration 
 
X 
 
 
 
X 
 
 
 
Clinical Outcome 
 
 
 
X 
X 
X 
X 
X 
 
Biologic Tissue or Fluids for 
Microbiologic Cultureso 
X 
 
 
X 
X 
X 
X 
X 
 
Microbiological Outcome 
 
 
 
X 
X 
X 
X 
X 
 
Blood PK Samples  
(S-649266 Group) 
 
 
Xp 
Xp 
 
 
 
 
 
AE Assessment 
X 
 
 
 
 
 
 
 
X 
Concomitant Therapy 
X 
 
 
 
 
 
 
 
X 
Hospitalization 
X 
 
 
 
 
 
 
 
X 
Vital Status 
X 
 
 
 
 
 
 
 
X 


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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. In case treatment duration is extended beyond 14 days, an additional assessment will be conducted on Day 14. 
c. 
EOT evaluations occur on the last day of study treatment.  EOT can be any time after the patient had at least one dose of study treatment, duplication of 
assessments for a given day and EOT is not necessary. 
d. The use of investigational diagnostics or diagnostics that are not the local standard of care for determination of carbapenem resistance will require that the 
investigational diagnostics section of the informed consent be signed by the patient or legally authorized representative. 
e. 
Include a review of prior/concomitant therapies. 
f. 
A complete physical examination including measurement of body weight and height will be performed at Screening only. 
g. A limited physical examination relevant to the patient’s current condition will be performed. 
h. If end of study evaluation is by phone, physical examination, laboratory tests, and vital signs will not be performed. 
i. 
Patients receiving an oxygen inhalation treatment. 
j. 
For ventilated patients treated with S-649266, specified ventilator parameters will be captured at the start of the infusion (acceptable time window; 0 hours to 
end of infusion) which PK sampling will be taken.   
k. At German sites, 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. 
l. 
Urine or serum pregnancy test only for females who are not diagnosed as postmenopausal or surgically sterile.   
m. The CrCl (the Cockcroft-Gault equation) and eGFR (the MDRD equation) will be calculated from the serum creatinine.  For patients with eGFR ≥ 
90 mL/min/1.73 m2 at baseline, urine samples will be collected a time interval as short as 2 hours or up to 8 hours. 
n. Blood pressure (systolic/diastolic pressures), body temperature, pulse rate, and respiratory rate. 
o. Biologic tissue or fluids (including blood regardless of the infection site) for microbiologic cultures will be obtained with 48 hours of the start of treatment, 
and at specified times and at the investigator's discretion.  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 after at least the sixth dose of study drug; one draw just prior to the infusion of the dose, 1 hour after start of 
infusion, at the end of infusion, and at 1 hour after the end of infusion.  Patients with non-stable renal function resulting in a dosage adjustment at EA will 
undergo another blood PK sampling (4 samples at the above specified timepoints) within 24 to 72 hours after their dosing adjustment.  If possible, a single 
blood draw should be performed as soon as possible at EOT in case of premature EOT.  
 


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Appendix 2 
SIRS Criteria 
Patient exhibits 2 or more of the following responses: 
1. Temperature greater than 38°C (100.4°F) or less than 36°C (96.8°F) 
2. Heart rate greater than 90 beats/minute 
3. Respiratory rate greater than or equal to 20 breaths/minute or PaCO2 less than 
32 mmHg 
4. WBC greater than 12,000/mm3 or less than 4000/mm3 or > 10% immature (band) 
forms 
Reference: 
Bone RC, Balk RA, Cerra FB. Definitions for sepsis and organ failure and guidelines for 
the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference 
Committee. American College of Chest Physicians/Society of Critical Care Medicine. 
Chest. 1992;101:1644-55. 
 


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Appendix 3 
European Medicines Agency Completes Review of 
Polymyxin-based Medicines 
Information to Healthcare Professionals  
The recommendations of European Medicines Agency (EMA) are based on a review of 
the available clinical, pharmacological, and pharmacokinetic data, although significant 
gaps still exist, particularly with regard to the pharmacokinetics in special populations 
such as children and patients with renal impairment. Research currently underway may 
provide further information on pharmacodynamics and pharmacokinetics of these 
medicines to improve the evidence-base behind any dose recommendations. However, it 
was considered that in the interim the product information should be updated throughout 
the EU to reflect what was currently known.  
● Doses should always be expressed in IU of colistimethate sodium.  To address the 
differences in the way in which the strength of colistimethate sodium and colistin 
are expressed in the EU and in other regions such as the USA and Australia, 
which has led to errors in reporting in the medical literature and could potentially 
lead to serious medication errors, the following table has been recommended for 
inclusion in product information: 
Colistimethate sodium 
(IU) 
Colistimethate sodium 
(mg) 
Colistin-base activity (CBA) 
(mg)1 
12,500  
1 
0.4 
150,000  
12 
5 
1,000,000  
80 
34 
4,500,000  
360 
150 
9,000,000  
720 
300 
1 
Based on a nominal potency of the drug substance of 12,500 IU/mg or 0.424 mg CBA/mg: both IU and 
mg CBA are expressions of potency and have only approximate relation to the mass of drug substance. 
● Intravenous colistimethate sodium is indicated in adults and children including 
neonates for the treatment of serious infections due to aerobic Gram-negative 
pathogens in patients with limited treatment options. Consideration should be 
given to coadministration with another antibacterial agent whenever this is 
possible.  
● Dosage should be in line with relevant treatment guidelines. Based on the limited 
available evidence the recommended dose in adults is 9 million IU daily in 2 or 3 
divided doses as a slow intravenous infusion; in critically ill patients, a loading 
dose of 9 million IU should be given. Doses should be reduced according to 
creatinine clearance in patients with renal impairment.  
● Intravenous colistimethate sodium does not cross the blood-brain barrier to a 
significant extent. Where appropriate, adult doses of 125,000 IU for 
intraventricular administration and no more than this for intrathecal administration 
are recommended.  


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● Use of intravenous colistimethate sodium together with other medications that are 
potentially nephrotoxic or neurotoxic should be undertaken with great caution.  
Reference: 
European Medicine Agency. European Medicines Agency completes review of 
polymyxin-based medicines. Recommendations issued for safe use in patients with 
serious infections resistant to standard antibiotics. October 2014.  
 
 


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Appendix 4 
Microbiology Tests 
Appropriate clinical specimens will be obtained from all patients within 48 hours prior to 
the start of the infusion of the first dose of study treatment therapy.  Biologic tissue or 
fluids for microbiologic cultures will be sent to the local laboratory for identification of 
all pathogens causing the infection.  Two blood samples from separate venipunctures will 
be obtained from all patients and sent to the local laboratory.  After initiation of study 
treatment, appropriate clinical specimens including blood culture will be obtained at the 
specified evaluation points (Appendix 1).   
Identified isolates in unscheduled cultures should be sent to the central lab. 
In general, all specimens should also have Gram stain of infected material (not swab).  A 
report of both inflammatory cells and bacteria is necessary.   
Inappropriate clinical specimens should not be used for confirmatory culture 
identification of causative pathogens.   
1. 
HAP/VAP/HCAP Specific Procedures  
Patients enrolled in a HAP/VAP/HCAP study should have a baseline respiratory 
specimen obtained for Gram stain and culture [1].  In addition to defining the bacterial 
etiology for HAP/VAP/HCAP, the Gram stain and culture are important considerations 
because they may be used to define analysis populations and to characterize the quality 
and findings of the respiratory specimen sent for culture.  More specifically, 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 (eg, fewer than 10 squamous epithelial 
cells and greater than 25 neutrophils is an example of an adequate expectorated sputum 
specimen).  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).  When bacterial growth is obtained on culture of the 
respiratory specimen, in vitro susceptibility tests should be performed by using 
standardized methods unless otherwise justified.  
Endobronchial culture specimens collected by BAL or protected specimen brush (PSB) 
should be grown quantitatively with appropriate method specific dilutions. 
2. 
cUTI Specific Procedures  
Clean-Catch Mid-Stream Urine Specimen: After appropriate patient preparation, a 
specimen should be collected and immediately sent to the microbiology laboratory or 
properly stored for no longer than 24 hours. 
Urine Specimen from Patients with Indwelling Urinary Catheters:  Because biofilms on 
indwelling catheters (eg, Foley catheters) are more likely to be present after the catheter 
has been in place for a period of time, samples should be collected following the 
placement of a new catheter.  If the placement of a new catheter is contraindicated or is 


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not feasible, specimens should be collected using aseptic techniques with the urine 
obtained through a properly disinfected collection port.  Urine samples should never be 
obtained from the collection bag.  
Urine Evaluations: A microscopic evaluation (eg, Gram stain) or dipstick analysis for 
leukocytes, nitrates, or a catalase test should be performed and the specimen cultured.  In 
general, bacteria identified at 1 x 105 CFU/mL or greater should be considered a bacterial 
pathogen (probability of true pathogen is greater than that of contamination).  
Quantitative urine culture by appropriate methods should be performed using a calibrated 
loop that would identify bacteria at a lower limit of 103 CFU/mL.  In vitro antibiotic 
susceptibility testing of the isolates to the investigational drug and to other antibiotic 
drugs that may be used to treat cUTIs should be performed using standardized methods 
unless otherwise justified. 
If possible, the identity of bacteria that are demonstrated in culture between 103 CFU/mL 
and 104 CFU/mL should be determined as these may be background bacteria associated 
with the method of collection. 
3. 
Bloodstream and Sepsis Infections: Specific Procedures 
For infections categorized as BSI/sepsis, the following guidelines are provided (for 
details see reference infectious disease society of America/ American society for 
micobiology (IDSA/ASM) guidelines [2]).  These guidelines apply to blood cultures and 
infection site tissue or fluids cultures for patients with infections other than 
HAP/VAP/HCAP or cUTI. 


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Culture Procedures 
Infection Site 
Culture Method (Gram Stain Required for All 
Cultures or Appropriate Specimen) 
Blood Stream Infection 
(Bacteremia) 
 
Primary (Not Endocarditis) 
2-3 separate “sets” of blood cultures (10 mL/bottle) 
drawn from peripheral vein 
Secondary  
2-3 separate “sets” of blood cultures (10 mL/bottle) 
drawn from peripheral vein 
Line Related 
2-3 separate “sets” of blood cultures (10 mL/bottle) 
drawn from peripheral vein 
Skin/Skin Structure Infections 
 
Primary Skin Infection (eg, 
Necrotizing Fasciitis) 
Quantitative, semi-quantitative tissue culture (not swab) 
Burn Wound Infection 
Quantitative, semi-quantitative tissue culture (not swab) 
Human/Animal Bite Infection  
Tissue culture or aspirate (not swab) 
Surgical Site Infection  
Tissue culture or aspirate (not swab) 
Trauma Associated Skin Infection 
Post debridement tissue culture or aspirate (not swab) 
Intra-Abdominal Infections 
 
Spontaneous Bacterial Peritonitis 
Culture aspirate or inoculate blood culture bottle 
Tertiary Peritonitis (Post-Surgical) 
Fluid aspirate or tissue culture 
Abscess of Liver 
Lesion aspirate 
Biliary Tract Infection 
Lesion aspirate 
Secondary Pancreatic Infection 
Lesion aspirate 
Respiratory Tract other than 
HAP/VAP/HCAP 
 
Community Acquired Pneumonia 
Expectorated sputum, or bronchoscopic specimen 
Lung Abscess 
Lesion aspirate or bronchoscopic specimen 
Pleural Space, Empyema 
Culture aspirate or inoculate blood culture bottle 
Pelvic Infection (Post-Surgical)  
Fluid aspirate or tissue culture 
 
References: 
1. Guidance for Industry Hospital-Acquired Bacterial Pneumonia and Ventilator-
Associated Bacterial Pneumonia: Developing Drugs for Treatment.  Department of 
Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). May 2014 (revision 2). 
2. Baron EJ, Miller JM, Weinstein MP, et al. A Guide to Utilization of the Microbiology 
Laboratory for Diagnosis of Infectious Diseases: 2013 Recommendation by the 
Infectious Diseases Society of America (IDSA) and the American Society for 
Microbiology (ASM). Clinical Infectious Diseases 2013;57(4):e22-e121.  
 


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Appendix 5 
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 
Localising 
5 
Normal flexion 
4 
Flexing 
3 
Extension 
2 
None 
1 
 
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. The Lancet Neurology. 2014;13:844-54. 
 


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Appendix 6 
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) 
 
Chronic Health Points: If the patient has a history of severe organ system insufficiency or 
is immunocompromised as defined below, assign points as follows: 5 points for 
nonoperative or emergency postoperative patients and 2 points for elective postoperative 
patients.  


