Conditions: Bacterial Pneumonia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
The primary purpose of the study is to determine the degree of penetration of cefiderocol into infected lung tissue in hospitalized adults with bacterial pneumonia who are being mechanically ventilated.

Detailed description:

Arms:
arm 1: All participants were receiving standard of care (SOC) antibiotic treatment for pneumonia. Forty hours after the start of SOC treatment, participants will be administered 2 g doses of cefiderocol (or renally adjusted doses) infused intravenously over 3 hours, every 8 hours (or every 6 hours for participants with augmented renal function), for an expected minimum of 3 doses and up to a total of 6 doses in participants with normal renal function and participants with mild or moderate renal impairment, and for an expected minimum of 6 doses and up to a total of 9 doses in participants with severe renal impairment.

Interventions: intervention 1: Cefiderocol intervention 2: Standard of Care Antibiotic
Intervention descriptions: intervention 1: Administered intravenously, at a dosage determined based on renal function. intervention 2: Standard of care antibiotic treatment for pneumonia

Protocol document:
Prot_001.pdf: 
 
Shionogi Study Title:  
An Open-label, Multicenter, Single-arm, Phase 1 Study 
to Assess the Intrapulmonary Concentrations of 
Cefiderocol at Steady State in Hospitalized Subjects 
with Known or Suspected Bacterial Pneumonia on 
Treatment with Standard of Care Antibiotics and 
Requiring Mechanical Ventilation 
Shionogi Study Number: 
1713R2117 
ClinicalTrials.gov 
Registration No. 
NCT03862040   
Study Document 
Protocol Version 3 (Amendment 1) 02 Nov 2018 
 
History of Protocol Amendments 
Version 1 (Original) 
30 Apr 2018 
This version of the protocol was not used to enroll participants 
Version 2 
02 Nov 2018 
 




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Confidentiality Statement 
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi. This Confidential Material 
should only be viewed by those individuals or companies that have been given prior 
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: 
An Open-label, Multicenter, Single-arm, Phase 1  Study to Assess the Intrapulmonary 
Concentrations of Cefiderocol at Steady State in Hospitalized Subjects with Known or 
Suspected Bacterial Pneumonia on Treatment with Standard of Care Antibiotics and 
Requiring Mechanical Ventilation 
Study Number: 
1713R2117 
Study Phase: 1b 
Primary Objectives: 
• To estimate the concentration of cefiderocol in epithelial lung fluid (ELF), at 
steady state in hospitalized subjects with known or suspected bacterial pneumonia 
being treated with standard of care (SOC) antibiotics and requiring mechanical 
ventilation 
• To estimate the ratio of the concentration for cefiderocol in ELF relative to plasma 
(RC,E/P) in hospitalized subjects with known or suspected bacterial pneumonia on 
treatment with SOC antibiotics and requiring mechanical ventilation 
Study Design: 
This is a multicenter, single-arm, open-label Phase 1b study to assess the intrapulmonary 
and plasma concentrations of cefiderocol at steady state after multiple-dose 
administration in hospitalized subjects with known or suspected bacterial pneumonia on 
treatment with SOC antibiotics and requiring mechanical ventilation. Subjects meeting 
eligibility criteria will receive 2-g doses of cefiderocol (or renally adjusted dose), 
administered intravenously over 3 hours, every 8 hours (q8h), or every 6 hours (q6h) if 
augmented renal function. Cefiderocol will be administered for an expected minimum of 
3 doses and up to a total of 6 doses in subjects with normal or augmented renal function 
and subjects with mild, or moderate renal impairment, and for an expected minimum of 6 
doses and up to a total of 9 doses in subjects with severe renal impairment. 
Bronchoalveolar lavage (BAL) procedure (Mini-BAL is not allowed in this study) will be 
conducted at 3rd dosing (or 6th for severe renal impairment subjects). If 3rd dosing is not 
convenient for the subject or the institution to perform the BAL procedure (or 6th dosing 
for severe renal impairment subjects), 4th, 5th, or 6th dosing could be considered as the 
timing for the BAL procedure (or 7th, 8th, or 9th dosing for severe renal impairment 
subjects).  
Study Population: 
Subjects with known or suspected bacterial pneumonia being treated with SOC 
antibiotics and requiring mechanical ventilation will be enrolled. 
Criteria for Inclusion and Exclusion 
Inclusion Criteria: 
Subjects who fulfill the following criteria will be included in the study: 
1. Subject is male or female,18-80 years (both inclusive) at the time written 


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informed consent is obtained 
2. Subject has provided written informed consent or informed consent has been 
provided by subject’s legally authorized representative (Note: Country-specific 
rules and/or local state laws and local Ethics Committee approval for legally 
authorized representative informed consent will determine whether or not and 
how a subject unable to comprehend or sign the informed consent is allowed to be 
enrolled in the study) 
3. Subject has a clinical diagnosis of bacterial pneumonia, documented or suspected, 
(even if later known that the subject does not have bacterial pneumonia, 
discontinuation of the study is not necessary) 
4. Subject is hospitalized and receiving SOC antibiotic treatment for pneumonia 
5. Subject is mechanically ventilated and expected to remain mechanically 
ventilated for at least 48 hours (or 72 hours for subjects with severe renal 
impairment) after the first dose of cefiderocol 
6. Subject has a life expectancy of at least 3 weeks from the Screening visit 
7. Female meeting 1 of the following criteria: 
a. Surgically sterile (has had a hysterectomy and/or bilateral oophorectomy, or a 
bilateral salpingectomy or tubal ligation for the purpose of contraception for at 
least 6 weeks with appropriate documentation of such surgery) 
b. Postmenopausal (defined as older than 45 years of age with cessation of 
regular menstrual periods for at least 6 months and a history of a follicle-
stimulating hormone level of > 40 mIU/mL, or amenorrhea for at least 
12 months) 
c. Of childbearing potential and using combined (estrogen and progestogen) or 
progestogen-only hormonal contraception associated with inhibition of 
ovulation (including oral, intravaginal, injectable, implantable, and 
transdermal contraceptives), or an intrauterine device (IUD), or intrauterine 
hormone-releasing system for the entire duration of the study 
d. Of childbearing potential and practicing abstinence as a preferred and usual 
life style and/or agrees to continue practicing abstinence from Screening for 
the entire duration of the study 
e. Of childbearing potential and whose sole heterosexual partner has been 
successfully vasectomized and agrees to not have other heterosexual partners 
for the entire duration of the study 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Subject has a chemical/aspiration pneumonia that does not require antibiotic 
treatment (including aspiration of gastric acid, inhalation injury). The term 
chemical pneumonia refers to the aspiration of substances that are toxic to the 
lower airways causing chemical burn and injuries in the airway. 
2. Subject has 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 


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uneventful re-exposure is not a contraindication to enrollment)  
3. Subject has extensive cystic lesion(s) or severe structural abnormality (eg, cystic 
fibrosis, emphysema, cystic lesions of sarcoidosis or tuberculosis, post obstructive 
pneumonia due to lung cancer, etc) of the lung that hinders recovery of 
bronchoalveolar lavage fluid (BALF)  
4. Subject is receiving peritoneal dialysis 
5. Subject has severe renal impairment requiring hemodialysis (HD) or end-stage 
renal disease requiring HD with creatinine clearance (CrCl) < 15 mL/min 
6. Subject is in refractory septic shock defined as persistent hypotension despite 
adequate fluid resuscitation or despite vasopressive therapy at Screening 
7. Subject is a female who has a positive pregnancy test at Screening or who is 
lactating  
8. Subject has received another investigational drug within 30 days prior to 
Screening 
9. Subject has previously participated in this clinical study and has received at least 
1 dose of cefiderocol 
10. Subject has any condition or circumstance that, in the opinion of the investigator, 
would compromise the safety of the subject or the quality of the study data 
Test Drug, Dose, and Mode of Administration: 
Cefiderocol, 2 g, is to be administered intravenously q8h as a 3-hour infusion in subjects 
with normal, mild, moderate or severe renal function (or q6h if subject has augmented 
renal function) in addition to the subject’s treatment with SOC. Dose adjustment for renal 
function is required, and the dosing recommendations are presented in the protocol, 
Section 3.1.  
Control Drug, Dose, and Mode of Administration: 
Not applicable 
Duration of Treatment: 
The treatment duration for cefiderocol is anticipated to be 3 to 4 days depending on the 
subject’s renal function.  
Prohibited Concomitant Therapy: 
Not applicable 
Efficacy Assessments: 
Not applicable 
Pharmacokinetic Assessments: 
Pharmacokinetic (PK) assessments will be performed for ELF and plasma samples 
obtained from each subject. The ELF sample for determination of cefiderocol 
concentrations will be collected by BAL procedure 3, 5, or 7 hours, depending on the 
ELF cefiderocol concentration data obtained, after administration of at least 3 doses of 
cefiderocol in subjects with normal or augmented renal function and subjects with mild 
or moderate renal impairment and after administration of at least 6 doses of cefiderocol in 
subjects with severe renal impairment. A total of 4 blood samples for determination of 


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plasma cefiderocol concentrations will be collected at prespecified time points 
corresponding to the time point at which the ELF sample is collected. Pharmacokinetic 
assessment of concentration data from both ELF and plasma samples is planned to be 
performed for every 3 subjects to determine if modifications of the ELF sampling time 
point in subsequent subjects are needed.  
Safety Assessments: 
Subject safety will be assessed by the identification of adverse events (AEs) from the 
time of having signed informed consent to the end of the study, up to 7 days after the last 
dose of cefiderocol. Additional safety assessments include physical examinations, vital 
sign measurements, chest X-ray, and clinical laboratory tests. 
Statistical Methods: 
Pharmacokinetics 
Individual plasma and ELF concentrations of cefiderocol will be listed and summarized 
by nominal sampling time with N, Mean, standard deviation (SD) and coefficient of 
variation (CV%, calculated by SD/Mean × 100), geometric mean (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 standard 
deviation for natural log (ln)-transformed data. Concentration ratios in ELF to plasma 
(RC,E/P) in each subject will be calculated, listed, and summarized with number (N), 
Mean, SD, CV%, Geometric Mean and CV% Geometric Mean, and median, minimum 
and maximum values by nominal sampling time. The time courses of individual and 
mean plasma and ELF concentrations and individual and mean RC,E/P will be presented by 
appropriate graphics. Population PK analyses will be performed using a nonlinear mixed 
effects model approach. 
Safety 
The number and percentage of subjects who experienced at least 1 treatment-emergent 
adverse event (TEAE), deaths, serious adverse events (SAEs), and TEAEs leading to 
discontinuation will be summarized. The number of those TEAEs, which are counted by 
cases reported, will also be presented. Treatment-related TEAEs will be summarized in 
the same way as TEAEs for overall summary. 
Study Duration:  
Study duration for individual subjects: maximum of 13 days (Screening, approximately 
2 days; Treatment Period, 3 to 4 days; Follow-up Period, 7 days) 
Expected duration of the study: 8 months 
Date of Original: 30 Apr 2018 
Date of Latest Amendment: 02 Nov 2018 


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TABLE OF CONTENTS 
SYNOPSIS ...........................................................................................................................3 
TABLE OF CONTENTS .....................................................................................................7 
LIST OF IN-TEXT TABLES ............................................................................................10 
LIST OF IN-TEXT FIGURES...........................................................................................10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................11 
1. 
INTRODUCTION .....................................................................................................14 
1.1 
Rationale of Study............................................................................................14 
1.2 
Background and Rationale of Cefiderocol Development ................................14 
1.3 
Biological Features of Cefiderocol for Injection .............................................15 
1.4 
Nonclinical Experience ....................................................................................18 
1.4.1 
Pharmacokinetics/Pharmacodynamics ...................................................19 
 
Animal Models of Efficacy ..........................................................19 
1.5 
Clinical Experience ..........................................................................................21 
1.5.1 
Phase 1 ...................................................................................................21 
1.5.2 
Phase 2 and Phase 3 ...............................................................................22 
 
Phase 2 Complicated Urinary Tract Infections ............................22 
 
Phase 3 .........................................................................................22 
2. 
STUDY OBJECTIVES ..............................................................................................23 
2.1 
Primary Objectives...........................................................................................23 
3. 
INVESTIGATIONAL PLAN ....................................................................................24 
3.1 
Overall Study Design and Plan ........................................................................24 
3.2 
Rationale for Study Design and Control Group ...............................................26 
3.3 
Study Duration .................................................................................................27 
3.3.1 
Study Duration in Individual Subjects ...................................................27 
3.3.2 
Planned Study Duration .........................................................................27 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ...................................................28 
4.1 
Study Population ..............................................................................................28 
4.2 
Inclusion Criteria .............................................................................................28 
4.3 
Exclusion Criteria ............................................................................................29 
4.4 
Screen Failures .................................................................................................29 
4.5 
Withdrawal of Subjects from the Study or Discontinuation from Study 
Drug .................................................................................................................30 
5. 
STUDY TREATMENT(S) ........................................................................................31 
5.1 
Description of Treatment(s) .............................................................................31 
5.1.1 
Test Drug ...............................................................................................31 
5.2 
Treatments to be Administered ........................................................................31 
5.3 
Selection and Timing of Dose for Each Subject ..............................................32 


