A Single Arm, Open-label Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of Cefiderocol in Hospitalized Paediatric Subjects 3 Months to <18 Years of Age With Suspected or Confirmed Aerobic Gram-negative Bacterial Infections
Phase: PHASE2
Conditions: Gram-negative Bacterial Infections, Bloodstream Infections (BSI), Complicated Intra-abdominal Infection (cIAI), Hospital Acquired Pneumonia (HAP), Ventilator-acquired Pneumonia, Complicated Urinary Tract Infection (cUTI), Sepsis
Sponsor: Shionogi

CLINICAL STUDY PROTOCOL: 1802R2135 
Study Title: 
A Single Arm, Open-label Study to Assess the Safety, 
Tolerability, and Pharmacokinetics of Single and 
Multiple Doses of Cefiderocol in Hospitalized 
Paediatric Subjects 3 Months to < 18 Years of Age with 
Suspected or Confirmed Aerobic Gram-negative 
Bacterial Infections 
Study Number: 
1802R2135 
EudraCT Number: 
2019-002120-32 
Study Phase: 
2 
Product Code Number: 
Cefiderocol (S-649266) 
Sponsor: 
Shionogi B.V. 
Kingsfordweg 151 
Amsterdam, 1043GR The Netherlands 
Sponsor Contact: 
 
Shionogi Inc. 
300 Campus Drive 
Florham Park, NJ 07932 USA  
Tel: 
 
Email: 
 
Medical Monitor in 
Shionogi: 
 
Shionogi Inc. 
300 Campus Drive 
Florham Park, NJ 07932 USA 
Tel : 
 
Email: 
 
Medical Monitor CRO: 
 
 
 
Tel: 
 
Mobile Tel: 
 
NCT #: NCT04335539

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Clinical Study Protocol: 1802R2135 
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Issue Date: 
 
Version 1 (Draft): 
20 Mar 2017 
Version 2: 
10 Jul 2019 
Version 3: 
11 Oct 2019 
Version 4: 
28 Apr 2020 
Version 5:  
19 Jan 2021 
Version 6: 
04 Mar 2021 
Version 7: 
18 Nov 2021 
* The study sponsor may be 1 or more of the above companies. Throughout the protocol, 
the term “sponsor” represents the various legal entities identified in the “Sponsor List of 
the Study Administrative Structure” in the protocol. The above companies are referred to 
as Shionogi. 
 
 
Confidentiality Statement 
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi. This Confidential Material 
should only be viewed by those individuals or companies that have been given prior 
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 
A Single Arm, Open-label Study to Assess the Safety, Tolerability, and Pharmacokinetics 
of Single and Multiple Doses of Cefiderocol in Hospitalized Paediatric Subjects 
3 Months to < 18 Years of Age with Suspected or Confirmed Aerobic Gram-negative 
Bacterial Infections 
Study Number: 1802R2135 
Study Phase: 2 
Primary Objectives: 
 To assess the safety and tolerability of cefiderocol after single-dose administration 
in hospitalized paediatric subjects 3 months to < 18 years of age with suspected or 
confirmed aerobic Gram-negative bacterial infections 
 To assess the pharmacokinetics (PK) of cefiderocol after single-dose 
administration of cefiderocol in hospitalized paediatric subjects 3 months to 
< 18 years of age with suspected or confirmed aerobic Gram-negative bacterial 
infections 
 To assess the safety and tolerability of cefiderocol after multiple-dose 
administration in hospitalized paediatric subjects 3 months to < 12 years of age 
with suspected or confirmed aerobic Gram-negative bacterial infections 
 To assess the PK of cefiderocol after multiple-dose administration in hospitalized 
paediatric subjects 3 months to < 12 years of age with suspected or confirmed 
aerobic Gram-negative bacterial infections 
Secondary Objective:  
 Multiple-dose phase only: Whenever cefiderocol is administered alone, to assess 
the clinical response at the Posttreatment visit (7 [±◦4] days following End of 
Treatment [EOT]) and at the End-of-study (EOS) visit, AND to assess the 
microbiological response at the Posttreatment visit (7 [±◦4] days) following EOT 
and EOS (if available). 
Exploratory Objectives: 
 To estimate the probability of target attainment (PTA) for the percent of time that 
free drug concentrations in plasma exceed the minimum inhibitory concentration 
(MIC) over the dosing interval (%fT>MIC) of ≥ 75% with infections caused by 
pathogens with MICs ≤ 4 µg/mL 
 Multiple-dose phase only: To describe the clinical outcome of cefiderocol when 
given alone or in combination with standard of care (SOC) antibiotics to treat 
infections caused by aerobic Gram-negative pathogens in hospitalized paediatric 
subjects 3 months to < 12 years of age at the Posttreatment visit, EOT, and EOS 
 Multiple-dose phase only: To describe the microbiological outcome of cefiderocol 
when given alone or in combination with SOC antibiotics to treat infections 
caused by aerobic Gram-negative pathogens in hospitalized paediatric subjects 
3 months to < 12 years of age at the Posttreatment visit, EOT, and EOS 