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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 (GI) 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 (ie, 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 patient 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 7 
SOFA Score 
The Sequential Organ Failure Assessment (SOFA) Score* 
 
SOFA Score 
Variables 
0 
1 
2 
3 
4 
Respiration 
 PaO2/FiO2, mm Hg 
> 400 
≤ 400 
≤ 300 
≤ 200† 
≤ 100† 
Coagulation 
 Platelets ×103/μL 
> 150 
≤ 150 
≤ 100 
≤ 50 
≤ 20 
Liver 
 Bilirubin, mg/dL‡ 
< 1.2 
1.2 – 1.9 
2.0 – 5.9 
6.0 – 11.9 
> 12.0 
Cardiovascular 
 Hypotension 
No 
hypotension 
Mean 
arterial 
pressure 
< 70 mmHg 
Dop ≤ 5 or 
dob (any 
dose)§ 
Dop > 5, 
epi ≤ 0.1, 
or norepi 
≤ 0.1 § 
Dop > 15, 
epi > 0.1, 
or norepi > 
0.1 § 
Central Nervous System 
 Glasgow Coma Score 
Scale 
15 
13 - 14 
10 - 12 
6 - 9 
< 6 
Renal 
 Creatinine, mg/dL or 
Urine Output, mL/d|| 
< 1.2 
1.2 – 1.9 
2.0 – 3.4 
3.5 – 4.9 
or < 500 
> 5.0  
or < 200 
* 
Norepi indicates norepinephrine; dob, dobutamine; Dop, dopamine; epi, epinephrine; and FiO2, 
fraction of inspired oxygen. 
† 
Values are with respiratory support. 
‡ 
To convert bilirubin from mg/dL to μmol/L, multiply by 17.1. 
§ 
Adrenergic agents administered for at least 1 hour (doses given are in μg/kg/minute). 
|| 
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 8 
Clinical Pulmonary Infection Score (CPIS) 
Parameters 
CPIS Points 
0 
1 
2 
Tracheal Secretions* 
Few 
Moderate 
Large 
Chest X-Ray Infiltrates† None 
Patchy or diffuse 
Localized 
Temperature (°C) 
≥ 36.1 and ≤ 38.4 
≥ 38.5 and ≤ 38.9 
≥ 39.0 or ≤ 36.0 
Leukocytes (/mm3) † 
≥ 4000 and ≤ 11,000 
< 4000 or > 11,000 
 
PaO2/FiO2 (mmHg)‡ 
> 240 or evidence of 
Acute Respiratory 
Distress Syndrome 
(ARDS) 
 
≤ 240 and no evidence 
of ARDS 
* 
If purulent: +1 
† 
For post baseline CPI scores where the radiograph or leukocytosis has improved: −1 
‡ 
Use first blood gas measure in morning. For non-ventilated patients who, based on local practice, 
do not have blood gasses done, a PaO2/FiO2 point value of zero may be assigned. 
 
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 9 
Management Criteria for Abnormal Liver Function 
Tests 
Management Criteria for Abnormal Liver Function tests have been designed to ensure 
patient safety and evaluate liver event etiology. 
Abnormal Liver Chemistry Criteria: 
The investigator or sub-investigator must review study patient laboratories to identify if 
any levels meet the following criteria a.-e.: 
a. AST or ALT > 5 × ULN (if baseline ALT is ≤ ULN); 
b. AST or ALT > 8 × ULN; 
c. AST or ALT > 3 × ULN and total bilirubin (TBL) > 2 × ULN or PT-INR > 1.5, if 
PT-INR measured; 
d. AST or ALT > 3 × ULN (if baseline ALT is ≤ 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%]), 
OR 
e. AST or ALT > 3 × increase from baseline ALT 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%]); 
Patients who develop AST or ALT > 5× ULN (if baseline ALT is > ULN) should be 
followed weekly until resolution or stabilization. 
Action to Be Taken by Investigator: 
If any one of abnormal liver chemistry criteria is met, the investigator or sub-investigator 
must do the following: 
 Following the initial observed elevation, every effort should be made to have the 
patient reassessed within 48 to 72 hours to repeat liver function chemistries and 
for further hepatic evaluation.   
 Patients must be monitored 2 to 3 times per week until liver function chemistries 
(ALT, AST, ALP, total bilirubin) resolve, stabilize or return to within the normal 
range or to baseline levels. 
 This event must be reported to the sponsor within 48 to 72 hours of learning after 
its occurrence on the Liver Event Form.  
 Consultation with a specialist such as a hepatologist is considered. 
 Liver imaging (ie, ultrasound, magnetic resonance imaging [MRI], computerized 
tomography (CT) is considered. 


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 For criteria c, termed “Hy’s law,” the case must be reported as an SAE (if baseline 
AST or ALT is ≤ ULN).  
If baseline AST or ALT is > ULN, the case that meets the following criteria must 
be reported as an SAE. 
AST or ALT > 3 × increase from baseline AST or ALT and TBL > 2 × increase 
from baseline TBL 
 
Follow-up Examination: 
If any of abnormal liver chemistry criteria are met, the following assessments should be 
obtained at FUP and documented in the Liver Event Form: 
 Clinical signs and symptoms course 
 Concomitant medications: OTC/herbal/dietary supplements (start and stop dates) 
 Alcohol use 
 Risk factors for nonalcoholic steatohepatitis (NASH) 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 patients with total bilirubin of > 1.5 ULN, conjugated bilirubin should be 
measured 
Complete blood count with differential 
 


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Appendix 10 
Sponsor Signature 
Form 510-01 
Approval of the Protocol 
 
 
Study Protocol Title: A Multicenter, Randomized, Open-label Clinical Study of S-649266 
or Best Available Therapy for the Treatment of Severe Infections 
Caused by Carbapenem-resistant Gram-negative Pathogens 
Study Protocol Number: 1424R2131 
Edition Number: 3 
Issue Date of Original: 11 November 2015 
Issue Date of Latest Version 4: 16 November 2017 
 
 
Sponsor signatory: 
 
 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor: 
 
 
 
 
Date: day-month-year 
 


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Appendix 11 
Investigator’s Signature  
Study Title: 
A Multicenter, Randomized, Open-label Clinical Study of 
S-649266 or Best Available Therapy for the Treatment of Severe 
Infections Caused by Carbapenem-resistant Gram-negative 
Pathogens 
Study Number: 
1424R2131 
Date of Original: 
11 November 2015 
Date of Version 4 
16 November 2017 
 
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, Open-label Clinical Study 
of S-649266 or Best Available Therapy for the 
Treatment of Severe Infections Caused by Carbapenem-
resistant Gram-negative Pathogens 
Shionogi Study Number: 
1424R2131 
ClinicalTrials.gov 
Registration No. 
NCT02714595    
Study Document 
Statistical Analysis Plan Version 3     27 Jun 2019 
 
History of Statistical Analysis Plan Amendments 
Version 1 (Original) 
13 Jul 2017 
Version 2 
24 Jul 2018 
Version 3 
27 Jun 2019 
Revisions  to Version  1 and 2 are documented in Version 3 
 


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Statistical Analysis Plan: 1424R2131 
 
 
 
Study Title:  
A Multicenter, Randomized, Open-label Clinical Study 
of S-649266 or Best Available Therapy for the 
Treatment of Severe Infections Caused by Carbapenem-
resistant Gram-negative Pathogens 
Study Number: 
1424R2131 
Study Phase: 
3  
Product Name: 
Cefiderocol 
Sponsor: 
Shionogi Inc.  
Edition Number: 
Version 3.0 
Issue Date: 
27 Jun  2019 
 
 
 
 
 
 
 
 
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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RECORDS ON REVISIONS 
Version 
Date for 
creation or 
modification 
Person in 
charge 
Remarks 
Ver 1.0 
13 Jul 2017 
 
 
Originally prepared 
Ver 2.0 
24 Jul 2018 
 
・Update per Clinical Study Protocol 
Version 4 
・Update objective of this study 
・Specify time point for vital sign 
(Section 10.3) 
・Delete section ECG analysis 
(Section 10.4) 
・Add description for subjects with 
Stenotrophomonas maltophilia will be included 
in CR MITT population (Section 5.3) 
・Update criteria for eradication for cUTI 
subject (section 9.1) 
・Add description for DSMB 
・Specify using corrected APACHE II score 
9.3.2.2 
・Add the rule of analysis visit and baseline 
definition (Sections 6.3 and 6.5) 
・Add logic for missing time (Section 6.4.1) 
・Add data handling if reported bacteria name 
is different between local and central 
(Section 6.7.1) 
・Add definition of additional antibiotics 
(Section 6.8) 
・Add definition of study drug regimen and 
add subgroup analysis using it (Sections 6.9, 
9.4.1.1, and 9.4.1.2) 
・Add analysis for new infection (Section 
9.4.1.2) 
・Add analysis regarding susceptibility 
(Section 7.2) 
・Add sensitivity clinical and microbiological 
outcome (Section 9.2) 
・Add indeterminate at TOC carried forward 


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to FU (Sections 9.1.2 and 9.1.4) 
・Add subgroup analysis for type of CR 
baseline pathogen, region and APACHE II 
(Section 9.3.3) 
・Add analysis for HABP/VABP/HCABP + 
BSI/sepsis (Section 9.4.1) 
・Add analysis for cUTI for mortality 
(Section 9.4.1) 
・Clarify using standard unit for laboratory 
data analysis (Section 10.2) 
・Specify decimal space for PK analysis 
(Section 14) 
・Change decimal space for standard deviation 
and error. (section 14) 
2.1 
15 Aug 2018
・Clarify analysis for baseline pathogen 
(section 7.2) 
・Add decimal space for calculated value. 
(section 14) 
・Add calculation formula for appendix 2. 
2.2 
03 Dec 2018 
 
・Change the wording from sensitivity to 
supplementary per ICH E9 R1 
・Clarify the interim analysis for DSMB 
・Exclude neomysin oral administration from 
additional antibiotics (section 6.8). 
・Clarify Composite of Survival and No 
Change in Antibiotic Treatment will be 
determined by Shinogi internally rather than 
EDC data (section 9.4.1.9). 
・Exclude PTT from LAB analysis (section 
10.2) 
・Minor update of wording 
2.3 
12 Feb 2019 
・Specify meical monitor will adjudicate 
additional antibiotics based on available data, 
and delete sentences about neomisyin oral 
administration. 
2.4 
11 Apr 2019 
 
・Delete signature page to use Veeva Vault 
eSigniture due to chage TMF management 
plan. 
・Terminology change from microbiological 


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eradication/failure to eradication/persistence. 
(Section 9.1.6, 9.1.7, 9.2.6) 
・Change terminology from protocol deviation 
list to protocol deviation specification. Also 
clarify criteria for ME population is specified 
in the document. (section 5.4 and 8.1) 
・Change the definition of new/super infection 
to new pathogen on or after Day 3 by the input 
from medical group. (section 9.1.5) 
3.0 
27 Jun 2019 
・Add time imputation for lab data and 
microbiological data if time is missing (section 
6.4.1 and 6.4.2) 
・Add CR MITT 2 Population (section 5.3.1) 
and analysis using CR MITT2 (section 7.1, 
9.4.1.1 and 9.4.1.2) 
・Add data handling for subject who receive 
cefiderocol after BAT completion (section 5.5 
and 10.1.1) 
・Add analysis window for premature EOT 
・Differentiate persistence and recurrence 
which was originally counted together (section 
9.1.6) and update table 9-3 
・Add overall mortality until EOS. In addition, 
add overall mortality including death after 
EOS. (section 9.4.1.6) 
・Add analysis for fatal AE (section 10.1) 
・Clarify if investigator consider BSI subject 
as clinically cured and no need to collect blood 
sample, considered as presumed eradication 
(section 9.1.3.3 and 9.1.4.3). 
 


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TABLE OF CONTENTS 
RECORDS ON REVISIONS ..............................................................................................2 
LIST OF IN-TEXT TABLES ..............................................................................................8 
LIST OF IN-TEXT FIGURES.............................................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................9 
1. 
INTRODUCTION .....................................................................................................11 
2. 
STUDY OVERVIEW ................................................................................................11 
3. 
STUDY OBJECTIVES ..............................................................................................11 
3.1 
Primary Objective ............................................................................................11 
3.2 
Secondary Objectives .......................................................................................11 
4. 
STUDY DESIGN ......................................................................................................12 
4.1 
Study Blinding .................................................................................................12 
4.2 
Randomization to Treatment Groups ...............................................................12 
4.3 
Sample Size ......................................................................................................13 
4.4 
Study Schematic...............................................................................................13 
5. 
ANALYSIS POPULATIONS ...................................................................................14 
5.1 
Intent-to-treat Population .................................................................................14 
5.2 
Microbiological Intent-to-treat Population ......................................................14 
5.3 
Carbapenem-resistant Microbiological Intent-to treat Population ...................14 
5.4 
Carbapenem-resistant Microbiologically Evaluable Population .....................15 
5.5 
Safety Population .............................................................................................15 
5.6 
Pharmacokinetic Concentration Population .....................................................15 
6. 
STATISTICAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ..............................................................................................................16 
6.1 
Statistical Reporting .........................................................................................16 
6.2 
Statistical Testing .............................................................................................16 
6.3 
Analysis Windows ...........................................................................................16 
6.4 
Missing Data ....................................................................................................17 
6.4.1 
Missing or Partial Dates and Times .......................................................17 
6.4.2 
Missing Microbiological or Clinical Outcome ......................................18 
6.5 
Baseline Definition ..........................................................................................18 
6.6 
Study Day Definition .......................................................................................19 
6.7 
Handling for Microbiologic Data .....................................................................19 
6.8 
Additional Antibiotics ......................................................................................19 
6.9 
Study Drug Regimen at Day 1 and 2 ...............................................................19 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................20 
7.1 
Subject Disposition and Discontinuation .........................................................20 
7.2 
Demographic and Baseline Characteristics .....................................................20 