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5.4 
Method of Assigning Subjects to Treatment Groups .......................................32 
5.5 
Blinding............................................................................................................32 
5.6 
Packaging and Labeling ...................................................................................33 
5.7 
Storage and Accountability ..............................................................................33 
5.8 
Investigational Product Retention at Study Site ..............................................33 
5.9 
Treatment Compliance .....................................................................................33 
6. 
RESTRICTIONS .......................................................................................................34 
6.1 
Prior Therapy ...................................................................................................34 
6.2 
Concomitant Therapy During the Study ..........................................................34 
6.2.1 
Prohibited Therapy.................................................................................34 
7. 
STUDY PROCEDURES AND METHODS OF ASSESSMENTS ..........................35 
7.1 
Informed Consent.............................................................................................35 
7.2 
Baseline, Subject Characteristics, and Medical History ..................................35 
7.3 
Enrollment in the Study and Dispensing Study Drug ......................................35 
7.4 
Efficacy Assessments.......................................................................................35 
7.5 
Pharmacokinetics Assessments ........................................................................36 
7.5.1 
Plasma Samples .....................................................................................36 
7.5.2 
Epithelial Lining Fluid Sample ..............................................................36 
 
Ventilator Parameters...................................................................38 
7.6 
Safety Assessments ..........................................................................................38 
7.6.1 
Physical Examination.............................................................................38 
7.6.2 
Vital Signs ..............................................................................................39 
7.6.3 
Chest X-Ray ...........................................................................................39 
7.6.4 
Clinical Laboratory Tests .......................................................................39 
 
Laboratory Parameters .................................................................40 
 
Sample Collection, Storage, and Shipping ..................................41 
7.6.5 
Adverse Event Assessments ..................................................................41 
 
Definition and Assessment of Adverse Events ............................41 
 
Assessment Period .......................................................................42 
 
Severity ........................................................................................42 
 
Relationship to the Study Drug ....................................................42 
 
Expectedness ................................................................................42 
 
Adverse Event Assessment of Clinical Laboratory and Other 
Safety Parameters.........................................................................43 
 
Serious Adverse Events ...............................................................43 
 
Special Situations - Abuse, Misuse, Overdose, and 
Medication Error ..........................................................................45 
 
Pregnancy .....................................................................................46 


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Treatment-emergent Adverse Events ...........................................46 
7.7 
Appropriateness of Measurements ...................................................................46 
7.8 
Allowable Time Window .................................................................................46 
8. 
STUDY ACTIVITIES ...............................................................................................48 
9. 
PLANNED STATISTICAL METHODS ..................................................................49 
9.1 
General Considerations ....................................................................................49 
9.2 
Determination of Sample Size .........................................................................49 
9.3 
Analysis Populations ........................................................................................49 
9.4 
Handling of Missing Data ................................................................................50 
9.5 
Subject Disposition ..........................................................................................50 
9.6 
Demographic and Baseline Characteristics .....................................................50 
9.7 
Extent of Exposure and Treatment Compliance ..............................................50 
9.8 
Prior Therapies .................................................................................................50 
9.9 
Concomitant Therapies ....................................................................................50 
9.10 
Efficacy Analysis .............................................................................................50 
9.11 
Safety Analyses ................................................................................................50 
9.11.1 
Adverse Events ......................................................................................50 
9.11.2 
Vital Signs ..............................................................................................51 
9.11.3 
Clinical Laboratory Analysis .................................................................51 
9.12 
Pharmacokinetic Analysis ................................................................................51 
9.13 
Other Analysis .................................................................................................52 
9.14 
Interim Analysis ...............................................................................................52 
10. ADMINISTRATIVE CONSIDERATIONS ..............................................................53 
10.1 
Study Administrative Structure........................................................................53 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .......54 
10.3 
Ethical Conduct of the Study ...........................................................................54 
10.4 
Informed Consent Process ...............................................................................54 
10.5 
Subject Confidentiality ....................................................................................54 
10.6 
Study Monitoring .............................................................................................55 
10.7 
Case Report Forms and Source Documents.....................................................55 
10.7.1 
Case Report Forms .................................................................................55 
10.7.2 
Source Data and Source Documents ......................................................56 
10.7.3 
External Data .........................................................................................56 
10.8 
Committees ......................................................................................................56 
10.8.1 
Case Review Committee ........................................................................56 
10.8.2 
Independent Data Monitoring Committee .............................................56 
10.8.3 
Other Committees ..................................................................................56 
10.9 
Termination or Suspension of the Study ..........................................................56 


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10.9.1 
Termination or Suspension of the Entire Study .....................................56 
10.9.2 
Termination or Suspension of the Study by Study Site .........................57 
10.10 Protocol Modifications and Deviations ...........................................................57 
10.11 Data Management ............................................................................................58 
10.12 Retention of Data .............................................................................................58 
10.13 Quality Control and Assurance ........................................................................58 
10.14 Publication and Disclosure Policy ...................................................................58 
10.15 Financial Disclosure.........................................................................................59 
11. REFERENCE LIST ...................................................................................................60 
Appendix 1 
Time and Events Schedule .....................................................................63 
Appendix 2 
PK and Urea Samples ............................................................................65 
Appendix 3 
Management and Discontinuation Criteria for Abnormal Liver 
Function Tests .......................................................................................67 
Appendix 4 
Sponsor’s Signature ...............................................................................70 
Appendix 5  
Investigator’s Signature .........................................................................71 
 
LIST OF IN-TEXT TABLES 
Table 3-1 
Cefiderocol Dosing and Bronchoalveolar Lavage Procedure 
for Various Degrees of Renal Function .......................................24 
Table 3-2 
Study Schematic ...........................................................................26 
Table 5-1 
Dosing Recommendations of Cefiderocol Based on Renal 
Function .......................................................................................32 
Table 7-1 
Routine Laboratory Tests .............................................................40 
Table 7-2 
Allowable Time Window .............................................................47 
 
LIST OF IN-TEXT FIGURES 
Figure 1-1 
Depiction of Cefiderocol Cell Entry and Mechanism of 
Action ...........................................................................................17 
Figure 1-2 
Efficacy of Cefiderocol (Human 3- and 1-hr Infusion of 
2 g IV q8h) Compared with Meropenem (Human 1 g IV q8h) 
Against K. pneumoniae VA-384 in a Respiratory Tract 
Infection Model in Cannulated Rats ............................................20 
Figure 7-3 
Epithelial Lining Fluid Sampling Procedure Schematic ..............38 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ΔΔQTcF 
placebo-corrected QTc intervals 
%fT>MIC 
the percentage of the dosing interval for which the free-drug 
concentration in plasma exceeds the minimum inhibitory 
concentration 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
BAL 
bronchoalveolar lavage  
BALF 
bronchoalveolar lavage fluid 
BLA 
β-lactamase 
BLQ 
below the limit of quantification  
CBAL 
cefiderocol concentration in the supernatant BALF 
CBC 
Complete blood count 
CELF 
cefiderocol concentration in the ELF 
CI 
confidence interval  
Cmax 
maximum plasma concentration  
CrCl 
creatinine clearance 
CRO 
clinical research organization 
CSR 
clinical study report 
cUTI 
complicated urinary tract infection 
CT 
computed tomography 
CV% 
coefficient of variation 
DDI 
drug-drug interaction 
ECG 
electrocardiogram/electrocardiography 
EDC 
electronic data capture 
eCRF 
electronic case report form 
ELF 
epithelial lining fluid 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
fT>MIC 
time during which plasma concentrations are above the mean 
inhibitory concentration 
GCP 
Good Clinical Practice 
HABP 
hospital-acquired bacterial pneumonia 


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HCABP 
healthcare-associated bacterial pneumonia  
HD 
hemodialysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IgM 
immunoglobulin M 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
KPC 
Klebsiella pneumoniae carbapenemase 
LS 
least squares  
MATE 
multidrug and toxin extrusion 
MBL 
metallo-β-lactamase 
MDR 
multidrug resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
mean inhibitory concentration 
NTC 
nontreatment control 
OAT 
organic anion transporter 
OATP1B3 
organic anion transporting polypeptide 1B3 
OCT 
organic cation transporter 
PD 
pharmacodynamic(s) 
PEEP 
positive end-expiratory pressure 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PT-INR 
prothrombin time-international normalized ratio 
q6h 
every 6 hours 
q8h 
every 8 hours 
QT 
QT interval (measure between Q wave and T wave in the heart’s 
electrical cycle) 
QTc 
corrected QT 
QTcF 
Fridericia’s corrected QT 
RC,E/P 
ratio of the concentration for cefiderocol in epithelial lining fluid 
relative to plasma 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
standard of care 


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SOP 
standard operating procedure 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TQT 
thorough QT 
ULN 
upper limit of normal 
Urea,BAL 
urea concentrations in the BALF  
Urea,SERUM 
urea concentrations in the serum 
VABP 
ventilator-associated bacterial pneumonia 
VBAL 
BALF volume 
VELF 
calculated volume of ELF 
WBC 
white blood cell 
WHO 
World Health Organization 
XDR 
extensively drug resistant 
 


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1. INTRODUCTION 
1.1 
Rationale of Study 
The primary purpose of the current study is to estimate the degree of penetration of 
cefiderocol into infected lung tissue in hospitalized subjects with known or suspected 
bacterial pneumonia who are being mechanically ventilated. The lung penetration is 
considered as a surrogate pharmacodynamic (PD) marker for characterizing the effect of 
antibiotics on bacterial pneumonia. However, β-lactam antibiotics, including 
cephalosporins such as cefiderocol, have demonstrated a high degree of variability and 
varying degrees of penetration into the lung tissue (range: 30% to 100%), despite proven 
efficacy and wide-spread use of these agents to treat bacterial pneumonia [1]. Even with 
this limitation, evaluation of lung penetration is a generally recommended method for 
estimating investigational antibiotic efficacy. The concentration of cefiderocol in 
epithelial lining fluid (ELF) will be measured at steady state at up to 3 post infusion time 
points and compared with a corresponding concentration of cefiderocol in plasma to 
estimate the concentration in ELF to plasma ratio (RC,E/P), representing the % penetration 
of cefiderocol into infected lung tissue. Each individual will contribute to one time point, 
and overall up to 18 subjects (a minimum of 3 subjects) are planned to be assessed in this 
study. The data from this study along with modeling and simulations will support the 
potential efficacy of cefiderocol in subjects with known or suspected bacterial 
nosocomial pneumonia due to Gram-negative bacteria. 
1.2 
Background and Rationale of Cefiderocol Development 
The ability to treat bacterial infections due to multidrug resistant (MDR) and extensively 
drug-resistant (XDR) Gram-negative bacteria, including Enterobacteriaceae and the 
nonfermenters Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and 
Acinetobacter baumannii, is a critical and growing unmet medical need. In particular, the 
emergence of resistance to carbapenems in Gram-negative bacteria, including 
Enterobacteriaceae, Pseudomonas, and Acinetobacter species, over the last decade has 
become a major concern worldwide, because of its rapid spread and the lack of 
development of new antimicrobial drugs effective in this area [2].  
Since the description of imipenemase-1, a metallo-β-lactamase (MBL), in P. aeruginosa, 
oxacillinase-23, a serine carbapenemase, in A. baumannii, and Klebsiella pneumoniae 
carbapenemase-1 (KPC-1), a serine carbapenemase, in K. pneumoniae, 
carbapenemase-encoding genes have spread worldwide and are now distributed 
throughout different species of Gram-negative MDR bacteria. They are now responsible 
for a large and increasing number of nosocomial infections. These carbapenemases 
inhibit almost all β-lactam antibiotics, including carbapenems, and are reported mainly in 
Enterobacteriaceae, A. baumannii, and P. aeruginosa [2]. 
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 