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Study Design:  
This is a multicenter, single-arm, open-label, single- and multiple-dose study to assess the 
safety, tolerability, and PK of cefiderocol in hospitalized paediatric subjects 3 months to 
< 18 years of age with a suspected or confirmed aerobic Gram-negative bacterial 
infection (including but not limited to complicated urinary tract infection [cUTI], 
complicated intra-abdominal infection [cIAI], hospital-acquired pneumonia 
[HAP]/ventilator-acquired pneumonia [VAP], and sepsis or bloodstream infections 
[BSI]) caused by a suspected or confirmed aerobic Gram-negative pathogen requiring 
systemic antibiotics for an expected 5 to 14 days.  
The study will consist of 4 separate cohorts of paediatric subjects, grouped according to 
age range (Table S-1). 
Table S-1 
Cohort Description 
Cohort 
Age Range 
Single-dose Phase 
(minimum per cohort) 
Multiple-dose Phase 
(minimum per cohort) 
1a 
12 to < 18 yrs 
N = 6 
Cohort 1 not applicable in 
multiple-dose phase 
2a,b 
6 to < 12 yrs 
N = 6 
N = 10 
3a,b 
2 to < 6 yrs 
N = 6 
N = 10 
4c 
3 mos to < 2 yrs 
N = 6 
N = 10 
mos = months; PK = pharmacokinetic; yrs = years 
a 
Cohorts 1, 2, and 3 in the single-dose phase will be initiated in parallel. 
b 
The multiple-dose phase (Cohorts 2, 3, and 4) will begin after safety and PK data from 6 subjects in 
the corresponding single-dose cohort have been assessed. 
c 
Cohort 4 (single dose) will begin after safety and PK data from at least 6 subjects from the 
single-dose Cohorts 1, 2, and 3 (with a minimum of 3 subjects from Cohort 3) have been assessed. 
The single-dose phase in all 4 cohorts will confirm cefiderocol exposures in at least 
6 subjects prior to conducting a multiple-dose phase (Cohorts 2, 3, and 4) in additional 
subjects. 
Enrollment will be stopped for the applicable cohort to allow for analysis of the PK data 
prior to moving from single-dose to multiple-dose in Cohorts 2, 3, and 4.  
Overall, at least 54 evaluable paediatric subjects will be enrolled in the study across all 
4 cohorts.  
Screening will occur within 4 days prior to Treatment Day 1 or on Treatment Day 1 in 
both the single- and multiple-dose phase. Prior to Screening, sites will be asked to send a 
Permission to Screen Form containing limited information of the potential subject to 
Shionogi medical monitors for evaluation and agreement. The purpose of this form is to 
check the eligibility of subjects being enrolled into the study.   
In the single-dose phase, cefiderocol will be administered (in addition to SOC) at any 
time during the SOC treatment regimen. In the multiple-dose phase, cefiderocol will be 
administered on Day 1 (in addition to SOC), within 72 hours of the start of potentially 
effective treatment with SOC antibiotics for infection. Subjects will subsequently receive 
cefiderocol every 8 hours (q8h) for an expected 5 to 14 days; the total duration of 

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cefiderocol administration will be determined by the investigator based on clinical 
assessment of each subject’s infection status. Each dose of cefiderocol will be 
administered intravenously (IV) over 3 hours. The infusion may be shortened if this is in 
the best interest of the subject and if approved by the sponsor via the Request for 
Shortened Infusion Duration Form. The single-dose phase will include only those 
subjects with normal renal function or mild renal impairment. The dose of cefiderocol for 
the single-dose phase will be determined based on body weight only; the maximum dose 
to be administered is not to exceed 2000 mg. The dose for the multiple-dose phase will be 
determined based on both body weight and renal function; the maximum dose to be 
administered is not to exceed 2000 mg. The SOC administered will be selected by the 
investigator based on the suspected or confirmed pathogen(s) for the infection in 
accordance with local standards and can be modified at any time during the subject’s 
participation in the study at the investigator’s discretion. In the multiple-dose phase, if the 
subject’s infection is confirmed to be Gram-negative only before starting treatment, 
monotherapy with cefiderocol may be allowed. 
End-of-Treatment (EOT) assessments will occur within 24 hours after administration of 
cefiderocol (single-dose phase) or within 24 hours after administration of the last dose of 
study treatment (multiple-dose phase), or at early termination. A further clinical 
assessment will occur at a Posttreatment visit 7 (± 4) days after EOT for the multiple-
dose phase, which is analogous to a Test of Cure time point and EOS if microbiological 
samples are available. The EOS visit will occur 28 (+ 7) days after administration of 
cefiderocol in the single-dose phase or 28 (+ 7) days after administration of the last dose 
of study treatment in the multiple-dose phase; this visit may be performed on-site or via 
phone call.  
The total duration of cefiderocol administration will be determined by the investigator 
based on clinical assessment of each subject’s infection status but should be expected (at 
time of enrollment) to be 5 to 14 days. Note: a minimum of 6 doses will be permissible if, 
in the opinion of the investigator, it is in the subject’s best interest. The dose of 
cefiderocol administered to each subject will be determined by the investigator based on 
dosing recommendations. 
Blood samples for determination of plasma cefiderocol concentrations will be collected 
from each subject at prespecified time points during and/or after the cefiderocol infusion 
for both the single- and multiple-dose phase. Cefiderocol PK will be determined in all 
6 subjects in the single-dose phase in Cohorts 1, 2, 3, and 4; cefiderocol dose 
recommendations may be revised by the sponsor prior to initiating enrollment of subjects 
in the multiple-dose phase of each respective cohort (for Cohorts 2, 3, and 4 only). 
Study Population: 
Hospitalized paediatric subjects 3 months to < 18 years of age with a suspected or 
confirmed infection (including but not limited to cUTI, cIAI, HAP/VAP, sepsis, or BSI) 
caused by a suspected or confirmed aerobic Gram-negative pathogen.  
If the subject’s infection is confirmed to be Gram-negative only before starting treatment, 
monotherapy with cefiderocol may be allowed. 