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8. 
STUDY CONDUCT ..................................................................................................21 
8.1 
Protocol Deviations ..........................................................................................21 
8.2 
Treatment Exposure and Compliance ..............................................................21 
8.3 
Study Drug Regimen........................................................................................22 
8.4 
Prior Therapy and Concomitant Therapy Other Than Best Available 
Therapy/Adjunctive Antibiotics .......................................................................22 
9. 
EFFICACY ................................................................................................................22 
9.1 
Efficacy Assessment ........................................................................................23 
9.1.1 
Clinical Outcomes for EOT and TOC ...................................................23 
9.1.2 
Clinical Outcomes for Follow-up ..........................................................24 
9.1.3 
Microbiological Outcomes per Baseline Pathogen for EOT and TOC ..25 
9.1.4 
Microbiological Outcomes per Baseline Pathogen for Follow-up ........26 
9.1.5 
New Pathogens.......................................................................................27 
9.1.6 
Per Subject Microbiological Outcomes .................................................27 
9.1.7 
Definition for Composite of Clinical and Microbiological Outcome ....28 
9.1.8 
Clinical Pulmonary Infection Score .......................................................29 
9.1.9 
Sequential Organ Failure Assessment Score .........................................29 
9.2 
Supplementary Efficacy Assessment ...............................................................29 
9.2.1 
Analysis Time Window .........................................................................29 
9.2.2 
Supplementary Clinical Outcomes for EOT and TOC ..........................29 
9.2.3 
Supplementary Clinical Outcomes for Follow-up .................................30 
9.2.4 
Microbiological Outcomes per Baseline Pathogen for EOT and TOC ..31 
9.2.5 
Microbiological Outcomes per Baseline Pathogen for Follow-up ........32 
9.2.6 
Per Subject Microbiological Outcomes .................................................33 
9.3 
Primary Efficacy Endpoint ..............................................................................33 
9.3.1 
Primary Analyses for the Primary Efficacy Endpoint ...........................34 
9.3.2 
Supplementary Analyses for the Primary Efficacy Endpoint ................34 
9.3.3 
Subgroup Analyses ................................................................................35 
9.4 
Secondary Endpoints .......................................................................................35 
9.4.1 
Analyses for Secondary Efficacy Endpoints ..........................................36 
10. SAFETY ....................................................................................................................39 
10.1 
Adverse Events ................................................................................................40 
10.2 
Clinical Laboratory Evaluations ......................................................................40 
10.3 
Vital Sign Measurements .................................................................................42 
11. PHARMACOKINETIC ANALYSES .......................................................................42 
12. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ............................43 
13. INTERIM ANALYSES .............................................................................................43 
14. PROGRAMMING CONVENTIONS ........................................................................44 


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15. CHANGES FROM PROTOCOL ..............................................................................45 
Appendix 1 
Time and Events Schedule .....................................................................46 
Appendix 2 
 Calculation Confidence Interval for Cochran-Mantel-Haenzel Test ....50 
 


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LIST OF IN-TEXT TABLES 
Table 6-1 
Analysis Window .........................................................................16 
Table 7-1 
Demographic and Baseline Characteristics .................................21 
Table 9-1 
Per Subject Microbiological Outcome .........................................27 
Table 9-2 
Clinical and Microbiological Outcome: EOT and TOC ..............28 
Table 9-3 
Composite Outcome: Follow-up ..................................................28 
Table 9-4 
Analysis Window .........................................................................29 
Table 10-1 
Outlier for Each Parameter in Laboratory Test ............................41 
Table 10-2 
Outlier for Each Parameter in Vital Sign Measurements .............42 
Table 14-1  
Display Digit of Statistics for Efficacy and Safety ......................44 
Table 14-2  
Subject Characteristics and Items of Therapeutic Process ..........45 
 
LIST OF IN-TEXT FIGURES 
Figure 4-1 
Study Schematic ...........................................................................14 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BAL 
bronchoalveolar lavage 
BAT 
best available therapy 
BMI 
body mass index 
BSI 
bloodstream infections 
CFUs 
colony-forming units 
CI 
confidence interval 
CLSI 
Clinical and Laboratory Standards Institute 
CR-ME 
Carbapenem-resistant Microbiologically Evaluable Population 
CR Micro-ITT 
Carbapenem-resistant Microbiological Intent-to-treat Population 
CrCl 
creatinine clearance 
cUTI 
complicated urinary tract infection 
DSMB 
data safety monitoring board 
EA 
Early Assessment 
ECG  
electrocardiogram  
eCRF  
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
EUCAST 
European Committee on Antimicrobial Susceptibility Testing 
FiO2 
fraction of inspired oxygen 
FU 
Follow-up 
HABP 
hospital-acquired bacterial pneumonia 
HCABP 
healthcare-associated bacterial pneumonia 
IMP 
investigational medicinal product 
ITT 
intent-to-treat 
IWRS/IVRS 
interactive web or voice response system 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MIC 
minimum inhibitory concentration 
Micro-ITT 
Microbiological Intent-to-treat Population 
mITT 
modified intent-to-treat 
%Tf>MIC 
percentage of the dosing interval for free-drug plasma concentration to 
be above the minimum inhibitory concentration 
PaO2 
partial pressure of arterial oxygen 
PK 
pharmacokinetics 
PSB 
protected specimen brush 
PT-INR  
prothrombin time-international normalized ratio  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SIRS 
systemic inflammatory response syndrome  
SOC 
System Organ Class 
SOFA 
Sequential Organ Failure Assessment 
TIBC 
total iron-binding capacity 
TOC 
Test of Cure 
ULN 
upper limit of normal 
VABP 
ventilator-associated bacterial pneumonia 
WBC 
white blood cell (count) 
WHO 
World Health Organization 
 
 
 


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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) presents details, including methods of analyses, of 
the efficacy and safety analyses described in Section 9: “PLANNED STATISTICAL 
METHODS” of the protocol (Protocol No. 1424R2131: Version 4 dated 16 Nov 2017). 
Details of outputs (or mock-ups of tables, figures, and listings) from analyses in this SAP, 
will be included in a separate document (“Tables, Figures, and Listings Shells”) prepared 
separately. Any deviations from this analysis plan will be substantiated by sound 
statistical rationale and will be documented in the final clinical study report. 
2. STUDY OVERVIEW 
This is a Phase 3, multicenter (multinational), open-label, parallel-group, randomized, 
active-controlled study in approximately 150 subjects with documented carbapenem-
resistant Gram-negative bacterial infections. Subjects meeting eligibility criteria and 
assessed by the investigator to require 7 to 14 days of intravenous treatment in hospital 
will be randomized (2:1) to either cefiderocol 2 g received intravenously over 3 hours, 
every 8 hours, or best available therapy (BAT). 
The treatment duration for cefiderocol or BAT is anticipated to be 7 to 14 days, which are 
consistent with published treatment guidelines for serious infections. Based on the 
investigator’s clinical assessment of the subject, treatment may be extended up to 21 days. 
3. STUDY OBJECTIVES 
3.1 
Primary Objective 
 To assess, at Test of Cure (TOC)1, the clinical outcome to therapy with 
cefiderocol or BAT in adult subjects with either hospital-acquired bacterial 
pneumonia (HABP)/ventilator-associated bacterial pneumonia 
(VABP)/healthcare-associated bacterial pneumonia (HCABP) or bloodstream 
infections/sepsis (BSI/sepsis)2 caused by carbapenem-resistant Gram-negative 
pathogens 
 To assess, at TOC, the microbiological outcome to therapy with cefiderocol or 
BAT in adult subjects with complicated urinary tract infection (cUTI) caused by 
carbapenem-resistant Gram-negative pathogens 
3.2 
Secondary Objectives  
 To assess the safety of cefiderocol 
 To assess the clinical outcome of treatment with cefiderocol or BAT in subjects 
with either HAP/VABP/HCABP or BSI/sepsis at End of Treatment (EOT)3 and 
Follow-up (FU)4  
 To assess the clinical outcome of treatment with cefiderocol or BAT in subjects 
with cUTI at EOT, TOC, and FU 


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 To assess the microbiological outcome of treatment with cefiderocol or BAT in 
subjects with either HABP/VABP/HCABP or BSI/sepsis at EOT, TOC, and FU 
 To assess the microbiological outcome of treatment with cefiderocol or BAT in 
subjects with cUTI at EOT and FU 
 To assess the microbiological outcome of treatment with cefiderocol or BAT in 
subjects with bacteremia (regardless of the primary infection diagnosis) at EOT, 
TOC, and FU 
 To assess the composite clinical and microbiological outcome of treatment with 
cefiderocol or BAT in subjects with cUTI at EOT, TOC, and FU 
 To assess the all-cause mortality at Day 14 and Day 28 in subjects with 
HABP/VABP/HCABP and BSI/sepsis 
 To compare cefiderocol with BAT in subjects with HABP/VABP/HCABP, cUTI, 
or BSI/sepsis based on the composite endpoint of survival and no change in 
antibiotic treatment due to either lack of therapeutic benefit or drug-related 
toxicity at TOC 
1  
TOC is defined as End of Treatment (EOT) + 7 days (± 2 days). 
2  
BSI/sepsis is a group of patients with documented carbapenem-resistant Gram-negative infections in 
the bloodstream (BSI) or in a body site other than the urinary tract (cUTI) or lung 
(HABP/VABP/HCABP) and in case of sepsis, evidence of systemic inflammatory response syndrome 
(SIRS) is required. 
3  
EOT = End of Treatment is defined as the last day of study therapy. 
4  
FU = Follow-up is defined as EOT + 14 days (± 3 days). 
4. STUDY DESIGN 
4.1 
Study Blinding 
This is an open-label study.  
4.2 
Randomization to Treatment Groups 
The treatments will be randomized to subject identification numbers by the IXRS® 
provider in a 2:1 fashion, i.e., 2 × cefiderocol and 1 × BAT. An interactive web or voice 
response system (IWRS/IVRS) will be used to assign subjects to identification numbers 
for which treatment has already been randomly assigned. Randomization will be 
performed by the stochastic minimization method using their infection site 
(HABP/VABP/HCABP, cUTI, and BSI/sepsis), APACHE II score (≤ 15 and ≥ 16), and 
region (North America, South America, Europe, and Asia-Pacific) as allocation factors. 
To avoid deterministic allocation based on the ongoing allocation results, probabilistic 
allocation will be incorporated. 
The population with HABP/VABP/HCABP will be approximately 50% of randomized 
subjects; cUTI is limited to no more than 30% of randomized subjects, and the remainder 
of subjects will be enrolled under the BSI/sepsis diagnosis. The randomization ratio of 
subjects between treatment groups based on clinical diagnosis will be maintained through 
the allocation factor of clinical diagnosis at the time of randomization. The process for 


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subject number assignment and treatment assignment is described in the study procedure 
manual. 
4.3 
Sample Size 
Approximately 150 subjects will be randomized 2:1 (2 × cefiderocol and 1 × BAT) to 
each group. This sample size will ensure that approximately 100 subjects are treated with 
cefiderocol. 
4.4 
Study Schematic 
The study design is shown in Figure 4-1. The study time and events table is shown in 
Appendix 1. 


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Figure 4-1 
Study Schematic 
D −2 
to  
D 1 
D 1 
D 3 
(after 6 doses) 
D 3 to D 4 
Up to  
D 14a 
EOT  
+ 7  
(± 2) 
EOT  
+ 14 
 (± 3) 
EOT 
+ 28 
 (± 3) 
Screening 
Randomization 
 
PK 
Early 
Clinical/Micro 
Assessment (EA) 
 
End of Treatment (EOT) 
Test of Cure (TOC) 
Follow-up (FU) 
End of Study (EOS) 
Treatment Period 
Cefiderocol 2 g intravenous dosing  
at 8-hour intervalsb 
BAT either polymyxin-based or  
nonpolymyxin-based 
BAT = best available therapy; D = days; EA = Early Assessment; eCRF = electronic case report form; 
EOT = End of Treatment (last day of study treatment); PK = pharmacokinetics 
Each day is a calendar date (i.e., D2 is the next day/date after D1 in calendar). 
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 in the eCRF. 
b 
Dosing adjustments for augmented renal clearance and renal impairment (see Table 5-2 in protocol). 
5. ANALYSIS POPULATIONS 
The following analysis populations will be defined in this study. 
5.1 
Intent-to-treat Population 
The Intent-to-treat population is defined as all randomized subjects who received at least 
1 dose of the study treatment.  
5.2 
Microbiological Intent-to-treat Population 
The Microbiological Intent-to-treat (Micro-ITT) population includes all ITT subjects who 
have a baseline Gram-negative pathogen from an appropriate clinical specimen, 
regardless if the pathogen is carbapenem resistant or not. Subjects should not be excluded 
from this population based upon events that occurred postrandomization (e.g., lost to 
follow-up). 
5.3 
Carbapenem-resistant Microbiological Intent-to treat Population  
The Carbapenem-resistant Microbiological Intent-to-treat (CR Micro-ITT) population 
includes all Micro-ITT subjects whose at least 1 of the baseline Gram-negative pathogens 
is carbapenem resistant and the carbapenem-resistant pathogen is confirmed by central 
laboratory. Subjects with Stenotrophomonas maltophilia as baseline pathogen will also 
be included in this population. If subsequent central laboratory results confirm that the 
pathogen is not carbapenem resistant, the subject with the pathogen will not be included 
in this population. 