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bacterial nutrients) and efflux pumps (exit channels with active excretion mechanisms for 
removal of antibiotics from the bacterial cells). They are particularly prevalent among 
XDR P. aeruginosa [3, 4]. Not infrequently, more than 1 β-lactam resistance mechanisms 
exist in the same bacterial strain. 
In 2011, Nordmann et al observed that carbapenemases had been reported increasingly in 
Enterobacteriaceae during the previous 10 years and that their spread across the world 
was of great concern. They concluded that society was now at the edge of 2 concomitant 
epidemics of carbapenemase-producers worldwide; the first to be caused mainly by 
carbapenemase-producing Escherichia coli as a source of community-acquired 
infections, and the second, likely to be caused mainly by nosocomial 
carbapenemase-producing K. pneumoniae of all types [5].  
The outcome of a carbapenem-resistant infection can often be fatal. Falagas et al (2014) 
calculated that 26% to 44% of deaths in 7 studies were attributable to carbapenem 
resistance. A pooled analysis of 9 studies showed that the death rate was higher among 
those subjects infected with carbapenem-resistant Enterobacteriaceae than those infected 
with carbapenem-susceptible Enterobacteriaceae (relative risk 2.05, 95% confidence 
interval [CI] 1.56 to 2.69) [6]. 
Cefiderocol has an approved international nonproprietary name: cefiderocol. For 
purposes of this protocol, cefiderocol will be used to refer to the study drug.  
Cefiderocol is being developed to address the unmet medical need to treat 
carbapenem-resistant infections caused by Gram-negative bacteria, including 
Enterobacteriaceae, Pseudomonas, Stenotrophomonas, and Acinetobacter species 
independent of the underlying mechanism of carbapenem resistance. Although 
cefiderocol was designed to have bacterial-killing ability for carbapenem-resistant 
species of Gram-negative bacteria, it also has improved bacterial-killing ability for 
common community-acquired Gram-negative infections, as demonstrated by reduced 
minimum inhibitory concentration (MIC) values (for additional information refer to the 
current Investigator’s Brochure [IB]).  
1.3 
Biological Features of Cefiderocol for Injection 
Cefiderocol is an injectable siderophore cephalosporin discovered and being developed 
by Shionogi & Co., Ltd., Osaka, Japan. The antibacterial activity of cefiderocol is based 
on the inhibition of Gram-negative bacterial cell wall synthesis.  
The chemical structure of cefiderocol 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 cefiderocol 
compared with cefepime is the presence of a catechol group on the side chain at 
position 3. Cefiderocol also has a pyrrolidinium group in the side chain at position 3 and 
a carboxypropanoxyimino group in the side chain at position 7 of the cephem nucleus. As 


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a consequence of its structure, cefiderocol has the following features in addition to the 
basic mechanism of action to inhibit cell wall synthesis: 
1. A unique mode of action, which enhances entry into the periplasmic space of 
Gram-negative aerobic bacteria through the outer cell membrane. Cefiderocol 
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 (BLA) enzymes, including 
carbapenemases of the serine or MBL classes. 
3. Enhanced activity against aerobic Gram-negative bacteria, especially 
Enterobacteriaceae, particularly K. pneumoniae and E. coli, and the 
nonfermenters P. aeruginosa, S. maltophilia, and A. baumannii. 
4. No activity against Gram-positive bacteria and anaerobic bacteria.  
The host’s innate immune response to bacterial infection is to remove or severely limit 
the available free iron, an essential cation for bacterial growth [7]. In response, bacteria 
upregulate the production of extracellular molecules called siderophores that scavenge for 
available free iron [8]. Cefiderocol is a siderophore compound that 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 [3, 7-12]. A graphic depiction of this process is presented in Figure 1-1. This 
process achieves bactericidal concentrations at relatively low blood concentrations of 
cefiderocol. Once inside the periplasmic space of the Gram-negative bacteria, cefiderocol 
is resistant to the usual mechanisms of degradation of β-lactam or carbapenem antibiotics 
by bacterial BLAs. The primary bactericidal activity is due to inhibition of bacterial cell 
wall synthesis. 


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Figure 1-1 
Depiction of Cefiderocol Cell Entry and Mechanism of 
Action  
 
Source: Shionogi Inc. 
The greatest current unmet medical need is in the treatment of bacterial infections caused 
by MDR aerobic Gram-negative bacilli, broadly including the Enterobacteriaceae and the 
nonfermenters P. aeruginosa, S. maltophilia, and A. baumannii. Multidrug resistant 
bacteria, defined as > 3 class antibiotic resistance, include most Enterobacteriaceae 
producing AmpC, extended-spectrum BLAs, and serine BLAs. While they may be 
resistant to penicillins, cephalosporins, fluoroquinolones, and aminoglycosides, they 
have, for the most part, remained susceptible to carbapenems [3, 11, 12]. More recently, 
these same Enterobacteriaceae, particularly K. pneumoniae and E. coli, have acquired 
serine KPCs, oxacillinases, and MBLs (eg, Verona integron-encoded MBL, 
imipenemase, and New Delhi metallo-BLA-1) capable of hydrolyzing carbapenems [13-
15]. Most of these bacteria remain susceptible only to polymyxins (polymyxin B or 
colistin), and thus should be considered XDR, not just MDR. The nonfermenters P. 
aeruginosa, S. maltophilia, and A. baumannii have also acquired carbapenemases and are 
also considered XDR bacteria [16]. Rarely, these XDR pathogens may also be resistant to 
polymyxins, and, therefore, can be considered pandrug resistant organisms, defined as 
resistant to all classes [16, 17]. 


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The principal objective for cefiderocol clinical development is to demonstrate efficacy 
for the treatment of serious, life-threatening infections caused by Gram-negative bacteria, 
including Enterobacteriaceae and nonfermenters, such as P. aeruginosa, S. maltophilia, 
and A. baumannii. One of the most serious of these infections is pneumonia. 
Gram-negative pneumonia is almost always nosocomial, meaning it is associated with 
prior or current hospitalization or other contact with healthcare services [18]. Variably 
defined as hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial 
pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP), when the 
infection is caused by Gram-negative bacteria, the outcomes are especially dire, with 
mortality rates approaching 60% [18-22]. Increasing antibiotic resistance among 
Gram-negative organisms, particularly that to aminoglycosides, fluoroquinolones, and 
cephalosporins, has limited therapeutic options to carbapenems and polymyxins [18-26]. 
Clinical trials in HABP/VABP/HCABP are particularly challenging due to the severity of 
illness, preexisting comorbidities, and controversies over study endpoints [27]. Recent 
clinical trials have failed to meet predefined endpoints for noninferiority (tigecycline, 
doripenem). Despite these setbacks, the need for new antibiotic treatments for 
Gram-negative infections has resulted in renewed interest in HABP/VABP as an 
important area for clinical investigation. Both the Food and Drug Administration (FDA) 
and the European Medicines Agency (EMA) have updated their clinical trial guidelines 
for these indications [28, 29]. 
1.4 
Nonclinical Experience 
In vitro, cefiderocol showed potent antibacterial activity against carbapenem-resistant 
Enterobacteriaceae, including MBL producing isolates, MDR A. baumannii, and MDR P. 
aeruginosa. Cefiderocol also showed more robust antibacterial activity than other 
β-lactam antibiotics in systemic, lung, urinary tract, and subcutaneous animal models of 
infection due to MDR P. aeruginosa, carbapenem-resistant A. baumannii, or enteric 
bacteria, such as extended-spectrum BLA-producing E. coli and K. pneumoniae.  
As cefiderocol is not a substrate for human P-glycoprotein (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 cefiderocol 
mediated by these transporters is low. Since cefiderocol is not an inhibitor for human P-
gp or bile salt export pump, the risk of a DDI with cefiderocol as a perturbator of these 
transporters is low. Cefiderocol, 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 maximum plasma 
concentration (Cmax) value at the intended clinical dose (2 g, 3 times daily) was calculated 
to be 57.4 μmol/L (43.1 μg/mL) by multiplying the Cmax (119 μmol/L [89.7 μg/mL]) and 
the in vitro free fraction ratio of cefiderocol in human at 100 µg/mL (48.2%). Cefiderocol 


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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 [30] 
and EMA guideline [31] of drug interaction, and therefore, a clinical DDI study was 
performed (Study 1521R2115). Topline data from that DDI study showed no significant 
effects on the pharmacokinetics (PK) of furosemide (an OAT1 and OAT3 substrate) or 
metformin (an OCT1, OCT2, and MATE2-K substrate). Coadministration of cefiderocol 
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 (IV) antibiotics, the potential for a 
clinically meaningful outcome in the clinically setting is considered to be low.  
Refer to the current IB for additional details of completed studies. 
1.4.1 
Pharmacokinetics/Pharmacodynamics 
 
Animal Models of Efficacy 
As with all β-lactams that target penicillin-binding proteins, the controlling PD parameter 
for cefiderocol is the percentage of the dosing interval for which the free-drug 
concentration in plasma exceeds the minimum inhibitory concentration (%fT>MIC), and 
while the plasma PK measurements can determine the drug exposure over time, corrected 
for protein binding, the MIC remains the key variable in determining %fT>MIC. 
Shionogi has conducted a series of studies in animal models of infection, including 
urinary tract (murine), thigh (murine), and lung (murine and rat). In addition to the dose 
fractionation used in the murine models, the rat lung model was designed to reproduce 
human drug exposure, including infusion times of 1 and 3 hours (Figure 1-2).  




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1.5 
Clinical Experience 
1.5.1 
Phase 1 
The safety and tolerability of cefiderocol 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 PK study [Study 
1214R2112], a renal impairment study [Study 1222R2113], a mass balance study 
[Study 1516R2114], a thorough QT [TQT]/corrected QT [TQTc] study [Study 
1603R2116], and a 3-part drug interaction study [Study 1521R2115]). In these studies, 
healthy adult subjects or subjects with impaired renal function received single doses of 
cefiderocol 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, cefiderocol was 
safe and well tolerated in the clinical pharmacology studies. There were no treatment-
related or dose-dependent trends in vital sign measurements, 
electrocardiogram/electrocardiography (ECG) parameters, or clinical laboratory test 
results. There were no deaths or serious adverse events (SAEs) reported in any study. 
Adverse events (AEs) occurred relatively infrequently, were mostly mild in severity, and 
almost all resolved spontaneously without intervention. There were no dose-dependent 
trends in the frequency or type of AEs reported. 
Cefiderocol is primarily excreted unchanged (approximately 90%) in the urine 
(Study 1516R2114), has a plasma half-life of 2.75 hours, and is associated with linear PK 
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 1203R2111]) and single 2- to 4-g doses, infused over 3 
hours TQTc study (Study 1603R2116), the Cmax and AUC of cefiderocol increased in 
proportion to the dose. After administration of multiple 2-g doses of cefiderocol 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 
cefiderocol was observed, and plasma concentrations of cefiderocol reached steady state 
within 1 day of repeated administration (Study 1203R2111). After administration of a 
single 1000-mg (1-g) dose of [14C]-cefiderocol, cefiderocol 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 1516R2114). The majority (98.6%) of 
total radioactivity was excreted unchanged in urine, with negligible amounts (2.8%) 
excreted in feces (Study 1516R2114). 
A Phase 1 study to assess the repolarization effects of cefiderocol on the human heart was 
conducted as a TQTc study (Study 1603R2116) in accordance with the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) E14 Guidance and subsequent Questions & Answers. The first part of the 
study consisted of a sequential-group safety and tolerability study in which the safety of 
the supratherapeutic dose of cefiderocol was confirmed. The second part of the study 
consisted of a  TQTc study in which single 2-g (therapeutic) and 4-g (supratherapeutic) 


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doses of cefiderocol administered as 3-hour infusions were assessed along with placebo 
(to cefiderocol) and moxifloxacin (active control) in a double-blind, crossover design in a 
total of 48 subjects.  
The point estimates of the least squares (LS) means of baseline and placebo-corrected 
QTc intervals (ΔΔQTcF) calculated using Fridericia’s correction for the 2- and the 4-g 
doses of cefiderocol were < 5 msec and the upper bounds of the 1-sided 95% CI were 
< 10 msec at all postinitiation of the infusion time points. For the moxifloxacin treatment, 
a prolongation of Fridericia’s corrected QT (QTcF) interval was observed for all time 
points from 1 to 10 hours postdose, confirming that a positive effect on the QTcF interval 
could be detected in the study (the lower bound of 1-sided 95% CI of LS means in the 
ΔΔQTcF > 5 msec). The results indicate that single 2- and 4-g doses of cefiderocol 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 (Study 
1603R2116).  
1.5.2 
Phase 2 and Phase 3 
 
Phase 2 Complicated Urinary Tract Infections 
A Phase 2 study of the safety and efficacy of cefiderocol administered at a 2-g dose over 
a 1- hour infusion to 300 subjects with complicated urinary tract infections (cUTIs) has 
been completed (Study 1409R2121). The results support the safety profile of cefiderocol 
in a subject population using the same dose (2 g, q8h) proposed for this study.  
 
Phase 3 
A pathogen-based, Phase 3 study in subjects with evidence of carbapenem resistance, 
Gram-negative infections at various infection sites (CREDIBLE-CR, Study 1424R2131) 
and a Phase 3 study in subjects with pneumonia (APEKS-NP, Study 1615R2132) are 
currently on-going. 
Refer to the current IB for additional details of completed studies. 