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Criteria for Inclusion and Exclusion 
General Inclusion Criteria 
Subjects who fulfill the following criteria will be included in the study. 
1. Subject’s parent(s) or legally authorized representative (LAR) provides written 
informed consent in accordance with regional and country-specific laws and 
regulations. 
2. Subject provides written informed assent, when feasible (age of assent to be 
determined by institutional review boards/independent ethics committees 
[IRB's/IEC's] or be consistent with local legal requirements). 
3. Hospitalized subject is 3 months to < 18 years of age at the time written informed 
consent/assent is obtained for the single-dose phase. Hospitalized subject is 
3 months to < 12 years of age at the time written informed consent/assent is 
obtained for the multiple-dose phase. Premature babies will not be restricted, but 
the subject must have an adjusted or postnatal age of 3 months. 
4. Subject has a suspected or confirmed infection (including but not limited to cUTI, 
cIAI, HAP/VAP, sepsis, or BSI) that requires hospitalization for treatment with 
IV antibiotics. 
5. If subject is a sexually active female of childbearing potential and has reached 
menarche or Tanner stage 3, subject agrees to use barrier contraception (including 
condom, diaphragm, or cervical cap) with spermicide or agrees to use a highly 
effective method of contraception (including contraceptive implant, injectable 
contraceptive, combination oral contraceptive, or an intrauterine [IUD] 
contraceptive device) from Screening up to 28 days after administration of the last 
dose of cefiderocol. 
General Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Subject has a documented history of any hypersensitivity or allergic reaction to 
any β-lactam antibiotic (Note: for β-lactams, a history of a mild rash followed by 
uneventful re-exposure is not a contraindication to enrollment). 
2. Multiple-dose only: Subject has an infection caused only by a confirmed Gram-
positive pathogen. 
3. Subject has a suspected or confirmed central nervous system (CNS) infection 
(eg, meningitis, brain abscess, shunt infection) or osteomyelitis (which would 
require prolonged antibiotic therapy). 
4. Subject has cystic fibrosis. 
5. Single-dose phase: Subject has moderate or severe renal impairment based on 
estimated glomerular filtration rate (eGFR) (based on Schwartz equation [10] if 
≥ 3 months to < 1 year of age and modified Bedside Schwartz equation [11] if ≥ 1 
to < 18 years of age) of < 60 mL/min/1.73 m2 at Screening. 
Multiple-dose phase: Subject has an eGFR (based on Schwartz equation [10] if 
≥ 3 months to < 1 year of age and modified Bedside Schwartz equation [11] if ≥ 1 
to < 18 years of age) of < 15 mL/min/1.73 m2 at Screening. 
See Section 7.5.3.1.2 for eGFR calculations and ranges. 

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6. Subject has end-stage renal disease (ESRD), is on hemodialysis (HD), or 
receiving continuous venovenous hemofiltration (CVVH) 
7. Subject has experienced shock in the prior month or is in shock at the time of 
Screening.  
8. Subject has severe neutropenia or is severely immunocompromised 
9. Subject has multiorgan failure  
10. Subject has a life expectancy of < 30 days due to severity of a concurrent illness 
11. Subject is a female who has a positive pregnancy test at Screening 
12. Subject is a female who is breastfeeding 
13. Subject has received any other investigational medicinal product (IMP) within 
30 days 
14. 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 
including acute trauma to the pelvis or urinary tract 
15. Subject is receiving vasopressor therapy at Screening. 
The suspected or confirmed aerobic Gram-negative infection type (including but not 
limited to cUTI, cIAI, HAP/VAP, and sepsis or BSI) will be specified and recorded in the 
electronic case report form (eCRF). 
A cUTI is defined as a clinical syndrome characterized by pyuria and a microbial 
pathogen in the urine in the context of the following underlying features: recurrent 
urinary tract infections (2 or more in a 12-month period); obstructive uropathy; a 
functional or anatomical abnormality of the urinary tract, including anatomical 
malformations or neurogenic bladder; vesicoureteric reflux; urinary tract catheterization; 
an invasive urogenital procedure, such as cystoscopy or urogenital surgery; or azotemia 
caused by intrinsic renal disease. In addition, pediatric subjects should have at least 2 of 
the following signs and symptoms depending on their age: 
For subjects < 2 years of age 
Fever defined as body temperature ≥ 38.0°C, failure to thrive, recent weight loss, 
irritability, poor feeding, lack of normal level of activity, abdominal pain/tenderness on 
physical examination, vomiting, or jaundice 
For subjects ≥ 2 to < 18 years 
Fever defined as body temperature ≥ 38.0°C, chills or rigors, dysuria, urinary urgency, 
urinary frequency, new-onset urinary incontinence, suprapubic pain, flank pain, 
abdominal pain, pelvic pain, suprapubic tenderness or costovertebral angle tenderness on 
physical examination, nausea, or vomiting 
Hospital-acquired pneumonia is defined as an acute infection of the pulmonary 
parenchyma associated with clinical signs and symptoms, such as fever or hypothermia, 
chills, rigors, cough, purulent sputum production, chest pain, or dyspnea, accompanied by 
the presence of a new or progressive infiltrate on a chest radiograph in a patient 
hospitalized for more than 48 hours or developing within 7 days after discharge from a 
hospital. Patients with HAP may or may not require intubation and mechanical 
ventilation. 