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5.3.1 
Carbapenem-resistant Microbiological Intent-to-treat 2 Population 
The Carbapenem-resistant Microbiological Intent-to-treat 2 (CR Micro-ITT 2) population 
includes all subjects in the CR Micro-ITT population.  In addition, this CR Micro-ITT 2 
population will include subjects whose at least 1 of the baseline Gram-negative pathogens 
is carbapenem resistant confirmed by local laboratory if there is no central laboratory 
data available. 
5.4 
Carbapenem-resistant Microbiologically Evaluable Population 
The Carbapenem-resistant Microbiologically Evaluable (CR-ME) population includes all 
CR Micro-ITT subjects who follow important components of the study as specified in the 
protocol with no major protocol violations.  
Criteria for inclusion are: 
– ≥ 5 days of intravenous study treatment unless treatment was a failure 
– Underwent TOC assessment 
– Subjects without any major protocol inclusion or exclusion violations 
– Subjects with no violations of restrictions for concomitant therapy, including 
concomitant antibiotics effective against Gram-negative bacteria 
Details will be specified in protocol deviation specification. 
5.5 
Safety Population 
The Safety population includes all randomized subjects who receive at least 1 actual dose 
of the study treatment (ITT population). The population will be analyzed according to the 
treatment that the subjects actually received study drug regimen, rather than the treatment 
to which the subjects were randomized.  
Note that, as this is an open-label study, it has been observed that one subject received 
cefiderocol after completing the randomization assigned study treatment of BAT,.  This 
subject will be included in the Safety Population as having received BAT.  However,  a 
limited number of key safety analyses will be  repeated with this subject assigned to the 
cefiderocol arm. (see section 10.1.1 for details). 
5.6 
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, and the concentration summary. 


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6. STATISTICAL CONSIDERATIONS FOR DATA ANALYSES 
AND HANDLING 
6.1 
Statistical Reporting 
In this SAP, unless otherwise stated, summary statistics include the number of subjects, 
arithmetic mean, standard deviation (SD), minimum, median, and maximum. SAS® 
(Version 9.2 or later version) will be used for all statistical analyses. If the APACHE II 
score is corrected after randomization, the corrected score will be used in the analysis.  
6.2 
Statistical Testing 
No inferential testing will be performed except for the exploratory analysis described in 
Section 9.4.1.7. If statistical tests are performed, they will be performed at the 
0.05 significance level using 2-sided tests, except where otherwise noted. No multiplicity 
adjustment of statistical tests will be applied in this study. 
6.3 
Analysis Windows  
Measurements for efficacy or safety endpoints will be performed according to the 
schedule as shown in Section 4.4. The following analysis window (Table 6-1) will be 
used for analysis at a particular visit or time point to be included in by-visit summary 
statistics for the specified variables. Day 1 is defined as initial day of administration of 
drug.  
If there are multiple available values in an analysis time window, the closest value to the 
target day captured from scheduled visit or unscheduled visit will be used for analysis, 
and if there are multiple values within the same day, the latest value will be used.  
Table 6-1 
Analysis Window 
Time Point 
Target Day 
Analysis Time Window 
Early Assessment 
Day 3 or 4 
Not applicable 
End of Treatment 
End of last infusion 
Not applicable 
Test of Cure 
Date of end of last infusion + 7 
-2 to + 2 days 
Follow-up 
Date of end of last infusion + 14 
-3 to + 3 days 
PK sampling 
Just prior to the next 
infusion 
Next infusion start date and time 
–1 to 0 hours 
1 hour after the 
infusion 
Infusion start date and time + 1hr 
± 15 minutes 
At the end of infusion 
Infusion end date and time 
–15 minutes to end of infusion 
1 hour after end of 
infusion 
Infusion end date and time + 1hr 
± 0.5 hours 
Premature EOT 
Start date and time of last infusion 
Within 24 hours after last dose 
EOT = End of Treatment; PK = pharmacokinetic 
 


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Pharmacokinetic samples that are collected before the sixth dose administration will not 
be used for the summary of plasma cefiderocol concentrations (Pharmacokinetic samples 
just prior to the sixth dose will be included.). The target of the second PK sampling will 
be within 24 to 72 hours after the dosing adjustment. The target of PK sampling for 
premature EOT will be within 24 hours of the last dose. 
For all values including values obtained at an unscheduled visit, the analysis time 
window above will be applied. Values other than considered as TOC or FU, obtained at 
visit reported as EA and EOT will be used for analysis at EA and EOT, respectively. If a 
subject is received study drug more than 21 days, Day 21 will be considered as the date 
of end of last infusion. Unscheduled visits within an analysis time window for scheduled 
visit will be used to provide values for that scheduled visit. 
6.4 
Missing Data 
6.4.1 
Missing or Partial Dates and Times 
For classification of prior and concomitant medications, if the medication cannot be 
classified into concomitant medications or prior medications due to a partially missing 
date, the rules below will be applied for the classification. This rule will be applied for 
collection time of laboratory data as well if time is missing. 
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.  
If the year is observed but the time is missing, the first time of the day, 12:00 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 AM, 
will be used. 
If micro sample collection time is missing, the end time of the day, 23:59 AM, will be 
used. 
The imputed dates will not be displayed in the listings. 


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6.4.2 
Missing Microbiological or Clinical Outcome 
For clinical and microbiological outcomes, subjects who are lost to follow-up or have 
missing or “indeterminate” outcomes will be included in the denominator as 
indeterminate for cure/eradication rate, i.e., considered as not responders. If judged by the 
investigator that a subject died due to pneumonia, BSI/sepsis or cUTI, the clinical 
outcome will be considered as clinical failure after the event of death. If a subject died 
due to other reasons, the clinical outcome will be considered as “indeterminate” after 
death.   
For clinical outcome, if a subject recived additional antibiotics for target disease (i.e, 
baseline infection) before the target date, the outcome will be considered as "clinical 
failure". If  a subject did not receive additional antibiotics for target disease before the 
target date, the outcome will be considered as "indeterminate".  
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. 
6.5 
Baseline Definition 
- 
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 number 4). 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. Clinical specimens obtained by 
the site within the 2 days prior to signing informed consent form could be 
acceptable as screening/baseline cultures for this study. 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 rules will be applied:   
- 
In case same Gram-negative pathogens with different quantification are obtained 
from multiple samples from the same specimen type (i.e., blood, urine, respiratory 
specimen, or infection site that caused septic shock) that qualified a patient 
eligible for this study, the pathogen with the highest quantification/classification 
is considered as the baseline pathogen. The priority of quantitation is listed below: 
1. Highest value in quantification 
2. Largest value in semiquantification  
3. Largest value in no-quantification 
- 
In case same Gram-negative pathogens with same quantification are obtained 
from different specimens, the pathogen with the highest minimum inhibitory 
concentration (MIC) for 1. cefiderocol 2. Meropenem, 3. Imipenem, 4. colistin is 
considered as the baseline pathogen. 


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The appropriate clinical specimen type is sputum, tracheal aspirate, bronchoalveolar 
lavage (BAL) fluid, protected specimen brush, pleural fluid, lung biopsy for 
HABP/VABP/HCABP, blood for BSI/sepsis, or urine for cUTI. Tissue from primary 
infection site is also applicable for all baseline infection. Specimen that was collected 
from other site may be considered as appropriate specimen. This will be determined by 
the medical monitor.   
Only for subjects with cUTI, the pathogen whose quantification is 105 colony-forming 
units (CFUs)/mL or more will be considered as baseline pathogen. 
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.  
6.6 
Study Day Definition 
Day 1 is the calendar day on which each subject takes initial investigational medicinal 
product (IMP). However, Day 1 is the calendar day of randomization for subjects who 
did not take any IMP. Previous day to Day 1 is expressed as Day -1, and days before 
Day -1 in Screening Period are expressed as Day -2, Day -3, …, etc.  
6.7 
Handling for 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. In that case, quantification will be 
considered as missing. 
6.8 
Additional Antibiotics 
Additional antibiotics are defined as systemic antibiotics with Gram-negative activity. 
The medical group will determine which medications have Gram-negative activity. If the 
route of administration is ophthalmic, transdermal, nasal, topical, or vaginal, the 
medication will not be considered as a systemic antibiotic.Concomitant medications 
ending before initial study treatment start date/time plus 3 hours will not be considered as 
additional antibiotics. Antibiotics for Gram-negative pathogens that are allowed to be 
received (see Clinical Study Protocol Section 5.2.1.1) from Day 1 or Day 2, they will not 
be considered as additional therapy, but if they are received on Day 3 or after, they will 
be considered as additional therapy.  
Medical monitor will adjudicate additional antibiotics based on the available data if 
needed. 
6.9 
Study Drug Regimen at Day 1 and 2 
For efficacy analysis, response rate in the cefiderocol group will be calculated by 
cefiderocol monotherapy or not, and in the BAT group by colistin-based regimen or not. 


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Colistin-based regimen includes subjects who received  “COLISTIN”,  “POLYMYXIN” 
or “POLYMYXIN B” based on WHO Drug Dictionary Preferred Term (PT).  
7. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
7.1 
Subject Disposition and Discontinuation 
Subject disposition will be summarized for the all screened subjects. The following 
subjects’ disposition categories will be included: 
 Subjects who were screened 
 Subjects who were screen failed 
For the subjects who were screen failed, they will be also summarized by respective 
reasons.  
Subject disposition will be summarized by treatment group for the all randomized 
subjects. The following subjects’ disposition categories will be included: 
 Subjects who were randomized 
 Subjects who were randomized and treated 
 Subjects who completed treatment 
 Subjects who did not complete treatment 
 Subjects who completed the study 
 Subjects who discontinued early from the study 
Subjects who received study drug for 7 days or more (for cUTI subjects, 5 days or more) 
will be considered as subjects who completed treatment. Subjects who did not complete 
treatment and subjects who discontinued early from the study will be also summarized by 
respective reasons.  
The number of subjects in the ITT population, Micro-ITT population, CR Micro-ITT 
population, CR-ME population, and Safety population will be obtained by treatment 
group. The reasons for excluding subjects from each of the populations listed above will 
be summarized by treatment group. 
7.2 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized with descriptive statistics 
for the CR Micro-ITT population, , CR Micro-ITT 2 population, CR-ME population, 
Micro-ITT population, and Safety population. The distribution of demographic and other 
baseline characteristics shown in Table 7-1 will be summarized by treatment group. 
Summary statistics will be calculated for quantitative scale items, and frequency and 
proportion of subjects in each category will be obtained for qualitative (i.e., binary and 
nominal) scale items. Quantitative scale items except for height, body mass index, SOFA 
and CPIS will be categorized and tabulated by treatment group.  


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The baseline pathogen will be summarized for Micro-ITT and CR Micro-ITT. The 
baseline carbapenem-resistant pathogen will also be summarized. The pathogen which is 
collected from blood specimen at baseline will also be summarized.  
The baseline pathogen will also be summarized for the MIC values and susceptibility 
defined by Clinical and Laboratory Standards Institute (CLSI) and European Committee 
on Antimicrobial Susceptibility Testing (EUCAST) 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. 
The reported medical history will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA). Medical history will be summarized for the CR Micro-ITT 
population and Safety population for each treatment group by MedDRA System Organ 
Class (SOC) and PT.  
 
Table 7-1 
Demographic and Baseline Characteristics 
Quantitative 
scale items 
Age, height, weight, body mass index, creatinine clearance, total 
APACHE II score, baseline fever, SOFA score, CPIS  
Binary or 
nominal scale 
items 
Gender, race, ethnicity, region, infection site, clinical diagnosis, baseline 
fever group, medical history, prior therapy with Gram-negative coverage, 
number of Gram-negative pathogens from appropriate specimen, causal 
infection for BSI/sepsis, severity of the disease 
APACHE II = Acute Physiology and Chronic Health Evaluation II; CPIS = clinical pulmonary infection 
score; SOFA = Sequential Organ Failure Assessment 
Note: See Section 14 for categories.  
8. STUDY CONDUCT 
8.1 
Protocol Deviations 
For all randomized subjects, major protocol deviations will be listed. Major protocol 
deviations will be specified in the “Protocol deviation specification” separately. A final 
list of major protocol deviations will be determined based on data review prior to 
database lock.  
8.2 
Treatment Exposure and Compliance 
Extent of treatment exposure is defined as the actual dosing period during which subjects 
took medication as follows: 
(The day of the final IMP dose) – (The day of the first IMP dose) + 1 [day] 


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For the CR Micro-ITT population and Safety population, summary statistics of duration 
of treatment exposure will be calculated by treatment group based on EDC data. Also 
categorized duration of treatment will be summarized by treatment group (see Section 14 
about category). 
8.3 
Study Drug Regimen 
Best available therapy and adjunctive antibiotics taken from randomization to the end of 
study will be coded using World Health Organization (WHO) Drug Dictionary (Sep 2015 
or later). The number and percentage of subjects taking BAT or adjunctive medications 
will be summarized by Anatomical Therapeutic Class (ATC) and PT for each treatment 
group for the CR Micro-ITT population and Safety population. Although a subject may 
have taken 2 or more medications, the subject is counted only once within an ATC 
classification. The same subject may contribute to 2 or more PTs in the same 
classification. All study drug administration data will be listed by subjects. 
In addition, study drug regimen for Gram-negative pathogen that is received at Day 1 and 
Day 2 after first study drug administration will be summarized by treatment group for CR 
MITT and safety population. Study drug regimen includes only cefiderocol or 
BAT/adjunctive therapy and does not include concomitant medications. Generic names 
will be used for this summary.  
8.4 
Prior Therapy and Concomitant Therapy Other Than Best 
Available Therapy/Adjunctive Antibiotics 
Prior and concomitant medications will be coded using the WHO Drug Dictionary. If a 
subject received cefiderocol as concomitant medication, this will be reported as 
cefiderocol. Prior medications are defined as medications that were taken prior to the first 
dose date/time of the study drug. Concomitant medications are defined as medications 
that were taken on or after the first dose date/time of the study drug. 
The number and percentage of subjects taking concomitant medications or procedures 
will be summarized by ATC and PT for each treatment group for the CR Micro-ITT 
population and Safety population. Although a subject may have taken 2 or more 
medications, the subject is counted only once within an ATC classification. The same 
subject may contribute to 2 or more PTs in the same classification. Prior medications or 
procedures will be summarized in the same manner for the CR Micro-ITT population and 
Safety population.  
9. EFFICACY 
The primary population for efficacy analyses will be the CR Micro-ITT population. 
CR-ME population will be used as a supplementary analysis for primary efficacy 
endpoint. Micro-ITT population will be used to check the consistency of results for 
primary efficacy endpoints. Also, unless stated otherwise, a confidence interval (CI) of 
proportion will be calculated using the Clopper-Pearson method. 