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2. STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of this study are: 
• To estimate the concentration of cefiderocol in ELF, at steady state in hospitalized 
subjects with known or suspected bacterial pneumonia being treated with standard 
of care (SOC) antibiotics and requiring mechanical ventilation 
• To estimate the ratio of the concentration for cefiderocol in ELF relative to plasma 
(RC,E/P) in hospitalized subjects with known or suspected bacterial pneumonia on 
treatment with SOC antibiotics and requiring mechanical ventilation 
 
 
 
 


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3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, single-arm, open-label study to assess the intrapulmonary and 
plasma concentrations of cefiderocol at steady state after multiple-dose administration in 
hospitalized subjects with known or suspected bacterial pneumonia on treatment with 
SOC antibiotics and requiring mechanical ventilation.  
Screening of subjects will occur within 48 hours prior to administration of the first dose 
of cefiderocol on Day 1 of the study. A minimum of 3 (and up to approximately 18) 
qualified subjects will receive an initial 2-g dose (or renally adjusted dose) of cefiderocol 
on Day 1 (within 72 hours of the start of potentially effective treatment with SOC 
antibiotics for bacterial pneumonia) and subsequently receive cefiderocol q8h (or q6h if 
subject has augmented renal function) with the dosage specified in Table 3-1. 
Table 3-1 
Cefiderocol Dosing and Bronchoalveolar Lavage 
Procedure for Various Degrees of Renal Function  
Creatinine Clearance 
Dosage 
Number of Doses Prior to 
Performing BAL 
Augmented renal function  
(CrCl ≥ 120 mL/min)a 
2 g, q6h, 3-hour infusion 
3-6 doses 
Normal renal function  
(CrCl  < 120 mL/min) a 
2 g, q8h, 3-hour infusion 
3-6 doses 
Mild renal impairment 
(CrCl 60 to < 90 mL/min) a 
2 g, q8h, 3-hour infusion 
3-6 doses 
Moderate renal impairment 
(CrCl  30 to < 60 mL/min) a 
1.5 g, q8h, 3-hour infusion 
3-6 doses 
Severe renal impairment 
(CrCl  15 to < 30 mL/min) a 
1 g, q8h, 3-hour infusion 
6-9 doses 
BAL = bronchoalveolar lavage; CrCl = creatinine clearance; q8h = every 8 hours; q6h = every 6 hours 
a 
Creatinine clearance will be calculated by Cockcroft-Gault equation at Screening.  
 
The dose of cefiderocol administered to each subject will be determined by the 
investigator based on dosing recommendations (see Section 5.2). End of Treatment 
(EOT) assessments will occur within 24 hours after administration of the last dose of 
cefiderocol, or at early termination. The End of Study (EOS) visit will occur 7 days 
(± 3 days) if there is no SAE, after administration of the last dose of cefiderocol. For both 
cases EOS visit can be performed on-site or by telephone (see Table 3-2). If an SAE is 
observed it must be reported to Safety and all SAEs, regardless of causality, will be 
followed until resolution, stabilization, the condition becomes chronic, or the subject is 
lost to follow-up. The investigator will make an effort to collect AEs for 7 days after the 
last dose of study drug. 
One ELF sample for determination of cefiderocol concentrations will be collected by 
bronchoalveolar lavage (BAL) procedure at 3, 5, or 7 hours, depending on the ELF 
cefiderocol concentration data obtained, after administration of at least 3 doses of 


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cefiderocol in subjects with normal or augmented renal function and subjects with mild 
or moderate renal impairment and after administration of at least 6 doses of cefiderocol in 
subjects with severe renal impairment. In addition, data from any BAL procedures 
performed during the study as part of routine patient care will also be collected as part of 
study data. A total of 4 blood samples for determination of plasma cefiderocol 
concentrations will be collected at prespecified time points corresponding to the dose 
after which the ELF sample is collected. Ongoing PK assessment of concentration data 
from both ELF and plasma samples will be performed for every 3 subjects to determine if 
modifications of the ELF sampling time point in subsequent subjects are needed. All 
revised sampling time point modifications will be provided by the sponsor, discussed 
with the investigator, and documented (see Section 7.5). 
Blood and ELF samples will be collected also for determination of urea concentration. 
Urea is used as an endogenous marker of ELF because urea is small and relatively 
nonpolar and can travel across membranes freely to reach the outer surfaces of alveoli. 
The concentration of urea in ELF is considered to be same as the serum urea 
concentration, implying complete distribution. Therefore, the calculated volume of ELF 
(VELF) is adjusted for excess exogenous volume using the concentration of urea in blood 
and ELF (see Section 7.6.4.1.3). 
Safety assessments including physical examinations, vital sign measurements, and 
clinical laboratory tests will be performed at prespecified time points prior to, during, and 
after administration of cefiderocol. In addition, data will be captured at various time 
points during the study from safety assessments (physical examinations, vital sign 
measurements, chest X-rays, and clinical laboratory tests) performed as part of routine 
patient care (see Section 7.5.2.1), date and result will be entered in the source documents 
and the electronic case report form (eCRF). Adverse events will be monitored throughout 
the study from the time informed consent is obtained until 7 days after administration of 
the last dose of cefiderocol if there are no SAEs.  
 
 




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lungs due to a variety of considerations including alterations in blood flow and degree of 
penetrability resulting from thickened secretions.   
A minimum of 3 subjects will be enrolled to provide a summary of cefiderocol 
concentrations in ELF in hospitalized subjects with known or suspected bacterial 
pneumonia being treated with SOC antibiotics and requiring mechanical ventilation. 
However, if necessary, up to approximately 18 subjects may be enrolled to ensure 
adequate information is obtained to meet the objectives of this study. Nonevaluable 
subjects will be replaced. See Section 7.5.2 for more details. 
3.3 
Study Duration 
3.3.1 
Study Duration in Individual Subjects 
The maximum duration of study participation for an individual subject, from the time of 
Screening (within 48 hours prior to the administration of the first dose of cefiderocol) to 
the EOS visit (up to 7 days after administration of the last dose of cefiderocol), is 13 days. 
Cefiderocol dosing will be terminated once the BAL procedure has been performed and 
ELF samples, plasma PK samples, and urea samples have been collected for analyses at 
which time no further cefiderocol dosing will be permitted. 
3.3.2 
Planned Study Duration  
The expected time for study completion, from first subject in to last subject last visit is 
approximately 8 months. 
 


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4. STUDY ENROLLMENT AND WITHDRAWAL 
4.1 
Study Population 
Subjects with known or suspected bacterial pneumonia being treated with SOC 
antibiotics and requiring mechanical ventilation who fulfill the following eligibility 
criteria will be enrolled.  
4.2 
Inclusion Criteria 
Subjects who fulfill the following criteria will be included in the study: 
1. Subject is male or female, 18-80 years (both inclusive) at the time written 
informed consent is obtained 
2. Subject has provided written informed consent or informed consent has been 
provided by subject’s legally authorized representative (Note: Country-specific 
rules and/or local state laws and local Ethics Committee approval for legally 
authorized representative informed consent will determine whether or not and 
how a subject unable to comprehend or sign the informed consent is allowed to be 
enrolled in the study) 
3. Subject has a clinical diagnosis of bacterial pneumonia, documented or suspected, 
(even if later known that the subject does not have bacterial pneumonia, 
discontinuation of the study is not necessary) 
4. Subject is hospitalized and receiving SOC antibiotic treatment for pneumonia 
5. Subject is mechanically ventilated and is expected to remain mechanically 
ventilated for at least 48 hours (or 72 hours for subjects with severe renal 
impairment) after the first dose of cefiderocol 
6. Subject has a life expectancy of at least 3 weeks from the Screening visit 
7. Female meeting 1 of the following criteria: 
a. Surgically sterile (has had a hysterectomy and/or bilateral oophorectomy, or a 
bilateral salpingectomy or tubal ligation for the purpose of contraception for at 
least 6 weeks with appropriate documentation of such surgery) 
b. Postmenopausal (defined as older than 45 years of age with cessation of 
regular menstrual periods for at least 6 months and a history of a follicle-
stimulating hormone level of > 40 mIU/mL, or amenorrhea for at least 12 
months) 
c. Of childbearing potential and using combined (estrogen and progestogen) or 
progestogen-only hormonal contraception associated with inhibition of 
ovulation (including oral, intravaginal, injectable, implantable, and 
transdermal contraceptives), or an intrauterine device (IUD) or intrauterine 
hormone-releasing system for the entire duration of the study 
d. Of childbearing potential and practicing abstinence as a preferred and usual 
life style and/or agrees to continue practicing abstinence from Screening for 
the entire duration of the study 


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e. Of childbearing potential and whose sole heterosexual partner has been 
successfully vasectomized and agrees to not have other heterosexual partners 
for the entire duration of the study 
 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Subject has a chemical/aspiration pneumonia that does not require antibiotic 
treatment (including aspiration of gastric acid, inhalation injury). The term 
chemical pneumonia refers to the aspiration of substances that are toxic to the 
lower airways causing chemical burn and injuries in the airway. 
2. Subject has 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)  
3. Subject has extensive cystic lesion(s) or severe structural abnormality (eg, cystic 
fibrosis, emphysema, cystic lesions of sarcoidosis or tuberculosis, post obstructive 
pneumonia due to lung cancer, etc) of the lung that hinders recovery of 
bronchoalveolar lavage fluid (BALF)  
4. Subject is receiving peritoneal dialysis. 
5. Subject has severe renal impairment requiring hemodialysis (HD) or end-stage 
renal disease requiring HD with creatinine clearance (CrCl) < 15 mL/min 
6. Subject is in refractory septic shock defined as persistent hypotension despite 
adequate fluid resuscitation or despite vasopressive therapy at Screening 
7. Subject is a female who has a positive pregnancy test at Screening or who is 
lactating  
8. Subject has received another investigational drug within 30 days prior to 
Screening 
9. Subject has previously participated in this clinical study and has received at least 
1 dose of cefiderocol  
10. Subject has any condition or circumstance that, in the opinion of the investigator, 
would compromise the safety of the subject or the quality of the study data. 
 
4.4 
Screen Failures 
Screen failures are defined as subjects who provide consent to participate in the study but 
are not subsequently dosed in the study. Minimal information will include informed 
consent date, baseline subject characteristics, all eligibility criteria not met, reasons for 
screen failure including reporting of AEs that lead to screen failure if applicable, and any 
SAEs and will be entered in the source documents and the eCRF. 
Subjects who do not meet the criteria for participation in the study (screen failure) may 
be rescreened only once in this study. Rescreened subjects should be assigned a new 
subject number to distinguish it from the initial Screening.  


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4.5 
Withdrawal of Subjects from the Study or Discontinuation from 
Study Drug 
The investigator will make every reasonable attempt to complete the study for each study 
subject.  
A subject may withdraw consent to participate in the study at any time, for any reason.   
The investigator or subinvestigator may discontinue a subject from study drug at any time 
for any of the following reasons: 
• A serious or intolerable AE occurs and the investigator or subinvestigator 
considers that the subject should discontinue study drug  
• The subject recovers from the infection prior to the BAL procedure and 
inflammation no longer exists in the lung  
• The subject is unable to undergo the BAL procedure or unable to provide an 
appropriate ELF sample  
• The subject is proved to be ineligible for the study after the initiation of study  
• The investigator or subinvestigator determines that the subject should be 
discontinued from the study drug based on the management and discontinuation 
criteria for abnormal liver function tests (Appendix 2) 
• The investigator or subinvestigator determines that the subject should be 
discontinued from study drug for any other reasons (eg, extubation) 
• The study is prematurely terminated 
In the event a subject withdraws consent or a subject is prematurely discontinued from 
study drug by the investigator or subinvestigator, the investigator or subinvestigator will 
promptly notify the sponsor. If a subject is prematurely discontinued from study drug by 
the investigator or subinvestigator, EOT (or early termination) procedures including 
physical examination, vital sign measurements, and clinical laboratory tests will be 
performed. The reporting of AEs will be obtained until the EOS visit, which occurs 
7 days after the last dose of cefiderocol if there is no SAE. If an SAE is observed it must 
be reported to Safety and all SAEs, regardless of causality, will be followed until 
resolution, stabilization, the condition becomes chronic, or the subject is lost to follow-up. 
The investigator will make an effort to collect AEs for 7 days after the last dose of study 
drug. 
If a subject withdraws or is discontinued from study or study drug, a replacement subject 
may be enrolled if deemed appropriate by the sponsor.    
The date of withdrawal or discontinuation and reason for withdrawal or discontinuation 
will be entered in the source documents and the eCRF. 
 