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Ventilator-associated pneumonia is defined as an acute infection of the pulmonary 
parenchyma associated with clinical signs and symptoms, such as fever or hypothermia, 
chills, rigors, purulent respiratory secretions, and increased oxygen requirements. These 
signs and symptoms are in addition to laboratory abnormalities, such as leukocytosis 
accompanied by the presence of a new or progressive infiltrate on a chest radiograph in a 
patient on mechanical ventilation for a minimum of 48 hours. 
Study Drug, Dose, and Mode of Administration 
Cefiderocol will be administered IV over 3 hours (Note: 3 hours is the required duration 
to ensure adequate time over MIC for multidrug-resistant Gram-negative infections). 
Shorter infusion times may be allowed in the multiple-dose phase if agreed on by the 
sponsor via the Request for Shortened Infusion Duration Form and if in the best interest 
of the subject. Infusion time must be 3 hours in the single-dose phase. The single-dose 
phase will include only those subjects with normal renal function or mild renal 
impairment. The dose of cefiderocol for the single-dose phase will be determined based 
on body weight only; the maximum dose to be administered is not to exceed 2000 mg 
(Table S-2). The dose for the multiple-dose phase will be determined based on both body 
weight and renal function; the maximum dose to be administered is not to exceed 
2000 mg (Table S-3). Sites will be instructed to monitor renal function as per their 
routine practice/guidelines and to change doses immediately if renal function changes. 
The dose will be modified for subjects with moderate or severe renal impairment (Table 
S-4). All revised dosing recommendations will be provided by the sponsor, discussed 
with the investigator, and documented. 
Table S-2 
Dosing Limits for Cefiderocol in Single-dose Phase: 
Subjects with Normal Renal Function or Mild Renal 
Impairment 
Cohort 
Single-dose Phase Dose 
Infusion Time 
Body Weight 
≥ 34 kg 
< 34 kg 
1 (12 to < 18 years of age) 
2000 mg 
60 mg/kg* 
3 hours 
2 (6 to < 12 years of age) 
2000 mg 
60 mg/kg* 
3 hours 
3 (2 to < 6 years of age) 
2000 mg 
60 mg/kg* 
3 hours 
4 (3 months to < 2 years of age) 
2000 mg 
60 mg/kg* 
3 hours 
* 
No more than 2000 mg of cefiderocol should be administered.  
The single-dose phase will include only those subjects with normal renal function (estimated 
glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2) or mild renal impairment (eGFR 60 to 
< 90 mL/min/1.73 m2). See Section 7.5.3.1.2 for eGFR calculations and ranges. 
 

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Table S-3 
Dosing Limits for Cefiderocol in Multiple-dose Phase: 
Subjects with Normal Renal Function or Mild Renal 
Impairment 
Cohort 
Multiple-dose Phase Dose 
Frequency 
Infusion 
Time 
Body Weight 
≥ 34 kg 
< 34 kg 
1 (12 to < 18 years of age) 
Cohort 1 not applicable in multiple-dose phase 
2 (6 to < 12 years of age) 
2000 mg 
60 mg/kg* 
q8h 
3 hours 
3 (2 to < 6 years of age) 
2000 mg 
60 mg/kg* 
q8h 
3 hours 
4 (3 months to < 2 years of age) 
2000 mg 
60 mg/kg* 
q8h 
3 hours 
q8h = every 8 hours 
* 
No more than 2000 mg of cefiderocol should be administered. 
Shorter infusion times may be allowed in the multiple-dose phase if agreed by the sponsor via the 
Request for Shortened Infusion Duration Form, and if in the best interest of the subject. Infusion 
volume adjustments by age and weight will be provided in the pharmacy manual. 
See Section 7.5.3.1.2 for estimated glomerular filtration rate calculations and ranges. 
 
Table S-4 
Dosing Limits for Cefiderocol in Multiple-dose Phase: 
Subjects with Moderate or Severe Renal Impairment 
Renal Function 
Multiple-dose Phase Dose 
Body Weight ≥ 34 kg 
Body Weight < 34 kg 
Dose 
(mg) 
Frequency 
Infusion 
Time  
Dose 
(mg/kg) 
Frequency 
Infusion 
Time  
Moderate renal impairment 
(eGFR 30 to 
< 60 mL/min/1.73 m2) 
1500 
q8h 
3 hours 
45 
q8h 
3 hours 
Severe renal impairment (eGFR 
15 to < 30 mL/min/1.73 m2) 
1000 
q8h 
3 hours 
30 
q8h 
3 hours 
eGFR = estimated glomerular filtration rate; q8h = every 8 hours 
Shorter infusion times may be allowed in the multiple-dose phase if agreed by the sponsor via the Request 
for Shortened Infusion Duration Form, and if in the best interest of the subject. Infusion volume adjustments
by age and weight will be provided in the pharmacy manual. 
Expected total duration of cefiderocol administration is 5 to 14 days. A minimum of 6 doses will be 
permissible if, in the opinion of the investigator, it is in the subject’s best interest. 
Duration of Treatment: 
Single-dose phase: 1 day 
Multiple-dose phase: expected 5 to 4 days (a minimum of 6 doses will be permissible if, 
in the opinion of the investigator, it is in the subject’s best interest). In special 
circumstances, treatment beyond 14 days may be allowed following review and approval 
of individual cases by the Shionogi medical monitor. 
Safety Assessments: 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 study treatment. Additionally, safety data will 
be captured at various time points during the study as part of routine patient care. 