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9.1 
Efficacy Assessment 
9.1.1 
Clinical Outcomes for EOT and TOC 
The clinical outcomes will be assessed by the investigator according to the following 
criteria established for each infection site at 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 electronic case report form (eCRF). 
9.1.1.1 
HABP/VABP/HCABP 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms of pneumonia including a reduction in SOFA score and clinical 
pulmonary infection score (CPIS), and improvement or lack of progression of 
chest radiographic abnormalities such that no antibacterial therapy is required for 
the treatment of the current infection. 
 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. 
9.1.1.2 
cUTI 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms of cUTI, or return to preinfection baseline if known, such that no 
antibacterial therapy is required for the treatment of the current infection. 
 Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms of cUTI; or reappearance of signs and/or 
symptoms of cUTI; development of new signs and/or symptoms of cUTI 
requiring antibiotic therapy other than, or in addition to, study treatment therapy; 
or death due to cUTI. 
 Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 
9.1.1.3 
BSI/Sepsis 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms including a reduction in SOFA score, such that no antibacterial therapy 
is required for the treatment of BSI/sepsis. Subjects with bacteremia must have 
eradication of bacteremia caused by the Gram-negative pathogen. 
 Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms, reappearance of signs and/or symptoms; 


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development of new signs and/or symptoms requiring antibiotic therapy other 
than, or in addition to, study treatment therapy; or death due to BSI/sepsis. 
 Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 
9.1.2 
Clinical Outcomes for Follow-up 
The clinical outcomes will be assessed by the investigator according to the following 
criteria established for each infection site at FU. The clinical outcomes will be entered in 
the eCRF. 
9.1.2.1 
HABP/VABP/HCABP 
 Sustained Clinical Cure: Continued resolution or substantial improvement of 
baseline signs and symptoms of pneumonia, such that no antibacterial therapy is 
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. Indeterminate at TOC will be carried 
forward. 
 Clinical Failure: Clinical failure at TOC will be carried forward regardless of 
lost to follow-up. 
9.1.2.2 
cUTI 
 Sustained Clinical Cure: Continued resolution or improvement of baseline signs 
and symptoms of cUTI, or return to preinfection baseline if known, in a subject 
assessed as cured at TOC. 
 Relapse: Recurrence of signs and/or symptoms of cUTI, or appearance of new 
signs and/or symptoms of cUTI 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. Indeterminate at TOC will be carried 
forward. 
 Clinical Failure: Clinical failure at TOC will be carried forward regardless of 
lost to follow-up. 
9.1.2.3 
BSI/Sepsis 
 Sustained Clinical Cure: Continued resolution or substantial improvement of 
baseline signs and symptoms associated with reduction in SOFA score, such that 
no antibacterial therapy is required for the treatment of the subjects original 
BSI/sepsis in a subject assessed as cured at TOC. 


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 Relapse: Recurrence of signs and/or symptoms of BSI/sepsis, or appearance of 
new signs and/or symptoms of the subjects original BSI/sepsis 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. Indeterminate at TOC will be carried 
forward. 
 Clinical Failure: Clinical failure at TOC will be carried forward regardless of 
lost to follow-up. 
9.1.3 
Microbiological Outcomes per Baseline Pathogen for EOT and TOC 
The microbiological outcomes per baseline pathogen will be determined by the sponsor 
according to the following criteria established for each infection site at EOT and TOC. In 
case treatment duration is extended beyond 14 days, an additional microbiological 
outcome will be assessed on Day 14. 
9.1.3.1 
HABP/VABP/HCABP 
 Eradication: Absence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. If it is not possible to obtain an appropriate clinical 
culture and the subject has a successful clinical outcome, the response will be 
presumed to be eradication. 
 Persistence: Continued presence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. 
 Indeterminate: No culture obtained from an appropriate clinical specimen or 
additional antibacterial therapy for the treatment of the current infection. 
9.1.3.2 
cUTI 
 Eradication: A urine culture shows the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFUs/mL are reduced to < 103 CFUs/mL. 
 Persistence: A urine culture shows that the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFUs/mL grows ≥ 103 CFUs/mL. 
 Indeterminate: No urine culture obtained from an appropriate clinical specimen 
or additional antibacterial therapy for the treatment of the current infection. 
9.1.3.3 
BSI/Sepsis 
 Eradication: Absence of the baseline Gram-negative pathogen from a blood 
culture and/or other primary source as applicable. In the case of sepsis, if the 
subject has a successful clinical outcome and it is not possible to obtain an 
appropriate clinical culture, the response will be presumed to be eradication. In 
the case of BSI, if the subject has a successful clinical outcome and the 
investigator  considers no further need to obtain a clinical culture, the response 
will be presumed to be eradication. 


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 Persistence: Continued presence of the baseline Gram-negative pathogen from a 
blood culture or other primary source. 
 Indeterminate: No culture obtained from an appropriate clinical specimen or 
additional antibacterial therapy for the treatment of the current infection. The 
exception to this is noted in 9.1.3.3 definition of Eradication. 
9.1.4 
Microbiological Outcomes per Baseline Pathogen for Follow-up 
Microbiological outcomes by baseline pathogen will be determined by the sponsor 
according to the following criteria established for each infection site at FU. 
9.1.4.1 
HABP/VABP/HCABP 
 Sustained Eradication: Absence of the baseline Gram-negative pathogen from 
an appropriate clinical specimen after TOC. 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 sustained eradication. 
 Recurrence: Recurrence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen taken after TOC, and the TOC culture is negative. 
 Indeterminate: No culture obtained from an appropriate clinical specimen or 
subject received additional antibacterial therapy for the treatment of the current 
infection. Indeterminate at TOC will be carried forward. 
 Persistence: Persistence at TOC will be carried forward. 
9.1.4.2 
cUTI 
 Sustained Eradication: A culture taken any time after documented eradication at 
TOC, and a urine culture obtained at FU shows that the baseline uropathogen 
found at entry at ≥105 CFUs/mL remains < 103 CFUs/mL. 
 Recurrence: A culture taken any time after documented eradication at TOC, up 
to and including FU that grows the baseline uropathogen ≥ 103 CFUs/mL. 
 Indeterminate: No urine culture or subject received additional antibacterial 
therapy for the treatment of the current infection. Indeterminate at TOC will be 
carried forward. 
 Persistence: Persistence at TOC will be carried forward. 
9.1.4.3 
BSI/Sepsis 
 Sustained Eradication: Absence of the baseline Gram-negative pathogen from a 
blood culture or other primary source after TOC as applicable. In the case of 
sepsis, if the subject has a successful clinical outcome after TOC and it is not 
possible to obtain an appropriate clinical culture, the response will be presumed to 
be sustained eradication. In the case of BSI, if the subject has a successful clinical 
outcome and the investigator  considers no further need to obtain a clinical culture, 
the response will be presumed to be eradication. 


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 Recurrence: Recurrence of the baseline Gram-negative pathogen from a blood 
culture or other primary source after TOC and the TOC culture is negative. 
 Indeterminate: No culture from an appropriate clinical specimen or subject 
received additional antibacterial therapy for the treatment of the current infection. 
Indeterminate at TOC will be carried forward. . The exception to this is noted in 
9.1.4.3 definition of Eradication. 
 Persistence: Persistence at TOC will be carried forward. 
9.1.5 
New Pathogens 
New pathogens that emerge on or after Day 3 will be categorized as either superinfection 
or new infection as follows: Superinfection and new infection will be listed by Gram-
negative pathogen and the others. 
 Superinfection: The identification from an appropriate clinical specimen of a 
new pathogen from the original infection site.  
 New Infection: The identification from an appropriate clinical specimen of a new 
pathogen from an infection site different from the original infection site.  
9.1.6 
Per Subject Microbiological Outcomes 
As shown in Table 9-1, subjects who experience eradication of all baseline 
Gram-negative pathogens at EOT and TOC will be considered “ Eradication” and 
subjects who experience persistence of any baseline Gram-negative pathogen will be 
considered “persistence.” Subjects whose experiences are other than above will be 
considered “indeterminate.” At FU, subjects who experience sustained eradication of all 
baseline Gram-negative pathogens after documented eradication at the TOC will be 
considered “sustained eradication” and subjects who experience eradication at TOC but 
recurrence of any baseline Gram-negative pathogen will be considered as ”recurrence”, 
and subjects who are considered as “persistence” at TOC will be “persistence.” Subjects 
whose experiences are other than above will be considered “indeterminate.” 
Table 9-1 
Per Subject Microbiological Outcome 
Visit 
Per Subject Microbiological 
Outcome 
Definition 
EOT, TOC 
Eradication 
Eradication of all baseline Gram-negative pathogens 
Persistence 
Persistence of any baseline Gram-negative pathogens 
Indeterminate 
Other than those above 
FU 
Sustained  eradication 
Sustained eradication of all baseline Gram-negative 
pathogens after documented eradication at the TOC 
Persistence 
Persistence of any baseline Gram- at the TOC 
Recurrence 
Recurrence of any baseline Gram-negative pathogens 
for subjects eradication at the TOC 
Indeterminate 
Other than those above 
EOT = End of Treatment; FU = Follow-up; TOC = Test of Cure 


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For the subjects who have Gram-positive pathogens at baseline, the Gram-positive 
pathogens will be shown in the listing of local microbiological test and not be taken into 
account in either per pathogen microbiological outcome or per subject microbiological 
outcome.   
9.1.7 
Definition for Composite of Clinical and Microbiological Outcome 
The definition for composite of clinical and microbiological outcome based on possible 
combinations per subject microbiological outcome and clinical outcome is shown in 
Table 9-2 for EOT and TOC, and in Table 9-3 for FU. 
Table 9-2 
Clinical and Microbiological Outcome: EOT and TOC 
Per Subject Microbiological 
Outcome 
Clinical Outcome 
Composite of Clinical and 
Microbiological Outcome 
Eradication 
Clinical cure 
Response 
Eradication 
Clinical failure 
Failure 
Eradication 
Indeterminate 
Indeterminate 
Persistence 
Clinical cure 
Failure 
Persistence 
Clinical failure 
Failure 
Persistence 
Indeterminate 
Failure 
Indeterminate  
Clinical cure 
Indeterminate 
Indeterminate  
Clinical failure 
Failure 
Indeterminate  
Indeterminate 
Indeterminate 
 
Table 9-3 
Composite Outcome: Follow-up 
Per Subject Microbiological 
Outcome 
Clinical Outcome 
Composite of Clinical and 
Microbiological Outcome 
Sustained eradication 
Sustained clinical cure 
Response 
Sustained eradication 
Clinical failure 
Failure 
Sustained eradication 
Clinical relapse 
Failure 
Sustained eradication 
Indeterminate 
Indeterminate 
Persistence 
Sustained clinical cure 
Failure 
Persistence 
Clinical failure 
Failure 
Persistence 
Clinical relapse 
Failure 
Persistence 
Indeterminate 
Failure 
Recurrence 
Sustained clinical cure 
Failure 
Recurrence 
Clinical failure 
Failure 
Recurrence 
Clinical relapse 
Failure 
Recurrence 
Indeterminate 
Failure 
Indeterminate  
Sustained clinical cure 
Indeterminate 
Indeterminate  
Clinical failure 
Failure 
Indeterminate  
Clinical relapse 
Failure 
Indeterminate  
Indeterminate 
Indeterminate 
 


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9.1.8 
Clinical Pulmonary Infection Score  
Clinical pulmonary infection score is a surrogate for diagnosis and treatment response. 
Points (0, 1, or 2) will be assigned for observed findings for 5 variables, including body 
temperature, white blood cell (WBC) count, tracheal secretions, partial pressure of 
arterial oxygen (PaO2), fraction of inspired oxygen (FiO2), and chest radiograph. 
9.1.9 
Sequential Organ Failure Assessment Score 
The 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. 
9.2 
Supplementary Efficacy Assessment 
9.2.1 
Analysis Time Window 
Only for supplementary analysis described in Section 9.2, the time window below will be 
applied (Table 9-4). If there are multiple available values in an analysis time window, the 
data captured as corresponding visit will be used for analysis. If there is no such data, the 
closest value to the target day will be used for analysis, and if there are multiple values 
within the same day, the latest value will be used. 
Table 9-4 
Analysis Window 
Time Point 
Target Day/Time 
Analysis Time Window 
End of Treatment 
Date of end of last infusion 
-1 to + 3 days 
Test of Cure 
Date of end of last infusion + 7 
-3 to + 3 days 
Follow-up 
Date of end of last infusion + 14 
-3 to + 3 days 
 
9.2.2 
Supplementary Clinical Outcomes for EOT and TOC 
9.2.2.1 
HABP/VABP/HCABP 
 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 antibacterial therapy is required for the treatment of the current infection. 
 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 more than 48 hours of antibiotic therapy other than, or in 
addition to, study treatment therapy; progression of chest radiographic 
abnormalities; or death due to pneumonia or death after Day 4 (including) 
regardless of the reason. If EOT is clinical failure, TOC is also clinical failure. 
 Indeterminate: Lost to follow-up due to death other than pneumonia at Days 1, 2 
or 3, withdrawal, or no assessment. 