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5. STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Test Drug 
Cefiderocol will be supplied in vials containing 1 g of cefiderocol as a white to light 
yellow cake or powder, manufactured by Shionogi & Co., Ltd. Each cefiderocol vial will 
be reconstituted in 0.9% saline (normal saline) to produce a clear solution and then 
extracted for further dilution in normal saline to prepare an infusion solution with a final 
concentration of at least 20 mg/mL for IV administration.  
Each dose of cefiderocol will be prepared by the study pharmacist and labeled with 
appropriate information per local standards. A detailed procedure for preparation of the 
IV infusion solution will be provided in a separate pharmacy manual.  
5.2 
Treatments to be Administered 
The dose of cefiderocol administered to each subject will be determined based on renal 
function as described in this section (see Table 5-1). Dosing recommendations for 
subjects with moderate or severe renal impairment and subjects with augmented renal 
clearance are provided. For all subjects serum creatinine levels should be checked once 
daily to determine whether dose adjustments of cefiderocol should be made.     
Beginning on Day 1, subjects will be administered 2-g doses (or renally adjusted dose) of 
cefiderocol infused intravenously over 3 hours, q8h (or q6h for subjects with augmented 
renal function), for an expected minimum of 3 doses and up to a total of 6 doses in 
subjects with normal or augmented renal function and subjects with mild or moderate 
renal impairment, and for an expected minimum of 6 doses and up to a total of 9 doses in 
subjects with severe renal impairment. Cefiderocol dosing will be terminated once the 
BAL procedure has been performed and ELF samples, plasma PK samples, and urea 
samples have been collected for analyses at which time no further cefiderocol dosing will 
be permitted. After initiation of cefiderocol administration, doses of cefiderocol 
administered to each subject may be adjusted based on changes in renal function as 
assessed daily by CrCl (using the Cockcroft-Gault equation) and according to the dosing 
recommendations for subjects (see Table 5-1). Any dosing modifications based on the 
dosing recommendations will be agreed to by the investigator and documented. Please 
see the Renal Function and Dose Adjustment Log in the pharmacy manual.   
 


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Table 5-1 
Dosing Recommendations of Cefiderocol Based on 
Renal Function 
Creatinine Clearance 
Dosage 
Augmented renal function  
(CrCl ≥ 120 mL/min)a 
2 g, q6h, 3-hour infusion 
Normal renal function  
(CrCl < 120 mL/min)a 
2 g, q8h, 3-hour infusion 
Mild renal impairment 
(CrCl 60 to < 90 mL/min)a 
2 g, q8h, 3-hour infusion 
Moderate renal impairment 
(CrCl 30 to < 60 mL/min)a 
1.5 g, q8h, 3-hour infusion 
Severe renal impairment 
(CrCl 15 to < 30 mL/min)a 
1 g, q8h, 3-hour infusion 
CrCl = creatinine clearance; q6h = every 6 hours; q8h = every 8 hours 
a 
Creatinine clearance will be calculated by Cockcroft-Gault equation at Screening.  
 
5.3 
Selection and Timing of Dose for Each Subject 
Dosing recommendations were developed based on PK parameters estimated for subjects 
with bacterial pneumonia from a population PK model using PK data from healthy adult 
subjects to target equivalent systemic exposure (AUC) in the study population. 
Specifically, a population PK model was developed based on the data obtained from 
healthy adult subjects and subjects with cUTIs, where doses adjusted to be equivalent to a 
2-g dose of cefiderocol, q8h, and infused over 1 or 3 hours, were administered. 
Cefiderocol is renally excreted and requires dosage adjustment based on renal function 
estimated from serum creatinine concentration. Dosage adjustment based on reduced 
renal function will be made by the investigator or a qualified designee. Dosage 
adjustments for cefiderocol for subjects with various degrees of renal function are found 
in Table 5-1. 
5.4 
Method of Assigning Subjects to Treatment Groups 
This is a single-arm study and each qualified subject with normal or augmented renal 
function or mild or moderate renal impairment will receive administration of an expected 
minimum of 3 doses and up to a total of 6 doses while subjects with severe renal 
impairment will receive administration of an expected minimum of 6 doses and up to a 
total of 9 doses.    
If rescreening of a subject takes place, the rescreening subject number will be 100 more 
than the original (eg, Subject Number 001 will be replaced by Subject Number 101). 
5.5 
Blinding 
This is an open-label study. 


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5.6 
Packaging and Labeling 
Cefiderocol will be provided in vials containing 1 g of cefiderocol. Each vial will be 
labeled with the name of the active ingredient, protocol number, dosage form, strength, 
storage conditions, sponsor’s name and address, and cautionary statements according to 
Federal Regulations. 
5.7 
Storage and Accountability 
Cefiderocol vials will be stored in a tight, light-resistant container at 2oC to 8oC (36oF to 
46oF), and must be protected from light. 
The investigator will ensure that all study drug is stored and dispensed in accordance with 
the protocol and pharmacy manual concerning the storage and administration of 
investigational drugs. All drug supplies must be kept in a secure locked area with access 
limited to those authorized by the investigator. 
The qualified designee will maintain accurate records on the following information: 
receipt and condition of all study drugs, date of the receipt, when and how much study 
drug is dispensed and used by each subject in the study, and any reasons for departure 
from the protocol-specified dispensing regimen.  
The drug accountability records will be available for verification by the monitor or 
designee at each monitoring visit. At study completion, a final reconciliation of all used 
and unused clinical supplies will be performed. The study drug must not be used for any 
purpose other than the present study.   
5.8 
Investigational Product Retention at Study Site 
At the end of the study, all used and unused clinical supplies (cefiderocol) will be held at 
the study site although those supplies will not be required to be stored under the storage 
conditions defined above. All the used and unused clinical supplies must be returned to 
the sponsor (or designee) as per the sponsor’s written instructions or destroyed as per the 
clinical research organization’s (CRO’s) or local standard operating procedures (SOPs) 
upon agreement and written approval of the sponsor. 
5.9 
Treatment Compliance 
Start times and end times of the administration of IV treatments and the approximate 
extent of completion of all infusions will be recorded in the source documents and the 
eCRF. Any interruption or adjustment of the rate of an infusion will be noted in the 
source documents and the eCRF. The reason for interruption or adjustment also will be 
noted in the source documents and the eCRF.  


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6. RESTRICTIONS 
6.1 
Prior Therapy 
Prior therapy is defined as any therapy administered within 14 days prior to 
administration of the first dose of cefiderocol on Day 1 of the study.  
Any prior therapy (prescription drugs, over-the-counter drugs, procedures [eg, surgical or 
nonsurgical related to infection treatment or treatment-related complications such as 
dialysis] with or without any medication) taken by the subject within 14 days prior to the 
day of signing informed consent for the study, will be recorded in the source documents 
and the eCRF and the information will include name of drug used or procedures done, 
duration of treatment, and reason. If a drug is administered, route of administration will 
also be included.  
6.2 
Concomitant Therapy During the Study 
Concomitant therapy is defined as any therapy administered after administration of the 
first dose of cefiderocol until the EOS visit. 
Cefiderocol will be administered in combination with a SOC treatment regimen. 
Concomitant therapy, including prescription or nonprescription medications and 
procedures, will be recorded in the source documents and the eCRF and include the 
following information:   
• Name of medication or procedure  
• Start date 
• Stop date 
• Route of administration 
• Reason for use 
 
6.2.1 
Prohibited Therapy 
Not applicable. 
 


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7. STUDY PROCEDURES AND METHODS OF ASSESSMENTS 
The study procedures are summarized in the Time and Events Schedule in Appendix 1. 
7.1 
Informed Consent 
Informed consent will be obtained for all subjects prior to performing any study related 
procedures. A subject cannot be entered in the study until he/she or his/her legally 
authorized representative has signed and dated the informed consent form (ICF).  
The investigator or qualified designee will fully explain the nature of the study to the 
subject, or, if the subject is unable to give consent him/herself, to the subject’s legally 
authorized representative using the Institutional Review Board (IRB)-approved ICF. 
When the subject or his/her legally authorized representative agrees that he/she can 
participate in the study, the subject or his/her legally authorized representative must 
voluntarily sign an ICF prior to the initiation of any study procedures. A copy of the 
signed and dated ICF will be given to the subject or legally authorized representative. 
The signed and dated original ICF will be retained by the investigator. The date ICF was 
signed will be recorded in the source documents and the eCRF.  
The investigator, or qualified designee is responsible for ensuring that the subject (or 
legally authorized representative) understands the risks and benefits of participating in 
the study, including answering any questions the subject (or legally authorized 
representative) may have throughout the study and sharing any new information in a 
timely manner that may be relevant to the subject’s willingness to continue his/her 
participation in the study. 
7.2 
Baseline, Subject Characteristics, and Medical History 
A complete medical history including prior or concomitant antibiotics will be taken at 
Screening. Demographics and baseline characteristics, including date of birth, initials, sex, 
ethnicity, race, body weight, and height will be recorded in the source documents and the 
eCRF.   
7.3 
Enrollment in the Study and Dispensing Study Drug 
After a subject has signed informed consent, the investigator, or designee will enter the 
new subject into EDC by which a subject identification number will be assigned in EDC. 
If the subject is eligible according to the inclusion/exclusion criteria, the subject will 
enter the treatment period of the study. The investigator or subinvestigator will assign the 
appropriate dosage to the subject depending on the subject’s renal function. The site 
pharmacist will prepare and dispense the study drug as specified in Section 5.2.  
7.4 
Efficacy Assessments 
There are no efficacy assessments in this study. 


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7.5 
Pharmacokinetics Assessments 
Pharmacokinetic assessments will be performed for plasma and ELF samples obtained 
from each subject. The ELF and plasma sample collections must be done in connection 
with the same cefiderocol infusion. Detailed procedures for sample collection, handling, 
labeling, storage, and shipment to the bioanalytical laboratory will be provided by the 
sponsor in study-specific laboratory manual(s). Please see Appendix 2 of the protocol for 
more details on PK and urea sampling. 
7.5.1 
Plasma Samples 
A total of 4 blood samples for determination of plasma cefiderocol concentrations will be 
collected at prespecified time points after administration of at least 3 doses of cefiderocol 
in subjects with normal or augmented renal function and subjects with mild or moderate 
renal impairment, and after administration of at least 6 doses of cefiderocol in subjects 
with severe renal impairment: (1) 1 hour after the start of infusion, (2) 3 hours after the 
start of infusion (within 30 minutes prior to the end of infusion), (3) 2 hours after the end 
of infusion (within ± 1 hour), and (4) 4 hours after the end of infusion (within ± 1 hour). 
The plasma PK samples will be collected at time points around the same cefiderocol 
infusion that the BAL procedure is performed. A blood sample for urea assessment will 
be collected as part of plasma sample collection within 30 minutes prior to the BAL 
procedure.  
For each blood sample collected, the actual sampling time will be recorded in the source 
documents and the eCRF. 
7.5.2 
Epithelial Lining Fluid Sample 
A single BAL procedure must be performed by a medical doctor such as the principal 
investigator or subinvestigator. Mini-BAL is not allowed in this study. 
One ELF sample will be collected per subject for the determination of cefiderocol 
concentration by BAL procedure on the inflamed section of the lung (ie, a lobe where 
pneumonia is expected to be present, based on the last chest radiologic imaging) after 
administration of at least 3 doses of cefiderocol in subjects with normal renal function or 
augmented renal function and subjects with mild or moderate renal impairment and after 
administration of at least 6 doses of cefiderocol in subjects with severe renal impairment. 
If it is not convenient for the subject or the institution to perform the BAL procedure after 
the 3rd dosing (or 6th dosing for severe renal impairment subjects), the 4th, 5th, or 6th 
dosing could be considered as the timing for the BAL procedure (or the 7th, 8th, or 9th 
dosing for severe renal impairment subjects).  
The ELF sample for the determination of cefiderocol concentrations will be collected by 
BAL procedure 3, 5, or 7 hours after administration of cefiderocol depending on the data 
obtained during the conduct of the study (see Appendix 2). The ELF sample will be 
analyzed for white blood cell count and differential as well as urea. 


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Pharmacokinetic assessments in ELF will be performed for all subjects. After the 
enrollment and collection of PK samples from the first 3 subjects, the sites that are 
activated for enrollment will be instructed, via a phone call from the sponsor or CRO, to 
pause enrollment until the available data has been processed and evaluated. The phone 
call will be followed by written notification via “Dear Dr Letter” with copy to the CRO. 
The data obtained from the first 3 subjects will be evaluated by the sponsor, and the BAL 
collection time point for the ELF sample may subsequently be modified in accordance 
with the outlined procedure (see Figure 7-3 and Appendix 2).The sampling time point 
may be adjusted 3 times during the study, each time after evaluation of 3 subjects’ PK 
data. Upon evaluation of data, sponsor or CRO will notify sites via phone call and “Dear 
Dr Letter” with copy to the CRO about any changes in BAL sampling time point. Sites 
are required to provide written acknowledgement of receipt of changed BAL sampling 
time point. 
A sampling procedure scheme will be provided in the study Statistical Analysis Plan 
(SAP) prior to the first subject dosing in the study. The final sampling scheme will be 
presented in the clinical study report (CSR). The sampling procedure will be determined 
by the sponsor based on available data, and will be documented.  
After PK assessments have been completed and evaluated in a total of 9 subjects split 
evenly in the 3 sampling steps depicted in Figure 7-3, up to 9 additional subjects may be 
enrolled from whom ELF samples will be collected at time point(s) specified by the  
sponsor. The total number of 18 evaluable subjects may be enrolled in this study. 
Nonevaluable subjects will be replaced with new subjects. 
The BAL procedure will be detailed in a study-specific laboratory manual provided by 
the sponsor. The subject should be monitored per SOC and as clinically indicated. 
If the local laboratory performs a microbiology test using the BAL sample, the result 
must be recorded in the source documents and the eCRF. 
Refer to lab manual for BAL procedure and ELF sampling details. 