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Adverse events (AEs) will be collected and monitored from the time signed informed 
consent/assent is obtained through the end of study (EOS) visit or 28 (+ 7) days after the 
single dose of cefiderocol in the single-dose phase or 28 (+ 7) days after administration of 
the last dose of study treatment in the multiple-dose phase. Subjects with ongoing AEs 
will be monitored until either resolution or stabilization is achieved, the subject is 
referred for continued care to another health care professional, or until a determination of 
the cause being unrelated to the study drug or procedure is made or the subject is lost to 
follow-up. Investigator causality must be included with all SAEs reported to the sponsor. 
Serious AEs with missing investigator causality will be followed up by the CRO urgently 
until a response is provided to the sponsor. 
Pharmacokinetic Assessments: Blood samples for determination of plasma cefiderocol 
concentrations will be collected from each subject at prespecified based time points 
during and/or after the cefiderocol infusion (after dosing of cefiderocol in the single-dose 
phase and during one of the dosing intervals from the 6th to the 12th dose of cefiderocol in 
the multiple-dose phase).  
Efficacy Assessments (Multiple-dose Phase only):  
Clinical Outcome: Clinical outcome assessments (signs and/or symptoms of infection 
eg, fever, irritability, pain, physical signs such as increased heart rate) will be performed 
at EOT (within 24 hours of administration of the last dose of study treatment or early 
termination), and at a Posttreatment visit 7 (± 4) days after EOT (multiple-dose phase) 
and at EOS (conducted on site or as a phone call). Additionally, any available clinical 
outcome data used for the initial diagnosis of infection and obtained at any time after 
initiation of study treatment (cefiderocol alone or administration with SOC) as part of 
routine patient care will be captured as study data. 
Microbiological Outcome: If available, microbiological data (Gram stain, culture, colony 
forming units, or sensitivity results, and pathogen identification) for specimens collected 
at the initial diagnosis of infection and obtained at any time after initiation of study 
treatment as part of routine patient care will be captured as study data and used to assess 
microbiological outcome. The time points for collection of microbiological specimens are 
otherwise not prespecified by the protocol (EOT, Posttreatment Visit, and EOS, if 
applicable). In subjects where it is not possible to obtain a posttreatment culture and/or 
EOS culture, determination of presumed microbiological eradication may be made based 
on resolution of all presenting clinical sign and symptoms of the infection (clinical cure). 
Statistical Methods:  
Unless otherwise noted, continuous variables will be summarized by 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 by using the frequency count and the percentage of subjects in each category 
as summary statistics.   
For summary of plasma cefiderocol concentrations, evaluable subjects in the single-dose 
phase will include those who have received 1 dose of cefiderocol and who have at least 
1 PK blood sample above the limit of quantification. In the multiple-dose phase, 
evaluable subjects will include those who have received ≥ 4 doses of cefiderocol and who 
have at least 1 PK blood sample above the limit of quantification. 

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No inferential statistical testing will be performed in this study. 
In general, all tables will be presented by cohort and treatment regimen (ie, single-dose or 
multiple-dose). Individual subject data, PK data, and any derived data will be presented 
by treatment group and listed by subject. All analyses and tabulations will be performed 
by using both the SAS Version 9.4 or higher and/or WinNonlin Version 6.2.1 or higher. 
Analysis Populations 
 Safety population includes all enrolled subjects who receive at least 1 dose of 
cefiderocol. 
 Pharmacokinetic Concentration population includes all enrolled subjects who 
receive at least 1 dose of cefiderocol and have at least 1 PK blood sample. 
 Pharmacokinetic Concentration Summary population includes all enrolled 
subjects who receive 1 dose of cefiderocol in the single-dose phase and ≥ 4 doses 
of cefiderocol in the multiple-dose phase of the study and those who have at least 
1 PK blood sample above the limit of quantification. This population will be used 
for the concentration summary as well as for plotting the concentration-time data 
and the concentration data summary. 
 Intent-to-treat (ITT) population includes all enrolled subjects who receive at 
least 1 dose of cefiderocol.  
 Microbiological ITT (MITT) population includes all ITT subjects who have a 
baseline Gram-negative pathogen in the multiple-dose phase. 
Study Duration: Screening can last up to 4 days for the single-dose and multiple-dose 
phases. Study duration for individual subjects is approximately 28 days in the single-dose 
phase and 42 days (or longer if treatment beyond 14 days is allowed by the Shionogi 
medical monitor) in the multiple-dose phase from the time of first drug infusion. Planned 
duration of the entire study is approximately 2 years and 9 months from first subject in to 
last subject last visit. 
Date: XX Nov 2021 