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9.2.2.2 
cUTI 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms of cUTI, or return to preinfection baseline if known, such that no 
antibacterial therapy is required for the treatment of the current infection. 
 Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms of cUTI; or reappearance of signs and/or 
symptoms of cUTI; development of new signs and/or symptoms of cUTI 
requiring more than 48 hrs antibiotic therapy other than, or in addition to, study 
treatment therapy; or death due to cUTI or death after Day 4 (including) 
regardless of the reason. If EOT is clinical failure, TOC is also clinical failure. 
 Indeterminate: Lost to follow-up due to death other than cUTI at Days 1, 2 or 3, 
withdrawal, or no assessment. 
9.2.2.3 
BSI/Sepsis 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms including a reduction in SOFA score, such that no antibacterial therapy 
is required for the treatment of BSI/sepsis. Subjects with bacteremia must have 
eradication of bacteremia caused by the Gram-negative pathogen. 
 Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms, reappearance of signs and/or symptoms; 
development of new signs and/or symptoms requiring more than 48 hrs antibiotic 
therapy other than, or in addition to, study treatment therapy; or death due to 
BSI/sepsis or death after Day 4 (including) regardless of the reason. If EOT is 
clinical failure, TOC is also clinical failure. 
 Indeterminate: Lost to follow-up due to death other than BSI/Sepsis at Days 1, 2 
or 3, withdrawal or no assessment. 
9.2.3 
Supplementary Clinical Outcomes for Follow-up 
9.2.3.1 
HABP/VABP/HCABP 
 Sustained Clinical Cure: Continued resolution or substantial improvement of 
baseline signs and symptoms of pneumonia, such that no antibacterial therapy is 
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 or death regardless of the reason in a patient assessed as cured at TOC. 
 Indeterminate: Lost to follow-up due to death other than pneumonia at Days 1, 2 
or 3, withdrawal, no assessment, or received additional antibacterial therapy more 
than 48 hrs between TOC and FU for the treatment of the current infection. 
 Clinical Failure: Clinical failure at TOC will be carried forward. 


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9.2.3.2 
cUTI 
 Sustained Clinical Cure: Continued resolution or improvement of baseline signs 
and symptoms of cUTI, or return to preinfection baseline if known, in a subject 
assessed as cured at TOC. 
 Relapse: Recurrence of signs and/or symptoms of cUTI, or appearance of new 
signs and/or symptoms of cUTI in a subject assessed as cured at TOC. 
 Indeterminate: Lost to follow-up due to death other than cUTI at Day 1, 2 or 3, 
withdrawal, no assessment, or received additional antibacterial therapy more than 
48 hrs between TOC and FU for the treatment of the current infection. 
 Clinical Failure: Clinical failure at TOC will be carried forward. 
9.2.3.3 
BSI/Sepsis 
 Sustained Clinical Cure: Continued resolution or substantial improvement of 
baseline signs and symptoms associated with reduction in SOFA score, such that 
no antibacterial therapy is required for the treatment of the subjects original 
BSI/sepsis in a subject assessed as cured at TOC. 
 Relapse: Recurrence of signs and/or symptoms of BSI/sepsis, or appearance of 
new signs and/or symptoms of the subjects original BSI/sepsis or death due to 
BSI/sepsis in a subject assessed as cured at TOC. 
 Indeterminate: Lost to follow-up due to death other than BSI/sepsis at Days 1, 2 
or 3, withdrawal, no assessment, or received additional antibacterial therapy more 
than 48 hrs between TOC and FU for the treatment of the current infection.  
 Clinical Failure: Clinical failure at TOC will be carried forward. 
9.2.4 
Microbiological Outcomes per Baseline Pathogen for EOT and TOC 
The microbiological outcomes per baseline pathogen will be determined by the sponsor 
according to the following criteria established for each infection site at EOT and TOC. 
9.2.4.1 
HABP/VABP/HCABP 
 Eradication: Absence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. If it is not possible to obtain an appropriate clinical 
culture and the subject has a successful clinical outcome, the response will be 
presumed to be eradication. In the case of BSI, if the subject has a successful 
clinical outcome and the investigator  considers no further need to obtain a 
clinical culture, the response will be presumed to be eradication. 
 Persistence: Continued presence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen or death due to pneumonia. If EOT is persistence, 
TOC is also persistence. 
 Indeterminate: Lost to follow-up due to death not related to current infection, 
withdrawal, no assessment, or additional antibacterial therapy for the treatment of 
the current infection. 


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9.2.4.2 
cUTI 
 Eradication: A urine culture shows the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFUs/mL are reduced to < 103 CFUs/mL. 
 Persistence: A urine culture shows that the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFUs/mL grows ≥ 103 CFUs/mL or death due to cUTI. If 
EOT is persistence, TOC is also persistence. 
 Indeterminate: Lost to follow-up due to death not related to current infection, 
withdrawal, no assessment, or additional antibacterial therapy for the treatment of 
the current infection. 
9.2.4.3 
BSI/Sepsis 
 Eradication: Absence of the baseline Gram-negative pathogen from a blood 
culture and/or other primary source as applicable. If the subject has a successful 
clinical outcome and it is not possible to obtain an appropriate clinical culture, the 
response will be presumed to be eradication. In the case of BSI, if the subject has 
a successful clinical outcome and the investigator  considers no further need to 
obtain a clinical culture, the response will be presumed to be eradication. 
 Persistence: Continued presence of the baseline Gram-negative pathogen from a 
blood culture or other primary source or death due to BSI/sepsis. If EOT is 
persistence, TOC is also persistence. 
 Indeterminate: Lost to follow-up due to death not related to current infection, 
withdrawal, no assessment, or additional antibacterial therapy for the treatment of 
the current infection. 
9.2.5 
Microbiological Outcomes per Baseline Pathogen for Follow-up 
Microbiological outcomes by baseline pathogen will be determined by the sponsor 
according to the following criteria established for each infection site at FU. 
9.2.5.1 
HABP/VABP/HCABP 
 Sustained Eradication: Absence of the baseline Gram-negative pathogen from 
an appropriate clinical specimen after TOC. 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 is negative or 
death due to pneumonia. 
 Indeterminate: Lost to follow-up due to death not related to current infection, 
withdrawal, no assessment, or additional antibacterial therapy for the treatment of 
the current infection. 
 Persistence: Persistence at TOC will be carried forward. 


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9.2.5.2 
cUTI 
 Sustained Eradication: A culture taken any time after documented eradication at 
TOC, and a urine culture obtained at FU shows that the baseline uropathogen 
found at entry at ≥105 CFUs/mL remains < 103 CFUs/mL. 
 Recurrence: A culture taken any time after documented eradication at TOC, up 
to and including FU that grows the baseline uropathogen ≥ 103 CFUs/mL or death 
due to cUTI. 
 Indeterminate: Lost to follow-up due to death not related to current infection, 
withdrawal, no assessment, or additional antibacterial therapy for the treatment of 
the current infection. 
 Persistence: Persistence at TOC will be carried forward. 
9.2.5.3 
BSI/Sepsis 
 Sustained Eradication: Absence of the baseline Gram-negative pathogen from a 
blood culture or other primary source after TOC as applicable. In the case of 
sepsis, if the subject has a successful clinical outcome after TOC and it is not 
possible to obtain an appropriate clinical culture, the response will be presumed to 
be sustained eradication. In the case of BSI, if the subject has a successful clinical 
outcome and the investigator  considers no further need to obtain a clinical culture, 
the response will be presumed to be eradication. 
 Recurrence: Recurrence of the baseline Gram-negative pathogen from a blood 
culture or other primary source after TOC and the TOC culture is negative or 
death due to BSI/sepsis. 
 Indeterminate: Lost to follow-up due to death not related to current infection, 
withdrawal, no assessment, or additional antibacterial therapy for the treatment of 
the current infection. 
 Persistence: Persistence at TOC will be carried forward. 
9.2.6 
Per Subject Microbiological Outcomes 
As shown in Table 9-1, subjects who experience eradication of all baseline 
Gram-negative pathogens at EOT and TOC will be considered “ eradication” and subjects 
who experience persistence of any baseline Gram-negative pathogen will be considered 
“persistence.” Subjects whose experiences are other than above will be considered 
“indeterminate.” At FU, subjects who experience sustained eradication of all baseline 
Gram-negative pathogens after documented eradication at the TOC will be considered 
“sustained eradication” and subjects who experience persistence or recurrence of any 
baseline Gram-negative pathogen or subjects who are considered as “persistence” at TOC 
will be “persistence.” Subjects whose experiences are other than above will be considered 
“indeterminate.” 
9.3 
Primary Efficacy Endpoint 
The primary endpoints in subjects with HABP/VABP/HCABP or BSI/sepsis and in 
subjects with cUTI are the following: 


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 For subjects with HABP/VABP/HCABP or BSI/sepsis, clinical outcome per 
subject at TOC. 
 For subjects with cUTI, microbiologic outcome (for Gram-negative pathogen) per 
subject at TOC. 
9.3.1 
Primary Analyses for the Primary Efficacy Endpoint  
For the CR Micro-ITT population, the following analysis will be performed.  
The clinical outcomes at TOC will be summarized and clinical cure rates and its 95% CIs 
will be calculated by treatment group (cefiderocol or BAT) for subjects with 
HABP/VABP/HCABP or BSI/sepsis, separately. The clinical response rate will be 
calculated as the proportion of subjects whose clinical outcome is clinical cure at TOC.  
The microbiological outcomes at TOC will be summarized and microbiological 
eradication rates and its 95% CIs will be calculated by treatment group (cefiderocol or 
BAT) for the subjects with cUTI. The microbiological response rate will be calculated as 
the proportion of subjects whose all of baseline Gram-negative uropathogen(s) are 
eradicated at TOC. 
9.3.2 
Supplementary Analyses for the Primary Efficacy Endpoint 
9.3.2.1 
Supplementary Analyses for the Primary Efficacy Endpoint 
Using Different Population 
For the CR-ME population and Micro-ITT population, the primary analyses stated in 
Section 9.2.1 will be performed as supplementary analyses. 
9.3.2.2 
Supplementary Analyses for the Microbiological Outcome 
Changing Eradication Criteria for cUTI 
For the subjects with cUTI in the CR Micro-ITT population, CR-ME population and 
Micro-ITT population based on the definition of microbiological outcomes below, the 
outcomes at each time point will be summarized and its 95% CIs will be calculated by 
treatment group.   
For EOT and TOC: 
 Eradication: A urine culture shows the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFUs/mL are reduced to < 104 CFUs/mL. 
 Persistence: A urine culture shows that the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFUs/mL grows ≥ 104 CFUs/mL. 
 Indeterminate: No urine culture obtained or additional antibacterial therapy for 
the treatment of the current infection. 
For FU: 


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 Sustained Eradication: A culture taken any time after documented eradication at 
TOC, and a urine culture obtained at FU shows that the baseline uropathogen 
found at entry at ≥105 CFUs/mL remains < 104 CFUs/mL. 
 Recurrence: A culture taken any time after documented eradication at TOC, up 
to and including FU that grows the baseline uropathogen ≥ 104 CFUs/mL. 
 Indeterminate: No urine culture or subject received additional antibacterial 
therapy for the treatment of the current infection. Indeterminate at TOC will be 
carried forward. 
 Persistence: Persistence at TOC will be carried forward. 
9.3.3 
Subgroup Analyses 
Clinical outcome and microbiological outcome per subject at TOC will be summarized 
by age group, gender, race, and infection site, type of baseline CR pathogen, APACHE II 
score (≤ 15 and ≥ 16), and region (North America, South America, Europe, and Asia-
Pacific) for the CR Micro-ITT population.  The same analysis will be applied for 
microbiological outcome, and 28 days all-cause mortality. 
Other subgroup analyses may be performed if deemed necessary. 
9.4 
Secondary Endpoints 
The secondary endpoints of this study are the following: 
 Clinical outcome per subject at EOT and FU (HABP/VABP/HCABP or 
BSI/sepsis) 
 Clinical outcome per pathogen at EOT,TOC, and FU(HABP/VABP/HCABP, 
BSI/sepsis or cUTI) 
 Clinical outcome per subject/pathogen at EOT, TOC, and FU (cUTI) 
 Clinical outcome per subject/pathogen at EOT, TOC, and FU 
(HABP/VABP/HCABP + BSI/sepsis, overall) 
 Clinical outcome per CR pathogen at EOT, TOC, and FU (HABP/VABP/HCABP, 
BSI/sepsis, cUTI, HABP/VABP/HCABP + BSI/sepsis, overall) 
 Microbiological outcome (for baseline Gram-negative pathogens) per 
subject/pathogen at EOT, TOC, and FU (HABP/VABP/HCABP or BSI/sepsis) 
 Microbiological outcome (for baseline Gram-negative pathogens) per subject at 
EOT and FU (cUTI) 
 Microbiological outcome (for baseline Gram-negative pathogens) per pathogen at 
EOT, TOC, and FU (cUTI) 
 Microbiological outcome (for baseline Gram-negative pathogens) per 
subject/pathogen at EOT, TOC, and FU (HABP/VABP/HCABP + BSI/sepsis, 
overall) 