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Figure 7-3 
Epithelial Lining Fluid Sampling Procedure Schematic 
 
BAL = bronchoalveolar lavage; conc. = concentration; ELF = epithelial lining fluid; hr = hour; min = 
minutes; RC,E/P = ratio of the concentration for cefiderocol in ELF relative to plasma 
 
Ventilator Parameters 
Within 30 minutes prior to the start of the BAL procedure, the following ventilator 
parameters will be captured from all subjects: respiratory rate (breaths/minute) and 
positive end-expiratory pressure (PEEP). The results will be entered in the source 
documents and the eCRF. 
7.6 
Safety Assessments 
7.6.1 
Physical Examination 
A complete physical examination will be performed at Screening. Symptom-driven 
physical examination relevant to the subject’s current condition will be performed as 
clinically indicated (see Appendix 1) and at the investigator’s discretion from predose 
until end of treatment. Body weight in kilograms and height in centimeters will be 
obtained at Screening. The physical examination should be performed according to the 
normal practice of the clinical study site by the investigator or subinvestigator. Clinically 


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significant findings on physical examination will be recorded as an AE in the source 
documents and the eCRF. Weight and height will be entered in the source documents and 
the eCRF. 
7.6.2 
Vital Signs 
Blood pressure (systolic/diastolic), body temperature, pulse rate, and respiratory rate will 
be measured at Screening and at specified time points. 
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 of the 
infusions and continuing while the subject is receiving cefiderocol.  
Vital signs obtained through continuous monitoring methods, including intra-arterial 
catheters, may be used to record blood pressure, body temperature, and heart rate. 
The investigator or subinvestigator will consider whether changes from baseline are 
clinically significant (see also Section 7.6.5). Results of blood pressure, body temperature, 
pulse rate, and respiratory rate will be entered in the source documents and the eCRF. 
7.6.3 
Chest X-Ray 
A chest X-ray will be performed at Screening or within 48 hours of Screening per 
Appendix 1 and will be considered as baseline. Data from chest X-rays performed as part 
of routine patient care will be collected throughout the study. A computed tomography 
(CT) scan can be a substitute of chest X-ray if taken according to local SOC. The results 
will be entered in the source documents and the eCRF. 
Results of chest X-rays will be entered in the source documents and the eCRF.   
7.6.4 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed at prespecified time points per the Time and 
Events Schedule in Appendix 1. In addition to prespecified time points, data from clinical 
laboratory tests performed at other time points as part of routine patient care will be 
collected from the first dose of cefiderocol, during administration of cefiderocol until the 
last dose of cefiderocol. Clinical laboratory tests during the treatment period will be 
symptom-driven and at the investigator’s discretion. 
Routine samples such as hematology and blood chemistry parameters will be measured at 
a local laboratory, and the results will be entered in the eCRF. PK samples and other 
specialized samples for testing will be analyzed at a central laboratory and detailed 
procedures for sample collection, handling, labeling, storage, and shipping will be 
provided in the separate study laboratory manual. Shipping labels, instructions for 
shipping, and courier service will be provided from the sponsor or CRO. 
Date of specimen collection and whether or not specimen was collected will also be 
entered in the source documents and the eCRF. 


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Laboratory Parameters 
A list of the reference ranges for all clinical laboratory tests conducted must be provided 
by the study site prior to initiation of the study and updated by the study site if changes to 
the reference ranges are implemented during the study conduct. 
The investigator or subinvestigator will assess whether any abnormal changes from 
Screening (within 48 hours prior to the administration of the first dose of cefiderocol) are 
clinically significant. 
7.6.4.1.1 
Routine Laboratory Tests 
Routine hematology and blood chemistry parameters that will be assessed at local 
laboratory are presented in Table 7-1. Mandatory laboratory tests are, complete blood 
count (CBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma 
glutamyltransferase (GGT), alkaline phosphatase (ALP), total bilirubin (TBL), blood urea 
nitrogen, serum creatinine, blood glucose, serum or urine pregnancy test (female only) at 
Screening. The results will be entered in the source documents and the eCRF.  
If a microbiology test has been performed (before or during Screening) to confirm the 
clinical diagnosis, the result from the test done closest to the day of screening or on the 
day of screening should be recorded in the source documents and the eCRF.  
Table 7-1 
Routine Laboratory Tests 
Category 
Evaluation Parameters 
Hematology tests 
Hematocrit* 
Hemoglobin* 
Platelet count* 
RBC* 
WBC count with differential* and 
morphology incidences 
Blood chemistry 
tests 
Aspartate aminotransferase* 
Alanine aminotransferase* 
Gamma glutamyltransferase* 
Alkaline phosphatase* 
Total bilirubin* 
LDH 
C-reactive protein 
Total protein 
Albumin 
Blood urea nitrogen* 
Serum creatinine* 
Blood glucose* 
Uric acid 
Electrolytes (sodium, potassium, 
chloride, calcium, magnesium, and 
bicarbonate) 
Other 
Serum or urine pregnancy test at Screening (females only)* 
LDH = lactate dehydrogenase; RBC = red blood cell; WBC = white blood cell 
*mandatory laboratory tests 
 
7.6.4.1.2 
Creatinine Clearance 
Creatinine clearance will be calculated from serum creatinine by 
Cockcroft-Gault formula as described below to assess renal function and will be 
recorded in the source documents and the eCRF.  
● Cockcroft-Gault formula 
CrCl (mL/min) = (Weight [kg]) × (140 - age in years)/(72 × serum creatinine [mg/dL]) x (0.85 if female) 


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7.6.4.1.3 
Serum and ELF Sample Collection for Urea Analysis 
A blood sample will be collected for urea analysis from each subject prior to and within 
30 minutes to the start of the BAL procedure. 
The ELF sample collected from the BAL procedure will be used for urea analysis.  
7.6.4.1.4 
Pregnancy Tests 
A serum or urine pregnancy test will be performed at Screening for female subjects of 
childbearing potential only.  
 
Sample Collection, Storage, and Shipping 
Routine laboratory samples for clinical laboratory tests will be collected at specified time 
points by the investigator or qualified designee and sent to a local clinical laboratory for 
processing according to the clinical site SOPs.  
BAL and blood samples for PK and urea assessment will be collected, processed, frozen 
and stored locally until shipped to the central laboratory for analyses. 
Details can be found in the study lab manual. 
7.6.5 
Adverse Event Assessments 
 
Definition and Assessment of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product (including investigational drug) during the course of a clinical 
investigation. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
an investigational product, whether or not considered related to the investigational 
product. If signs and/or symptoms are part of a diagnosis, the diagnosis should be 
reported as the AE rather than the individual signs and/or symptoms.    
Adverse events will be found by the subject’s spontaneous complaint, subject comment 
cards, or as a result of nonleading questions, physical examination, vital signs, or 
laboratory tests. Adverse events include any occurrences that are new in onset or 
aggravated in severity or frequency from the baseline condition, or abnormal results of 
diagnostic procedures, including laboratory test abnormalities. Concurrent medical 
conditions present at baseline that worsen will be considered as AEs.  
The investigator or subinvestigator is responsible for assessing AEs. Adverse events 
should be fully investigated and recorded in detail in the source documents and the eCRF, 
including onset date, end date, of, severity, seriousness (with seriousness criteria), 
relationship with the study drug, action taken to manage the AE, and the outcome of the 
AE, including the date.  


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Assessment Period 
Adverse events will be collected from the time signed informed consent is obtained 
through the EOS visit (up to 7 days) after administration of the last dose of the study drug. 
If a subject is prematurely discontinued from study drug by the investigator or 
subinvestigator, the investigator will make an effort to collect AEs for 7 days after the 
last dose of study drug. All SAEs, regardless of causality, will be followed until 
resolution, stabilization, the condition becomes chronic, or the subject is lost to follow-up. 
 
Severity 
The severity of an event will be graded by the investigator or subinvestigator according to 
the following definitions: 
● Mild: A finding or symptom is minor and does not interfere with usual daily 
activities 
● Moderate: The event causes discomfort and interferes with usual daily activity or 
affects clinical status 
● Severe: The event causes interruption of the subject's usual daily activities or has 
a clinically significant effect 
The highest severity grades identified during the period in which the AE occurred will be 
recorded in the source documents and the eCRF and the SAE or other expedited form as 
required. 
 
Relationship to the Study Drug 
The relationship of an event to the study drug will be determined by the investigator or 
subinvestigator according to the following criteria: 
• Related: An AE that can be reasonably explained as having been caused by the 
study drug. For example, the occurrence of the AE can be explained by any of the 
following: a pharmacological effect of the study drug (eg, a similar event had 
been reported previously); an increase/decrease of the dose affects the occurrence 
or seriousness of the AE; or all other causative factors (eg, medical history, 
concomitant medication etc) can be ruled out after careful analysis of sufficient 
information. 
• Not related: An AE that cannot be reasonably explained as having been caused 
by the study drug. 
 
Expectedness 
An AE is considered expected if it is listed in Expected Adverse Reactions in Section 
“Undesirable Effects” of “SUMMARY OF DATA AND GUIDANCE FOR 
INVESTIGATORS” in the current IB for cefiderocol. 


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Adverse Event Assessment of Clinical Laboratory and Other Safety 
Parameters 
For any abnormal laboratory test results (hematology, blood chemistry, or urinalysis) or 
other safety assessments (eg, physical examination, vital signs) that occur or worsen 
following exposure to the study drug from baseline, the investigator or subinvestigator 
will consider whether those results are clinically significant. Abnormal laboratory test 
results are defined as values outside the reference range. For test results that are abnormal 
at baseline and significantly worsen following the initiation of the study, the investigator 
or subinvestigator must also consider whether those results are clinically significant. Any 
test results that are considered to be clinically significant by the investigator or 
subinvestigator are to be recorded as AEs in the source documents and the eCRF. If 
abnormal laboratory finding is associated with disease or organ toxicity, the investigator 
should report only the disease or organ toxicity as an AE. These AEs should also be 
assessed as to whether or not they meet the definition of serious and should be reported 
accordingly.  
The investigator or subinvestigator will consider test results to be clinically significant in 
the following circumstances (at their own discretion in the other circumstances): 
• Clinical laboratory test results that lead to any of the outcomes included in the 
definition of an SAE (see Section 7.6.5.7.1) 
• Clinical laboratory test results that lead to a change in dosing of study drug or 
discontinuation from the study 
• Clinical laboratory test results that lead to a concomitant medication treatment or 
other therapy 
• Clinical laboratory test results that require additional diagnostic testing (except for 
a confirmatory test) or other medical intervention 
• Clinical laboratory test results that meet the management and discontinuation 
criteria for abnormal liver function tests or transaminase elevations identified in 
Appendix 3. 
In addition, when any test result meets the management and discontinuation criteria for 
abnormal liver function tests (Appendix 3), the results of further assessments and 
required follow-up should be recorded in the Liver Event Form. 
 
Serious Adverse Events 
7.6.5.7.1 
Definition 
An SAE is defined by regulation as any AE occurring at any dose that results in any of 
the following outcomes: 
• Death 
• Life-threatening condition 
• Hospitalization or prolongation of existing hospitalization for treatment 




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OR  
 
 
 
 
 
If the sponsor requires a follow-up assessment, the investigator should enter new 
information into the EDC or by using the SAE Form if the EDC is unavailable. Discharge 
summaries, consultant reports (from other departments or other hospitals), 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; however do not send hospital medical records to the sponsor unless 
specifically requested. 
Appropriate remedial measures should be taken by the investigator using his/her best 
medical judgment to treat the SAE. These measures and the subject’s response to these 
measures should be recorded in the source documents and the eCRF. Clinical, laboratory, 
and diagnostic measures should be employed by the investigator as needed to adequately 
determine the etiology of the event.  
Any SAE occurring after AE assessment period specified in Section 7.6.5.2 that is 
considered to be related to the study drug by the investigator, must be reported to the 
CRO or the sponsor. 
The investigator will be responsible for reporting all SAEs to the IRB with the local 
regulatory requirement, as well as the sponsor. The sponsor will be responsible for 
reporting SAEs to the regulatory authorities as required by the applicable regulatory 
requirements. 
 