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TABLE OF CONTENTS 
SYNOPSIS ...........................................................................................................................3 
TABLE OF CONTENTS ...................................................................................................12 
LIST OF IN-TEXT TABLES ............................................................................................14 
LIST OF IN-TEXT FIGURES...........................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................16 
GLOSSARY ......................................................................................................................19 
1. INTRODUCTION .......................................................................................................20 
1.1 
Nonclinical Summary ......................................................................................21 
1.2 
Clinical Pharmacology Studies ........................................................................21 
1.3 
Rationale for Study ..........................................................................................24 
1.4 
Overall Paediatric Program ..............................................................................25 
2. STUDY OBJECTIVES AND ENDPOINTS ...............................................................26 
3. INVESTIGATIONAL PLAN ......................................................................................28 
3.1 
Overall Study Design and Plan ........................................................................28 
3.2 
Rationale for Study Design and Control Group ...............................................31 
3.3 
Study Duration .................................................................................................33 
3.3.1 
Study Duration for Individual Subjects ...............................................33 
3.3.2 
Study End .............................................................................................33 
4. STUDY ENROLLMENT AND WITHDRAWAL .....................................................34 
4.1 
Study Population ..............................................................................................34 
4.2 
General Inclusion Criteria ................................................................................34 
4.3 
General Exclusion Criteria ...............................................................................34 
4.4 
Screen Failures .................................................................................................36 
4.5 
Withdrawal of Subjects from the Study or Discontinuation from Study 
Treatment .........................................................................................................36 
5. STUDY TREATMENT(S) ..........................................................................................38 
5.1 
Description of Treatment(s) .............................................................................38 
5.1.1 
Test Drug .............................................................................................38 
5.1.2 
Standard of Care ..................................................................................38 
5.2 
Treatments to be Administered ........................................................................38 
5.3 
Selection and Timing of Dose for Each Subject ..............................................41 
5.4 
Method of Assigning Subjects to Treatment Groups .......................................42 
5.5 
Blinding............................................................................................................42 
5.6 
Packaging and Labeling ...................................................................................42 
5.7 
Storage and Accountability ..............................................................................42 
5.8 
Investigational Product Retention at Study Site ..............................................43 
5.9 
Treatment Compliance .....................................................................................43 

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6. RESTRICTIONS .........................................................................................................44 
6.1 
Prior Therapy ...................................................................................................44 
6.2 
Concomitant Therapy.......................................................................................44 
6.2.1 
Prohibited Therapy...............................................................................44 
7. STUDY PROCEDURES AND METHODS OF ASSESSMENTS ............................45 
7.1 
Informed Consent.............................................................................................45 
7.2 
Medical History, Demographics, and Baseline Characteristic ........................45 
7.3 
Enrollment in the Study and Dispensing Study Drug ......................................45 
7.4 
Pharmacokinetic Assessments .........................................................................46 
7.5 
Safety Assessments ..........................................................................................47 
7.5.1 
Physical Examination...........................................................................48 
7.5.2 
Vital Sign Measurements .....................................................................48 
7.5.3 
Clinical Laboratory Tests .....................................................................48 
7.5.4 
Adverse Events Assessments ...............................................................52 
7.6 
Efficacy Assessments (Multiple-dose Phase Only) .........................................58 
7.6.1 
Physician Clinical Response ................................................................58 
7.6.2 
Microbiological Response ...................................................................59 
7.7 
Appropriateness of Measurements ...................................................................60 
7.8 
Acceptable Time Windows ..............................................................................60 
8. STUDY ACTIVITIES .................................................................................................62 
9. PLANNED STATISTICAL METHODS ....................................................................63 
9.1 
General Considerations ....................................................................................63 
9.2 
Determination of Sample Size .........................................................................63 
9.3 
Analysis Populations ........................................................................................64 
9.4 
Handling of Missing Data ................................................................................64 
9.5 
Subject Disposition ..........................................................................................64 
9.6 
Demographic and Baseline Characteristics .....................................................64 
9.7 
Extent of Exposure and Treatment Compliance ..............................................64 
9.8 
Prior Therapies .................................................................................................65 
9.9 
Concomitant Therapies ....................................................................................65 
9.10 
Pharmacokinetic Analysis ................................................................................65 
9.11 
Safety Analysis ................................................................................................65 
9.11.1 
Adverse Events ....................................................................................65 
9.11.2 
Vital Signs ............................................................................................66 
9.11.3 
Clinical Laboratory Analysis ...............................................................66 
9.11.4 
Physical Examination...........................................................................66 
9.12 
Efficacy Analyses ............................................................................................66 
9.12.1 
Efficacy Endpoints ...............................................................................66 