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 Microbiological outcome (for baseline CR Gram-negative pathogens) per subject 
at EOT, TOC and FU (HABP/VABP/HCABP, BSI/sepsis, cUTI, 
HABP/VABP/HCABP + BSI/sepsis, overall) 
 Microbiological outcome (for baseline CR Gram-negative pathogens) per 
pathogen at EOT, TOC, and FU (HABP/VABP/HCABP, BSI/sepsis, cUTI, 
HABP/VABP/HCABP + BSI/sepsis, overall) 
 Microbiological outcome with documented carbapenem-resistant Gram-negative 
bacteremia (overall) at EOT, TOC, and FU 
 Composite clinical and microbiological outcome at EOT, TOC, and FU 
(HABP/VABP/HCABP, BSI/sepsis, cUTI) 
 All-cause mortality at Day 14 and Day 28  
 Composite endpoint of survival and no change in antibiotic treatment due to either 
lack of therapeutic benefit or drug-related toxicity at TOC 
 Survival time (HABP/VABP/HCABP, BSI/sepsis) 
 CPIS parameters at EOT, TOC, and FU (HABP/VABP/HCABP only) 
 SOFA score at EOT, TOC, and FU  
9.4.1 
Analyses for Secondary Efficacy Endpoints 
The following analyses of the secondary efficacy endpoints will be performed for the 
CR Micro-ITT population.  
9.4.1.1 
Clinical Outcome 
For the clinical outcome per subject, the outcomes will be summarized and the cure rate 
and its 95% CI at EOT,TOC (only for cUTI) and FU will be calculated by treatment 
group per infection site (HABP/VABP/HCABP, cUTI, and BSI/sepsis). The clinical 
response rate will be calculated as the proportion of subjects whose clinical outcome is 
clinical cure at each point. In addition, the clinical outcome per subject for 
HABP/VABP/HCABP + BSI/sepsis and overall will be analyzed in a similar manner. For 
Micro-ITT, CR-MITT2  and CR-ME population, same analysis will be applied. 
In addition, the outcomes will be summarized and the cure rate at TOC will be calculated 
by treatment group per study drug regimen and antibacterial treatment regimen at Day 1 
and Day 2. 
For the clinical outcome per pathogen, the outcomes will be summarized and the cure 
rate and its 95% CI at EOT, TOC and FU will be calculated by treatment group per 
infection site. In addition, the clinical outcome per subject for HABP/VABP/HCABP + 
BSI/sepsis and overall will be analyzed in a similar manner. Clinical outcome per CR 
pathogen will also be summarized.  For the CR-MITT2 population, the same analysis will 
be applied. 
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 


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baseline pathogen. For this analysis, MIC for cefiderocol, amikacin, aztreonam, 
ceftazidime-avibactam, meropenem, ceftolozane-tazobactam, ciprofloxacin, imipenem, 
cefepime, colistin, and tigecycline. For European Medicines Agency (EMA), the same 
analysis will be performed with the susceptibility defined by EUCAST. 
9.4.1.2 
Microbiological Outcome 
For the microbiological outcome per subject, the outcomes will be summarized and the 
eradication rate with 95% CI by treatment group per infection site at EOT, TOC (only for 
HABP/VABP/HCABP and BSI/sepsis) and FU will be calculated. The eradication rate is 
the proportion of subjects whose all of baseline Gram-negative pathogen(s) are eradicated 
at each time point. In addition, the microbiological outcome per subject for 
HABP/VABP/HCABP + BSI/sepsis and overall will be analyzed in a similar manner. For 
Micro-ITT, CR-MITT2 and CR-ME population, same analysis will be applied. 
In addition, the outcomes will be summarized and the cure rate at TOC will be calculated 
by treatment group per study drug regimen and antibacterial treatment regimen at Day 1 
and Day 2. 
For the microbiological outcome per subject with documented carbapenem-resistant 
Gram-negative bacteremia at baseline, the outcomes will be summarized and the 
eradication rate with 95% CI by treatment group at EOT, TOC and FU will be calculated 
as the proportion of subjects who have documented carbapenem-resistant Gram-negative 
bacteremia at baseline to subjects who experience eradication of baseline documented 
carbapenem-resistant Gram-negative bacteremia. For this analysis, the same criteria of  
9.2.4.3 and 9.2.5.3 will be used but only considering blood sample.  
For the microbiological outcome per pathogen, the outcomes will be summarized and the 
eradication rate with 95% CI will be calculated per infection site by treatment group at 
EOT, TOC and FU will be calculated. The microbiological outcome per pathogen only 
including baseline carbapenem-resistant pathogen will also be summarized. For the CR-
MITT2 population, the same analysis will be applied. 
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 EUCAST of the 
baseline pathogen. For this analysis, MIC for cefiderocol, amikacin, aztreonam, 
ceftazidime-avibactam, imipenem, ceftolozane-tazobactam, ciprofloxacin, meropenem, 
cefepime, colistin, and tigecycline. 
For supplementary analysis, the eradication rate, defined in Section 9.3.2, per pathogen at 
TOC will also be tabulated by the MIC values and susceptibility defined by CLSI. 
Super infections caused by a Gram-negative pathogen will be summarized and tabulated 
by the MIC values and susceptibility. Earliest MIC data for each super infection will be 
used for the analysis. 


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9.4.1.3 
Supplementary Clinical Outcomes 
For the supplementary clinical outcome per subject, the outcomes will be summarized 
and the cure rate and its 95% CI at EOT, TOC and FU will be calculated by treatment 
group per infection site (HAP/VAP/HCAP, cUTI, BSI/sepsis, HAP/VAP/HCAP plus 
BSI/sepsis and overall). The clinical response rate will be calculated as the proportion of 
subjects whose clinical outcome is clinical cure at each point. For Micro-ITT population, 
the same analysis will be applied.  
In addition, the outcomes will be summarized and the cure rate at TOC will be calculated 
by treatment group per study drug regimen and antibacterial treatment regimen at Day 1 
and Day 2. 
For the clinical outcome per pathogen, the outcomes will be summarized and the cure 
rate at EOT, TOC and FU will be calculated by treatment group. The clinical response 
rate will be calculated as the proportion of subjects whose clinical outcome is clinical 
cure at each point.  Supplementary clinical outcome per CR pathogen will also be 
summarized. 
9.4.1.4 
Supplementary Microbiological Outcomes 
For the supplementary microbiological outcome per subject, the outcomes will be 
summarized and the microbiological eradication rate and its 95% CI at EOT, TOC and 
FU will be calculated by treatment group per infection site (HAP/VAP/HCAP, cUTI, 
BSI/sepsis, HAP/VAP/HCAP plus BSI/sepsis and overall). The supplementary  
microbiological eradication rate will be calculated as the proportion of subjects whose 
supplementary microbiological outcome is microbiological eradication at each point. For 
Micro-ITT population, same analysis will be applied. 
In addition, the outcomes will be summarized and the eradication rate at TOC will be 
calculated by treatment group per study drug regimen and antibacterial treatment regimen  
at Day 1 and Day 2. 
For the supplementary microbiological outcome per pathogen, the outcomes will be 
summarized and the eradication rate at EOT, TOC and FU will be calculated by treatment 
group. The eradication rate will be calculated as the proportion of subjects whose 
microbiological outcome is eradication at each point.   
The supplementary microbiological outcome per pathogen only including baseline 
carbapenem-resistant pathogen will also be summarized.  
9.4.1.5 
Composite Outcome 
For the composite clinical and microbiological outcome, the outcomes will be 
summarized and the response rate with 95% CI at EOT, TOC, and FU will be calculated 
per infection site by treatment group as the proportion of subjects who have both clinical 
cure and microbiological eradication.  


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9.4.1.6 
All-cause Mortality and Survival Time 
All-cause mortality rate with 95% CI at Day 14, Day 28 and overall by treatment group 
will be calculated as the proportion of subjects who experienced mortality regardless of 
the cause at or before Day 14 and Day 28, respectively. In this analysis, deaths occurring 
after EOS will not be used for analysis and any subject who does not have vital status 
information at Day 14 and 28 will not be included in the analysis. This analysis will be 
performed for both CR MITT and ITT Population. 
In addition, for CR MITT Population, subgroup analysis regarding all-cause mortality at 
Day 28 will be performed. For the survival time up to End of Study (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 at last visit day. 
All-cause mortality rate at Day 14, Day 28 and overall incuding death after EOS will be 
calculated by treatment group for ITT population. 
9.4.1.7 
Sequential Organ Failure Assessment Score 
Sequential Organ Failure Assessment score (SOFA) and its change from baseline will be 
summarized by treatment group per infection site at Baseline, EOT, TOC, and FU. 
Change from baseline will also be summarized. In addition, SOFA score regardless of 
primary infection diagnosis will be analyzed in a similar manner. 
9.4.1.8 
Clinical Pulmonary Infection Score 
For the HABP/VABP/HCABP subjects, CPIS at EOT, TOC, and FU will be summarized 
by treatment group.  
9.4.1.9 
Composite of Survival and No Change in Antibiotic Treatment 
For the composite of survival and no change in antibiotic treatment due to either lack of 
therapeutic benefit or drug-related toxicity at TOC, the response rate with 95% CI by 
treatment group per infection site will be presented. This composite endpoint will be 
assessed by Shionogi medical expertise internally. The response rate in the cefiderocol 
treatment group will be compared with that in the BAT group using Cochran 
Mantel-Haenszel Method stratified by infection site. The 95% CI will be calculated by 
Wald method (see Appendix 2). 
10. SAFETY 
Safety assessments included adverse events (AEs), clinical laboratory safety tests 
(hematology, chemistry, and specialized test), vital sign measurements. All safety 
summaries and analyses will be performed based on the Safety population. 


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10.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a subject received a 
pharmaceutical product (including investigational drug) during the course of a clinical 
investigation. 
Adverse events will be collected from the time of signed informed consent through EOS. 
If adverse events onset after EOS were reported, the events will not be used for analysis. 
Adverse events will be classified by SOC and PT using MedDRA Version 18.1 or higher.  
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. 
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, serious adverse events (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 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. Treatment-related AEs, SAEs, treatment-related SAEs, AEs 
leading to discontinuation of study drug, and treatment-related AEs leading to 
discontinuation of study drug, death due to AEs 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. 
10.1.1 
Analysis of Adverse Events Changing Treatment Group for a 
Subject Who Received Cefiderocol after BAT Administration 
As this is an open-label study, it has been observed that one subject received cefiderocol 
after completion of the randomization assigned study drug regimen of BAT. Therefore, 
an limited set of key safety analyses which consider this subject as assigned to the 
cefiderocol arm will be performed for an overview of AEs.  These analyses are: the 
number and percentage of subjects with AEs, SAEs and death due to AEs by SOC and 
PT. 
10.2 Clinical Laboratory Evaluations 
Summary statistics for laboratory test data (hematology and serum chemistry parameters, 
and other specialized tests) will be presented for each scheduled time point measured 


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after randomization and for the change from baseline to each time point. If a site reports a 
laboratory value including sign for numeric value (i.e. “<”, “’>”) , the value removing 
sign will be used for analysis. 
The number and percentage of subjects with the following prespecified outlier category 
(Table 10-1) during the postdosing period including unscheduled will be presented by 
treatment group. 
Table 10-1 
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 x 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 
BUN (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; ULN = upper limit of 
normal 
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 


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laboratory measurements. Within the laboratory parameters, PTT will not be analyzed 
since during the study monitoring, study team found PTT was reported mixed with APTT. 
All central clinical laboratory data and local clinical laboratory data will be listed. Values 
outside the normal ranges will be flagged for the central laboratory measurements. 
10.3 Vital Sign Measurements 
Summary statistics for vital sign measurements (systolic and diastolic blood pressure, 
pulse rate, respiratory rate, and body temperature) will be presented for baseline, EOT 
and TOC and for the changes from baseline to postbaseline.  
Baseline vital sign measurements are defined as the last measurement obtained prior to 
the first infusion of the study drug. For postbaseline measurements, if multiple readings 
(ie, 3 readings) of vital signs are obtained in a day, the maximum body temperature 
within a study day 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. If the 
multiple maximum body temperatures are obtained in a day, the first result among them 
will be used for the summary. 
In addition, the number and percentage of subjects with the following prespecified outlier 
category (Table 10-2) during the postdosing period including unscheduled will be 
presented by treatment group. 
Table 10-2 
Outlier 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 
A listing of all vital sign measurements will be provided by subject. 
11. Pharmacokinetic Analyses 
Individual plasma concentrations of cefiderocol will be listed and summarized by 
nominal sampling time window. Individual plasma concentrations of cefiderocol will also 
be summarized by nominal sampling time window and dosing group based on renal 
function (augmented renal function, normal renal function, mild renal impairment, 
moderate renal impairment, severe renal impairment, end-stage renal disease, subjects 
with intermittent hemodialysis, continuous venovenous hemofiltration, continuous 
venovenous hemodialysis, and continuous venovenous hemodiafiltration). 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), 


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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 nonmissing 
observations at a time point is less than 3, the data at the time point will not be 
summarized.  
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. 
Population PK analyses will be planned and reported separately by the Clinical 
Pharmacology & Pharmacokinetics of Shionogi & Co., Ltd. 
12. Pharmacokinetic/Pharmacodynamic Analyses 
The pharmacokinetic/pharmacodynamic analyses 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 
A data safety monitoring board (DSMB) will periodically review the efficacy and safety. 
Interim analysis for DSMB is specified in SAP for DSMB. The sponsor reserves the 
option to submit preliminary data to competent regulatory authorities.   
 