Special Situations - Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error of the study drug (as defined below) must 
be reported to the CRO by the investigator using a Special Situations Report Form within 
24 hours of becoming aware (refer to Section 7.6.5.7.2 for reporting destination to the 
CRO; INC SAE Hotline). If SAE is suspected, the investigator will enter the SAE in the 
EDC.  
• 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 investigational product(s) in 
excess of the assigned dose in the protocol or labeling.  


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• Medication Error: Any unintended error in the prescribing, dispensing or 
administration of an investigational product(s). Cases of subjects missing doses of 
investigational product(s) are not considered reportable as medication error. 
 
Pregnancy 
If a female subject becomes pregnant during the study, the investigator (or 
subinvestigator) will immediately discontinue the study drug. All pregnancy exposures 
that occur after the first dose of the study drug until the EOS visit must be reported within 
24 hours from the time point when the investigator first becomes aware of the pregnancy 
and the Pregnancy Form will be submitted to the CRO or sponsor by the investigator 
(refer to Section 7.6.5.7.2 for reporting destination to the CRO; INC SAE Hotline). 
Pregnancy complications and elective terminations for medical reasons must also be 
reported as an AE or SAE as appropriate. Spontaneous abortions must be reported as an 
SAE. The outcome of the pregnancy (ie, birth, miscarriage, abortion) should be followed 
by the investigator and must also be reported using the Pregnancy Form, which must be 
submitted to the CRO or sponsor. 
 
Treatment-emergent Adverse Events 
Adverse events reported after the initial dose of study drug will be considered treatment-
emergent adverse events (TEAEs). 
7.7 
Appropriateness of Measurements 
The safety and PK evaluations selected for the study are typical for this subject 
population and type of investigation, and utilize widely accepted methods. The 
BAL procedure used in this study to obtain the ELF samples is known to be a 
safe and well-established clinical procedure [32]. 
7.8 
Allowable Time Window 
Measurements will be performed according to the Time and Events Schedule in 
Appendix 1, and the acceptable time deviations relative to the time points are specified in 
Table 7-2 below. Every effort should be made to adhere as closely as possible to 
procedure time points specified. 
 


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Table 7-2 
Allowable Time Window 
Study Activity  
Specified Time or Day 
Acceptable Time Window 
Blood sample collection at 1 hour after 
the start of infusion for PK 
 
± 15 minutes 
ELF and blood sample collection at 3 
hours after the start of infusion for PK 
 
Within 30 minutes prior to 
the end of infusion  
ELF and blood sample collection at 
2 hours or 4 hours after the end of 
infusion for PK 
 
± 1 hour  
Blood sample collection corresponding 
with ELF sample collection for PK 
 
± 5 minutes after ELF 
sample collection 
Safety assessments 
 
± 1 hour 
EOT assessments 
24 hours after the last dose of 
cefiderocol 
+ 1 day 
EOS visit 
7 days after the last dose of 
cefiderocol 
± 3 days 
ELF = epithelial lining fluid; EOS = End of Study; EOT = End of Treatment; PK = pharmacokinetic(s) 
 
 


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8. STUDY ACTIVITIES 
Study Activities are presented in the Time and Events Schedule (Appendix 1). 


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9. PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The statistical analysis and PK analysis will be performed by the sponsor or designee. 
The detailed statistical analysis methods will be specified in a SAP according to this 
section of the protocol. For the analyses changed from those outlined in the protocol, the 
reason for changes from the protocol will be described in the SAP. The first draft of the 
SAP will be available before the first subject is dosed, and any subsequent minor changes 
to the SAP will be noted in the CSR. 
Unless otherwise noted, continuous variables will be summarized using the number of 
nonmissing observations (N), arithmetic mean (Mean), standard deviation (SD), median, 
minimum, and maximum values as summary statistics; categorical variables will be 
summarized using the frequency count and the percentage of subjects in each category as 
summary statistics.   
No inferential statistical testing will be performed in this study. No efficacy 
measurements will be recorded or tabulated. 
All subject study data, including data not appearing in tables, will be presented in by 
subject data listings. Individual subject data, PK data, and any derived data will be 
presented by subject. All analyses and tabulations will be performed using both the SAS® 
Version 9.1 or higher and WinNonlin® Version 6.2.1 or higher. 
9.2 
Determination of Sample Size 
A minimum of 3 subjects will be enrolled to provide a summary of cefiderocol 
concentrations in ELF in hospitalized subjects with known or suspected bacterial 
pneumonia being treated with SOC antibiotics and requiring mechanical ventilation. 
However, if necessary, up to approximately 18 subjects may be enrolled to ensure 
adequate information is obtained to meet the objectives of this study. No formal 
calculations were performed to determine sample size for this study. Section 7.5.2 
outlines the algorithm regarding number of subjects to be enrolled in this study. 
9.3 
Analysis Populations 
The following analysis populations will be examined in this study:  
• The Safety population includes all enrolled subjects who receive at least 1 dose 
of the study drug. The population will be analyzed as treated. 
• The PK concentration population includes all subjects who receive at least 
1 dose of cefiderocol and have at least 1 evaluable concentration of cefiderocol in 
BALF.  This population will be used for the concentration listing. This population 
will also be used for plotting of the concentration-time data and the concentration 
summary.  
 


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9.4 
Handling of Missing Data 
Missing data will not be imputed. All analyses will be based on observed cases.   
9.5 
Subject Disposition 
Among the subjects enrolled into the study, the number and percentage of subjects who 
complete the study and the number and percentage of subjects who prematurely 
discontinue the study will be summarized. In addition, reasons leading to study 
discontinuation will be summarized. The number of subjects included in each analysis 
population will also be presented. 
9.6 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized with descriptive statistics 
for the safety population. 
9.7 
Extent of Exposure and Treatment Compliance 
The study drug exposure and compliance will be listed.   
9.8 
Prior Therapies 
Prior therapies for drugs will be coded using the World Health Organization (WHO) 
Drug Dictionary. Subjects who have received prior therapy(ies) will be listed for the 
safety population.     
9.9 
Concomitant Therapies 
Concomitant therapies for drugs will be coded using the WHO Drug Dictionary. Subjects 
who received concomitant therapy(ies) will be listed for the safety population.   
9.10 Efficacy Analysis 
There will be no efficacy analysis for this study. 
9.11 Safety Analyses 
The safety population will be used for all safety analyses. 
9.11.1 
Adverse Events 
Adverse events will be classified by System Organ Class and Preferred Term using 
Medical Dictionary for Regulatory Activities (MedDRA). Of reported AEs in the eCRF, 
TEAEs will be used for safety analyses. The definition of TEAE is described in 
Section 7.6.5.10. Treatment-emergent AE will be referred to as an AE in this section. 
The number and percentage of subjects who experienced at least 1 TEAE, deaths, SAEs, 
and TEAEs leading to discontinuation will be summarized. The number of those AEs, 
which are counted by cases reported, will also be presented. Treatment-related AEs will 


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be summarized in the same way as AEs for overall summary. The definition of treatment-
related AE is described in Section 7.6.5.4. 
For the summary of AE by MedDRA System Organ Class and Preferred Term the 
number of subjects who have experienced AEs will be presented with the percentage of 
subjects. The summary for severity and outcome will be presented by System Organ 
Class and Preferred Term.  
All AEs will be listed. 
9.11.2 
Vital Signs 
All vital sign data will be listed. 
9.11.3 
Clinical Laboratory Analysis  
All clinical laboratory data will be listed. 
9.12 Pharmacokinetic Analysis 
For each subject, the concentration of cefiderocol in ELF will be calculated and 
determined according to the following procedures. 
Calculation of cefiderocol concentration in ELF: 
 
VELF = VBAL × (Urea,BAL/Urea,SERUM) 
 
CELF = CBAL × (VBAL/VELF) 
VELF represents the calculated volume of ELF, VBAL is the BALF volume. Urea,BAL and 
Urea,SERUM are the urea concentrations in the BALF and serum, respectively. CELF and 
CBAL is the cefiderocol concentration in the ELF and the supernatant BALF, respectively. 
Individual plasma and ELF concentrations of cefiderocol will be listed and summarized 
by nominal sampling time with N, Mean, SD, and coefficient of variation (CV%, 
calculated by SD/Mean × 100), Geometric Mean and coefficient of variation for 
geometric mean (CV% Geometric Mean), and median, minimum, and maximum values. 
The CV% Geometric Mean will be calculated according to a formula:  
CV% Geometric Mean = [exp(sd2)−1]1/2 × 100 
where sd is the standard deviation for natural log (ln)-transformed data.  
Concentration ratios in ELF to plasma (RC,E/P) in each subject will be calculated, listed, 
and summarized with N, Mean, SD, CV%, Geometric Mean and CV% Geometric Mean, 
and median, minimum and maximum values by nominal sampling time. 
The time courses of individual and mean plasma and ELF concentrations and individual 
and mean RC,E/P will be presented by appropriate graphics. 


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Individual plasma and ELF 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 CSR along with justification for exclusion. 
For calculation of ELF concentration, the BALF concentration below the limit of 
quantification (BLQ) will be treated as zero (0). For summary of ELF concentration, the 
ELF concentration of zero will be included for calculations of Mean, SD, CV%, 
minimum, median and maximum and treated as missing for calculations of Geometric 
Mean value and CV% Geometric Mean. 
For summary of plasma concentration, the concentration BLQ will be treated as zero (0) 
for calculations of Mean, SD, CV%, minimum, median and maximum and treated as 
missing for calculations of Geometric Mean value and CV% Geometric Mean. 
If the plasma concentration is not quantifiable, the RC,E/P will not be calculated. If the 
plasma concentration is quantifiable and the ELF concentration is zero, RC,E/P will be 
calculated as zero (0). The RC,E/P of zero will be included for calculations of Mean, SD, 
CV%, minimum, median and maximum and treated as missing for calculation of 
Geometric Mean value and CV% Geometric Mean. 
Population PK analyses will be performed using a nonlinear mixed effects model 
approach. NONMEM® Version 7.3 or higher will be used for the analyses.  Population 
PK analyses will be performed and reported separately by the Clinical Pharmacology & 
Pharmacokinetics of Shionogi & Co., Ltd. 
9.13 Other Analysis 
No other analysis is planned. 
9.14 Interim Analysis 
Pharmacokinetic assessments for ELF will be performed for every 3 subjects. Based on 
the preceding data obtained thus far, the BAL collection time point for the ELF sample 
may subsequently be modified in accordance with the outlined procedure  
(see Figure 7-3). Additional details for determining whether to proceed to each next step 
will be based on the data obtained for each category. 




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10.2 Institutional Review Board or Independent Ethics Committee 
Approval 
The IRB will safeguard the rights, safety, and well-being of the subjects by reviewing the 
following study documents: the protocol, ICF, written information on subject recruitment 
procedures (if applicable), other written information given to the subjects, IB, 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. The IRB will be appropriately constituted in accordance with ICH GCP, and local 
requirements, as applicable. The study will be undertaken only after the IRB has given 
full approval and the investigator 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. The 
investigator will inform the IRB of any reportable AEs. 
10.3 Ethical Conduct of the Study 
The study will be conducted in accordance with all appropriate regulatory requirements 
and under the protocol approved by the IRB. The study will be conducted in accordance 
with current ICH GCP, all appropriate subject privacy requirements, and the ethical 
principles that are outlined in the Declaration of Helsinki.   
10.4 Informed Consent Process 
The sponsor will provide the investigators with a proposed ICF that complies with the 
ICH GCP guidelines and regulatory requirements. The investigator will review the ICF 
for the study and make any necessary changes according to local regulations. The sponsor 
must review and agree to any changes to the proposed ICF suggested by the investigator 
prior to submission to the IRB, and the IRB approved version must be provided to the site 
monitor after IRB approval. 
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 before use.  
The investigator, or qualified designee will explain the nature, purpose, methods, 
reasonable anticipated benefits, and potential hazards of the study to the subject or, if 
incapacitated, to his/her legally authorized representative in simple terms by using the 
ICF before the subject is entered into the study. The method of obtaining and 
documenting informed consent will comply with ICH GCP and all applicable regulatory 
requirements.  
10.5 Subject Confidentiality 
Procedures for protecting subject privacy must adhere to applicable data privacy laws and 
regulations. In order to maintain subject privacy, all eCRFs, study drug accountability 
records, study reports, and communications will identify the subject by the subject 


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identification code. 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 in the eCRFs and for verification of the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. The investigator 
and the sponsor are responsible for ensuring that sensitive information is handled in 
accordance with local 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. 
Subject data collected in the eCRFs during the study will be documented in an 
anonymous fashion and the subject will only be identified by the subject identification 
code. In the emergent or rare event that it is necessary to identify a subject for safety or 
regulatory reasons, 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 the 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 in the eCRFs, verify the eCRFs 
entries with direct access to source documents, collect any safety information on subjects, 
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 
An eCRF will be created for each subject who signed informed consent. The investigator 
or qualified designee will transcribe historical information and relevant data, as specified 
by the protocol, into the eCRF for each subject. All subject data from study visits must be 
legibly collected on source documents and eCRF entry completed in accordance with the 
eCRF Completion Guidelines. Electronic case report forms data entry is performed by the 
investigator, subinvestigator, and study coordinator who are authorized in to do data entry 
by the delegation log or other site personnel documentation. The investigator must ensure 
that data reported in the eCRF is accurate, complete, and timely, prior to signing the 
eCRFs to verify the integrity of the data recorded. When the sponsor or 
designee generates a query to a participating study site, an authorized user will update the 
eCRF data or provide a query response as appropriate.   
Reference ranges, for both local and central laboratories, for all protocol-specified 
laboratory tests will be collected prior to study site initiation. Reference ranges for all 
laboratory tests will be updated if the lab is recalibrated during the study.   