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9.12.2 
Analyses of Efficacy Endpoints ...........................................................66 
9.13 
Data Review .....................................................................................................66 
10. ADMINISTRATIVE CONSIDERATIONS ................................................................67 
10.1 
Study Administrative Structure........................................................................67 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .......68 
10.3 
Ethical Conduct of the Study ...........................................................................68 
10.4 
Informed Consent and Assent Process .............................................................68 
10.5 
Subject Confidentiality ....................................................................................69 
10.6 
Study Monitoring .............................................................................................69 
10.7 
Case Report Forms and Source Documents.....................................................69 
10.7.1 
Case Report Forms ...............................................................................69 
10.7.2 
Source Data and Source Documents ....................................................70 
10.7.3 
External Data .......................................................................................70 
10.8 
Committees ......................................................................................................71 
10.8.1 
Data Safety Monitoring Board .............................................................71 
10.9 
Termination or Suspension of the Study ..........................................................71 
10.9.1 
Termination or Suspension of the Entire Study ...................................71 
10.9.2 
Termination or Suspension of the Study by Study Site .......................71 
10.10 Protocol Modifications and Deviations ...........................................................71 
10.11 Data Management ............................................................................................72 
10.12 Retention of Data .............................................................................................72 
10.13 Quality Control and Assurance ........................................................................73 
10.14 Publication and Disclosure Policy ...................................................................73 
10.15 Financial Disclosure.........................................................................................73 
11. REFERENCE LIST .....................................................................................................74 
Appendix 1 
Time and Events Schedule ...................................................................75 
Appendix 2 
Management and Discontinuation Criteria for Abnormal Liver 
Function Tests ......................................................................................80 
Appendix 3 
Sponsor’s Signature .............................................................................82 
Appendix 4 
Investigator’s Signature .......................................................................83 
LIST OF IN-TEXT TABLES 
Table S-1 
Cohort Description .....................................................................4 
Table S-2 
Dosing Limits for Cefiderocol in Single-dose Phase: 
Subjects with Normal Renal Function or Mild Renal 
Impairment .................................................................................8 
Table S-3 
Dosing Limits for Cefiderocol in Multiple-dose Phase: 
Subjects with Normal Renal Function or Mild Renal 
Impairment .................................................................................9 

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Table S-4 
Dosing Limits for Cefiderocol in Multiple-dose Phase: 
Subjects with Moderate or Severe Renal Impairment ...............9 
Table 3-1 
Cohort Description ...................................................................28 
Table 3-2 
Study Schedule of Assessments ...............................................31 
Table 5-1 
Dosing Limits for Cefiderocol in Single-dose Phase: 
Subjects with Normal Renal Function or Mild Renal 
Impairment ...............................................................................40 
Table 5-2 
Dosing Limits for Cefiderocol in Multiple-dose Phase: 
Subjects with Normal Renal Function or Mild Renal 
Impairment ...............................................................................40 
Table 5-3 
Dosing Limits for Cefiderocol in Multiple-dose Phase: 
Subjects with Moderate or Severe Renal Impairment .............41 
Table 7-1 
Total PK Blood Sample Volumes ............................................46 
Table 7-2 
Blood Sampling Times after Start of Infusion .........................47 
Table 7-3 
Mandatory Laboratory Tests ....................................................49 
Table 7-4 
Maximum Allowable Research-related Blood Sample 
Volumes ...................................................................................49 
Table 7-5 
Total Average Blood Volume (Multiple-dose Phase) .............50 
Table 7-6 
Renal Function Ranges ............................................................51 
Table 7-7 
Acceptable Time Windows ......................................................61 
 
LIST OF IN-TEXT FIGURES 
Figure 3-1 
Study Schematic.......................................................................30 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
%fT>MIC 
percentage of time of the dosing interval that is required for plasma 
concentrations to be above the mean inhibitory concentration 
fT>MIC 
time during which plasma concentrations are above the mean inhibitory 
concentration 
AE 
adverse event 
ALCOA 
Attributable, Legible, Contemporaneous, Original and Accurate 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the concentration-time curve extrapolated from time 0 to 
infinity 
AUC0-τ 
area under the concentration-time curve over the dosing interval τ  
BLA 
β-lactamase 
BSI 
bloodstream infection 
CFU 
colony forming units 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
confidence interval  
cIAI 
complicated intra-abdominal infection 
Cmax 
maximum observed plasma concentration  
CNS 
central nervous system 
CR 
carbapenem-resistant 
CrCL 
creatinine clearance level 
CRO 
clinical research organization 
cUTI 
complicated urinary tract infections 
CV% 
coefficient of variation 
CVVH 
continuous venovenous hemofiltration 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram/electrocardiography 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
ESBL 
extended spectrum β-lactamase 
ESRD 
end-stage renal disease 

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EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMR 
geometric least squares mean ratio 
HAP 
hospital-acquired pneumonia (synonymous with hospital-acquired 
bacterial pneumonia [HABP]) 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HD 
hemodialysis 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IgM 
immunoglobulin M 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IPM/CS 
imipenem/cilastatin 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent to treat 
IUD 
intrauterine device 
IV 
intravenous(ly) 
KPC 
Klebsiella pneumoniae carbapenemase 
LAR 
legally authorized representative 
Max 
maximum 
MDR 
multidrug-resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
Min 
minimum 
MITT 
microbiological intent to treat 
MRI 
magnetic resonance imaging 
NDM 
New Delhi metallo-β-lactamase 
NP 
nosocomial pneumonia 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
OXA 
Class D oxacillinases 
PBP 
penicillin-binding protein 