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14. PROGRAMMING CONVENTIONS 
Unless otherwise stated, TFLs will be made in accordance with the following 
specifications on programming:  
1) Display Digit of Various Statistics 
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. For variables calculated from raw data like 
creatinine clearance, we will consider raw data is 1 decimal space.  
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, standard error 
One more decimal place than raw data 
 
Maximum, minimum 
Same number of decimal places as raw data 
Percentage (%) 
Round off to 1 decimal place 
Summary statistics for pharmacokinetics 
analysis 
Three significance digit 
2) Handling of Outliers 
Possible outliers will not be omitted from analyses. 
3) 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 
Age (years) 
< 65, ≥ 65 
Gender 
Male, Female 
Weight (kg) 
< 70, ≥ 70 
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown 
Race 
American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Other 
Region 
North America, South America, Europe, and Asia-Pacific 
Extent of exposure (days) 
< 5, ≥ 5 to < 7, ≥ 7 to ≤ 14, > 14 
Infection site 
HABP/VABP/HCABP, cUTI, and BSI/sepsis 
CrCl renal grading group 
>= 120, > 80 - < 120, > 50 - 80, 30 - 50, < 30 
Type of CR baseline pathogen 
Enterobacteriaceae, nonfermenters, mixed 
Severity of disease 
Mild, Moderate, Severe 
APACHE II score 
≤ 15, ≥ 16 
APACHE II = Acute Physiology and Chronic Health Evaluation II; BSI = bloodstream infections; CR = 
Carbapenem-resistant; CrCl = creatinine clearance; cUTI = complicated urinary tract infection; HABP = 
hospital-acquired bacterial pneumonia; HCABP = healthcare-associated bacterial pneumonia; VABP = 
ventilator-associated bacterial pneumonia 
15. CHANGES FROM PROTOCOL 
 Add analysis for HABP/VABP/HCABP + BSI/sepsis subgroup for efficacy 
endpoint 
 Add analysis by initial study drug regimen for clinical and microbiological 
outcome 
 Add analysis for supplementary clinical and microbiological outcome 
 Add subgroup analysis for all-cause mortality 
 Add analysis for microbiological outcome by MIC and interpretation  
 Add analysis for all-cause mortality for subjects with cUTI  
 Add analysis for new infectionChange target timepoint of analysis window for 
premature EOT (PK data), from end date/time of last infusion to start date/time of 
last infusion since EDC does not capture end of infusion date/time for premature 
EOT. 
 The reference point of prior/concomitant medication has been changed from 
randomication date to first drug infusion 
 If BSI, also allowed to consider presumed eradication.  
 Add imputation rule if date/time is missing (section 6.4) 
 


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Appendix 1 
Time and Events Schedule 
Evaluation 
Screening\Baseline 
Randomization 
Treatment 
Test of 
Cure 
(TOC) 
Follow-up 
(FU) 
End of 
Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
Day 1 
Day 3 
Early 
Asses. 
(EA)  
Day 
3 to 4 
(Day 14)b
End of 
Treatm
ent 
(EOT)c 
EOT + 7 
(± 2) 
EOT + 14 
(± 3)  
 
EOT + 28 
(± 3) 
 
Rapid Diagnostic for the 
Presence of a Carbapenemase  
Xd 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical Historye 
X 
 
 
 
 
 
 
 
 
Physical Examination 
Xf 
 
 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg,h 
Glasgow Coma Scale 
X 
 
 
X 
X 
X 
X 
X 
 
APACHE II 
X 
 
 
 
 
 
 
 
 
SOFA Score 
X 
 
 
X 
X 
X 
X 
X 
 
Clinical Assessment of Signs 
and/or Symptoms 
X 
 
 
X 
X 
X 
X 
X 
 
Oxygenation Status i  
X 
 
 
X 
X 
X 
X 
X 
 
Ventilator Parameters 
(ventilated subjects treated 
with cefiderocol 
 
 
Xj 
Xj 
 
 
 
 
 
Chest Radiographsk 
(HABP/VABP/HCABP) 
X 
 
 
X 
X 
X 
X 
X 
 
CPIS Parameters 
(HABP/VABP/HCABP) 
X 
 
 
X 
X 
X 
X 
X 
 
Pregnancy Testl   
X 
 
 
 
 
 
 
 
 


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Evaluation 
Screening\Baseline 
Randomization 
Treatment 
Test of 
Cure 
(TOC) 
Follow-up 
(FU) 
End of 
Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
Day 1 
Day 3 
Early 
Asses. 
(EA)  
Day 
3 to 4 
(Day 14)b
End of 
Treatm
ent 
(EOT)c 
EOT + 7 
(± 2) 
EOT + 14 
(± 3)  
 
EOT + 28 
(± 3) 
 
Hematology Tests, Blood 
Chemistry Tests, and 
Urinalysis 
X 
 
 
X 
X 
X 
X 
X 
X h 
TIBC, Transferrin Iron 
Saturation, Hepcidin 
X 
 
 
 
 
 
X 
 
 
CrCl from Serum Creatininem 
X 
Randomization 
 
 
X 
 
 
 
 
 
CrCl from Urinary 
Creatininem  
 
 
 
X 
 
 
 
 
 
Vital Signsn 
X 
X 
 
 
 
X 
X 
X 
Xh 
12-lead ECG 
X 
 
 
 
 
 
 
 
Drug Administration 
 
X 
 
 
 
X 
 
 
 
Clinical Outcome 
 
 
 
X 
X 
X 
X 
X 
 
Biologic Tissue or Fluids for 
Microbiologic Cultureso 
X 
 
 
X 
X 
X 
X 
X 
 
Microbiological Outcome 
 
 
 
X 
X 
X 
X 
X 
 
Blood PK Samples  
(cefiderocol group) 
 
 
Xp 
Xp 
 
 
 
 
 
AE Assessment 
X 
 
 
 
 
 
 
 
X 
Concomitant Therapy 
X 
 
 
 
 
 
 
 
X 
Hospitalization 
X 
 
 
 
 
 
 
 
X 
Vital Status 
X 
 
 
 
 
 
 
 
X 
AE = adverse event; APACHE = Acute Physiology and Chronic Health Evaluation II; CrCl = creatinine clearance; ECG = electrocardiogram; 
eGFR = estimated glomerular filtration rate; HACP = healthcare-associated bacterial pneumonia; HABP = hospital-acquired bacterial pneumonia; MDRD = 


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Evaluation 
Screening\Baseline 
Randomization 
Treatment 
Test of 
Cure 
(TOC) 
Follow-up 
(FU) 
End of 
Study 
(EOS) 
Day −2 to Same 
Day Prior to 
Randomizationa 
Day 1 
Day 3 
Early 
Asses. 
(EA)  
Day 
3 to 4 
(Day 14)b
End of 
Treatm
ent 
(EOT)c 
EOT + 7 
(± 2) 
EOT + 14 
(± 3)  
 
EOT + 28 
(± 3) 
 
modification of diet in renal disease; PK= pharmacokinetic; SOFA = Sequential Organ Failure Assessment; TIBC = total iron-binding capacity; VABP = 
ventilator-associated  bacterial pneumonia 
 
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 
In case treatment duration is extended beyond 14 days, an additional assessment will be conducted on Day 14. 
c 
EOT evaluations occur on the last day of study treatment. EOT can be any time after the patient had at least one dose of study treatment, duplication of 
assessments for a given day and EOT is not necessary. 
d 
The use of investigational diagnostics or diagnostics that are not the local standard of care for determination of carbapenem resistance will require that the 
investigational diagnostics section of the informed consent be signed by the patient or legally authorized representative. 
e 
Include a review of prior/concomitant therapies. 
f 
A complete physical examination including measurement of body weight and height will be performed at Screening only. 
g 
A limited physical examination relevant to the patient’s current condition will be performed. 
h 
If end of study evaluation is by phone, physical examination, laboratory tests, and vital signs will not be performed. 
i 
Patients receiving an oxygen inhalation treatment. 
j 
For ventilated patients treated with cefiderocol specified ventilator parameters will be captured at the start of the infusion (acceptable time window; 0 hours 
to end of infusion) which PK sampling will be taken.   
k 
At German sites, 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. 
l 
Urine or serum pregnancy test only for females who are not diagnosed as postmenopausal or surgically sterile.   
m The CrCl (the Cockcroft-Gault equation) and eGFR (the MDRD equation) will be calculated from the serum creatinine. For patients with eGFR 
≥ 90 mL/min/1.73 m2 at baseline, urine samples will be collected a time interval as short as 2 hours or up to 8 hours. 
n 
Blood pressure (systolic/diastolic pressures), body temperature, pulse rate, and respiratory rate. 


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27 Jun 2019 
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Page 49 of 51 
o 
Biologic tissue or fluids (including blood regardless of the infection site) for microbiologic cultures will be obtained with 48 hours of the start of treatment, 
at specified times and at the investigator’s discretion. 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 after at least the sixth dose of study drug; one draw just prior to the infusion of the dose, 1 hour after start of 
infusion, at the end of infusion, and at 1 hour after the end of infusion. Patients with nonstable renal function resulting in a dosage adjustment at EA will 
undergo another blood PK sampling (4 samples at the above specified time points) within 24 to 72 hours after their dosing adjustment. If possible, a single 
blood draw should be performed as soon as possible at EOT in case of premature EOT.  
 
 


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Clinical Study Protocol: 1424R2131 
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Page 50 of 51 
Appendix 2 
Calculation Confidence Interval for Cochran-Mantel-Haenzel Test 
Let ݔ௜௝ and ݊௜௝ denote the number of responders and the total number of patients in treatment ݅ and stratum ݆, respectively, where 
݅=1,2 represents the treatment group (cefiderocol or BAT) and ݆= 1,2,3 represents the stratum, the following 2 × 2 contingency table 
shows the total number of subjects and the number of responders in each treatment arm at stratum ݆. 
Category 
cefiderocol 
BAT 
Response 
ݔଵ௝ 
ݔଶ௝ 
No Response 
݊ଵ௝−ݔଵ௝ 
݊ଶ௝−ݔଶ௝ 
Total 
݊ଵ௝ 
݊ଶ௝ 
 
The proportion of patients with response (ߨ୧୨) in treatment ݅ and stratum ݆ can be estimated by: 
ߨො௜௝= ݔ௜௝݊௜௝
⁄
 
and the stratum-specific proportion difference (݀௝) is estimated by: 
݀መ௝= ߨොଵ௝−ߨොଶ௝. 
The adjusted estimate of the difference in the rate of responders between the two treatment groups (݀௔ௗ௝) is given as: 
݀መ௔ௗ௝= ෍
ݓ௝݀መ௝
ଷ
௝ୀଵ
 
using the CMH weights defined as ݓ௝= ൬
௡భೕ௡మೕ
௡భೕା௡మೕ൰
∑
௡భೕ௡మೕ
௡భೕା௡మೕ
ଷ
௝ୀଵ
൘
. 
Hence, the 2-sided stratified 95% Wald-type confidence intervals of ݀௔ௗ௝ based on the CMH weights is constructed as: 


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27 Jun 2019 
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݀መ௔ௗ௝± ݖఈ/ଶVar൫݀መ௔ௗ௝൯, 
where the variance of ݀ୟୢ୨ is given as: 
Var൫݀መ௔ௗ௝൯= ඨ෍
ݓෝ௝
ଶቆߨොଵ௝(1 −ߨොଵ௝)
݊ଵ௝
+ ߨොଶ௝(1 −ߨොଶ௝)
݊ଶ௝
ቇ
ଷ
௝ୀଵ
, 
and ݖఈଶ
⁄  is the 97.5th percentile of the standard normal distribution. 
 


 
Signature Page for 
Reason for signing: Approved
Date of signature: 27-Jun-2019 17:37:01 GMT+0000
Reason for signing: Approved
Date of signature: 27-Jun-2019 18:12:40 GMT+0000