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10.7.2 
Source Data and Source Documents 
Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should legibly document the dates and details of study 
procedures, AEs, and subject status. The following data can be recorded directly on an 
eCRF as source data:  
• Reason for use of prior therapy or concomitant therapy 
• Severity, seriousness, and relationship of an AE, and its causal relationship to the 
study drug 
• Clinical comments  
The investigator must maintain source documents such as laboratory reports, and 
complete medical history and physical examination reports. All the source documents 
must be accessible for verification by the site monitor, auditor, the IRB, and inspections 
of regulatory authority. Direct access to these documents must be guaranteed by the 
investigator, subinvestigator, or study coordinator, who must provide support at all times 
for these activities. For all sources of original data required to complete the eCRF, the 
nature and location of the source documents will be identified by the sponsor and the site 
staff. If electronic records are maintained at the study site, the method of verification 
must be specified in a document within the study site.   
10.7.3 
External Data 
The following data will be reported in separate documents from eCRFs.   
• Concentration data of cefiderocol and urea 
• PK analyses results derived from concentration data  
10.8 Committees 
10.8.1 
Case Review Committee  
No case review committee will be established for this study.   
10.8.2 
Independent Data Monitoring Committee 
No independent data monitoring committee will be established for this study. 
10.8.3 
Other Committees  
No other committees will be established for this study. 
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:   


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• Ensuring safety of the study is difficult due to safety concerns (eg, occurrence of 
many treatment-related SAEs) 
• Achieving the purpose of the study is considered impossible (eg, interim data 
suggesting lack of safety, inadequate recruitment of subjects) 
If the study is prematurely terminated or suspended, the sponsor should promptly inform 
the investigators. The investigator or subinvestigator should promptly inform the 
participating subjects and change the study drug to other appropriate therapy(ies).   
For withdrawal criteria for individual subjects, see Section 4.5. 
10.9.2 
Termination or Suspension of the Study by Study Site 
The investigator may prematurely terminate or suspend the study in the study site 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 SAEs). 
The sponsor may request the investigator to prematurely terminate or suspend the study 
in the study site at any time when major violations/deviations of protocol, other 
procedures, and ICH GCP were not improved. 
If the study site is prematurely terminated or suspended from the study, the investigator 
or subinvestigator should promptly inform the corresponding IRB and participating 
subjects and change the study treatment to other appropriate therapy(ies).   
10.10 Protocol Modifications and Deviations 
The investigator will conduct the study in compliance with the protocol provided by the 
sponsor and approval/favorable opinion given by the IRB and the regulatory 
authority(ies). Modifications to the protocol should not be performed without agreement 
of both the investigator and the sponsor. Changes to the protocol will require written IRB 
approval/favorable opinion prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to subjects or for other inevitable medical 
reasons.   
The investigator or subinvestigator should document any deviation from the protocol and 
the reason. If the investigator deviates from the protocol or makes a change to the 
protocol to eliminate an immediate hazard(s) to subjects, the record should be 
immediately submitted to the sponsor, the study site, and the IRB by the investigator and 
any deviations or modifications require expedited review and approval by the IRB. After 
the investigator obtained approval/favorable opinion from the IRB, the investigator 
should obtain a written agreement of the sponsor. 
When deviation from the protocol is required to eliminate immediate hazard(s) to 
subjects or for other inevitable medical reasons, the investigator will contact the sponsor, 
if circumstances permit, to discuss the planned course of action. Any deviations from the 


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protocol must be fully documented on source documentation. All protocol deviations will 
be collected and reported. 
10.11 Data Management 
The sponsor or designee will be responsible for data management. Procedures will be 
specified in documents including but not limited to the Data Management Plan. 
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 these documents from being accidentally or prematurely damaged. 
If the sponsor is granted manufacturing and marketing approval for the drug, the sponsor 
will promptly notify the head of the study site in writing. 
Records will be retained for the longest 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 local laws, regulations, and other regulatory 
requirements, whichever is latest 
However, the duration of retention may be prolonged in accordance with an agreement 
with the sponsor. If the investigator withdraws from the responsibility of keeping the 
study records, custody must be transferred to an appropriate person willing to accept the 
responsibility. 
10.13 Quality Control and Assurance 
The sponsor or designee will implement and maintain quality control and quality 
assurance procedures with written SOPs 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. 
Training necessary for the study will be provided to investigators and study site personnel 
prior to the initiation of the study. 
10.14 Publication and Disclosure Policy 
All information regarding cefiderocol supplied by the sponsor to the investigator is 
privileged and confidential. The investigator agrees to use this information to accomplish 


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the study and must 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 trial will be used toward the 
development of cefiderocol 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 may 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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2010;51(Suppl1):S48-S53. 
27. Talbot G, Powers J, Hoffmann S. Biomarkers Consortium of the Foundation for the 
National Institutes of Health CABP-ABSSSI and HABP-VABP Project Teams. 
Developing Outcomes Assessments as Endpoints for Registrational Clinical Trials of 
Antibacterial Drugs: 2015 Update From the Biomarkers Consortium of the 
Foundation for the National Institutes of Health. Clin Infect Dis 2016;62(5):603-7. 
28. 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) 2013, July. 
29. 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. 


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30. Guidance for Industry. Drug Interaction Studies. Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations. U.S. Department of Health 
and Human Services Food and Drug Administration Center for Drug Evaluation and 
Research (CDER) 2012 February. 
31. Guideline on the investigation of drug interactions. European Medicine Agency, 
Committee for Human Medicinal Products (CHMP) 21 June 2012 
EMA/CPMP/EWP/560/95/Rev. 1 Corr. 2. 
32. Kelly C, Hendrick D, Walters H. The effect of bronchoalveoar lavage on bronchial 
responsiveness in patients with airflow obstruction. Chest 1988; 93:325-8. 
33. FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation (July 2009).  
 




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e 
A symptom-driven physical examination relevant to the subject’s current condition will be performed as part of routine patient care and at the investigator’s 
discretion from predose (if applicable), through the first dose of cefiderocol, during administration of cefiderocol, and until the last dose of cefiderocol. 
f 
Blood pressure (systolic/diastolic), body temperature, pulse rate, and respiratory rate will be measured at Screening and at least 3 times a day at 
approximately evenly spaced intervals across the 24-hour day, starting on Day 1 of the infusions and continuing while the subject is receiving cefiderocol.  
g 
Data from chest X-rays performed as part of routine patient care will be collected at Screening and throughout the study in accordance with routine patient 
care; any chest X-ray taken within 48 hours of randomization can be considered as Screening (or baseline) chest X-ray. A computed tomography scan can be 
a substitute of chest X-ray if taken according to local standard of care. 
h 
Data from clinical laboratory tests performed as part of routine patient care will be collected at Screening and from the first dose of cefiderocol, during 
administration of cefiderocol, and until the last dose of cefiderocol. Clinical laboratory tests during the treatment period will be symptom-driven and at the 
investigator’s discretion. If a microbiology test has been performed to confirm the clinical diagnosis (before or during Screening), the results should be 
recorded in the source documents and the eCRF. 
i 
Creatinine clearance must be calculated at Screening and daily during treatment period to determine cefiderocol dose. 
j  
Female subjects of childbearing potential only. 
k  EOT assessments will occur within 24 hours after administration of the last dose of cefiderocol or at early termination. 
l 
If an SAE is observed it must be reported to Safety and all SAEs, regardless of causality, will be followed until resolution, stabilization, the condition 
becomes chronic, or the subject is lost to follow-up. The investigator will make an effort to collect AEs for 7 days after the last dose of study drug. 
m Multiple doses of cefiderocol administered as an intravenous infusion over 3 hours, every 8 hours (q8h), or every 6 hours (q6h) if augmented renal function, 
beginning on Day 1 and continuing for an expected minimum of 3 doses and up to a total of 6 doses in subjects with normal or augmented renal function and 
subjects with mild or moderate renal impairment and for an expected minimum of 6 doses and up to a total of 9 doses in subjects with severe renal 
impairment. Dose adjustments will be made based on renal function according to dosing recommendations per protocol. Dosing scheme of q6h is not 
illustrated in the Schedule of Events Table as it is expected to a rare situation.






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Appendix 3 
Management and Discontinuation Criteria for 
Abnormal Liver Function Tests 
Management and Discontinuation Criteria for Abnormal Liver Function tests have been 
designed to ensure subject safety and evaluate liver event etiology (see Guidance for 
Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, FDA: July 2009) 
[33]. 
1. Abnormal Liver Chemistry Criteria: 
The investigator or subinvestigator must review study subject laboratories to identify if 
any levels meet the following criteria: 
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 or AST 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%]) 
* Unless an alternative explanation for PT-INR > 1.5, such as the concomitant use of 
warfarin, is present. 
 
2. Action to Be Taken by Investigator: 
If any abnormal liver chemistry criterion is met, the investigator or subinvestigator must 
do the following: 
• This event must be reported to the sponsor as soon as possible but no later than 
72 hours of learning after its occurrence on the Liver Event Form.  
• For criteria c, the case must also be reported as an SAE, unless an alternate 
explanation exists. 
• Following the initial observed elevation, every effort should be made to have the 
subject return to the clinic within 72 hours to repeat liver function chemistries and 
for further hepatic evaluation.   
• Every effort should be made to have the subjects monitored 2 to 3 times per week 
until liver function chemistries (ALT, AST, ALP, TBL) resolve, stabilize or 
return to within the normal range or to baseline levels. 
• Consultation with a specialist such as a hepatologist is considered. 
• Liver imaging (ie, ultrasound, magnetic resonance imaging [MRI], CT scan) is 
considered. 
 


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3. Follow-up Examination: 
If any of the abnormal liver chemistry criteria are met, the following assessments should 
be performed at the follow-up visit(s) and documented in the Liver Event Form: 
• Clinical sign and symptoms course 
• 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 immunoglobulin M (IgM) antibody 
o Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (HBc 
antibody) 
o Hepatitis C RNA 
o Hepatitis E IgM antibody 
o Cytomegalovirus IgM antibody 
o Epstein-Barr viral capsid antigen IgM antibody 
– For subjects with TBL of > 1.5 ULN, conjugated bilirubin should be 
measured 
– CBC with differential to assess for eosinophilia 






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Appendix 5  
Investigator’s Signature 
 
Study Title: 
An Open-label, Multicenter, Single-arm, Phase 1 Study 
to Assess the Intrapulmonary Concentrations of 
Cefiderocol at Steady State in Hospitalized Subjects 
with Known or Suspected Bacterial Pneumonia on 
Treatment with Standard of Care Antibiotics and 
Requiring Mechanical Ventilation 
Study Number: 
1713R2117 
Date of Original: 
30 Apr 2018 
Date of Latest Amendment: 
02 Nov 2018 
 
 
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: ____________________________________________________ 
 
Printed Title:________________________________________________________ 
 
Printed Affiliation:___________________________________________________ 
 

SAP_000.pdf: 
 
Shionogi Study Title:  
An Open-label, Multicenter, Single-arm, Phase 1 Study 
to Assess the Intrapulmonary Concentrations of 
Cefiderocol at Steady State in Hospitalized Subjects 
with Known or Suspected Bacterial Pneumonia on 
Treatment with Standard of Care Antibiotics and 
Requiring Mechanical Ventilation 
Shionogi Study Number: 
1713R2117  
ClinicalTrials.gov 
Registration No. 
NCT03862040    
Study Document 
Statistical Analysis Plan Version 2     19 June 2019 
 
History of Statistical Analysis Plan Amendments 
Version 1 (Original) 
06 April 2018 
Version 2 
19 June 2018 
Revisions  to Version  1 are document within Version 2