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PD 
pharmacodynamic 
PDCO 
The Paediatric Committee (EMA’s scientific paediatric committee) 
PER 
Pseudomonas extended resistance 
PK 
pharmacokinetic(s) 
PTA 
probability of target attainment 
q8h 
every 8 hours 
QA 
quality assurance 
QC 
quality control 
RR 
reference range  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
standard of care 
SOP 
standard operating procedure 
t1/2,z 
apparent terminal elimination half-life 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TOC 
test of cure 
ULN 
upper limit of normal 
VAP 
ventilator-acquired pneumonia (synonymous with ventilator-acquired 
bacterial pneumonia [VABP]) 
VIM 
Verona integron-encoded metallo-β-lactamase 
WHO 
World Health Organization 
XDR 
extensively drug-resistant 
 
 
 

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GLOSSARY 
Concomitant 
antibiotics 
Any antibiotic used to treat an infection other than the qualifying 
Gran-negative infection 
Concomitant 
therapy 
Any therapy other than study treatment administered after the 
first dose of study treatment in the study 
End of Study 
(EOS) 
Defined as the last visit that occurs 28 (+ 7) days after 
administration of cefiderocol in the single-dose phase or 
28 (+ 7) days after administration of the last dose of study 
treatment (cefiderocol and SOC combination, cefiderocol alone 
[if Gram-negative infection confirmed in multiple-dose phase], 
in the multiple-dose phase; this visit may be performed on-site or 
via phone call 
End of Treatment 
(EOT) 
Defined as within 24 hours after single dose of cefiderocol 
(single-dose phase) or within 24 hours after administration of the 
last dose of study treatment (multiple-dose phase), or at early 
termination. 
Standard of Care 
(SOC) antibiotic 
Any antibiotic used to treat the qualifying Gram-negative 
infection 
Study drug 
Refers to cefiderocol 
Study treatment 
Refers to cefiderocol and SOC combination, cefiderocol alone (if 
the infection is confirmed to be caused by a Gram-negative 
pathogen only prior to starting treatment in the multiple-dose 
phase) 
 

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

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irreversibly inhibiting the transpeptidase activity responsible for cross-linking 
peptidoglycan from lipid precursors essential for bacterial cell wall synthesis. However, 
the molecular structure of cefiderocol offers several unique and important characteristics 
that result in enhanced activity against resistant Gram-negative bacteria. The chemical 
structure of cefiderocol is similar to ceftazidime and cefepime, which are third- to fourth-
generation cephalosporins with a feature of the good activity against Gram-negative 
bacteria due to their high stability to a variety of beta-lactamases including AmpC and 
extended-spectrum beta-lactamases (ESBL). Cefiderocol has a pyrrolidinium group in the 
side chain at position 3 of the cephem core similar to cefepime and a 
carboxypropanoxyimino group in the side chain at position 7 similar to ceftazidime. The 
major difference in the chemical structure of cefiderocol and these cephalosporins 
(ceftazidime and cefepime) is the presence of a catechol group on the side chain at 
position 3 of the cephem core. Importantly, in addition to passive diffusion through porin 
channels, the catechol moiety forms chelating complexes with trivalent (ferric) iron in 
plasma, resulting in the ability of cefiderocol to act as a siderophore and to be transported 
across the outer cell membrane of Gram-negative bacteria by the active iron transport 
system common to Gram-negative bacteria.  
As a result, cefiderocol overcomes 2 additional mechanisms of antibiotic resistance 
resulting from porin channel mutations or efflux-pump overproduction. Therefore, 
cefiderocol is the first β-lactam antibiotic that is associated with enhanced stability to 
hydrolysis by all known classes of BLAs, including serine-carbapenemases (Class A 
[eg, KPC] and Class D oxacillinases [OXA]) and metallo-carbapenemases (Class B [New 
Delhi metallo--lactamase [NDM], verona integron-encoded metallo-β-lactamase [VIM], 
and imipenemase), and because of the unique mechanism of cell entry, cefiderocol is 
associated with enhanced antibacterial activity against Gram-negative bacteria, including 
carbapenem-resistant strains. 
Cefiderocol is being developed to address the unmet medical need to treat 
carbapenem-resistant infections caused by Gram-negative bacteria, namely, the treatment 
of infections caused by carbapenem-resistant, Gram-negative bacteria, including 
Enterobacteriaceae, such as E. coli and K. pneumoniae, and nonfermenters, such as 
P. aeruginosa, S. maltophilia, and A. baumannii, independent of the underlying 
mechanism of carbapenem resistance. 
1.1 
Nonclinical Summary 
See the current Investigator’s Brochure (IB) for a summary of nonclinical studies. 
1.2 
Clinical Pharmacology Studies 
To date, a total of 212 healthy adult subjects or subjects with impaired renal function who 
participated in 6 completed clinical pharmacology studies (a single-and multiple-
ascending dose study [Study 1203R2111], an intrapulmonary pharmacokinetic (PK) study 
[Study 1214R2112], a renal impairment study [Study 1222R2113], a mass balance study 
[Study 1516R2114], a thorough QT/QTc study [Study 1603R2116], and a 3-part drug 
interaction study [Study 1521R2115]) have received single doses of cefiderocol ranging 

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from 100 to 4000 mg (4 g) or multiple doses of up to 2000 mg (2 g) for up to 10 days, 
infused intravenously (IV) over 1 or 3 hours.  
In general, cefiderocol was safe and well tolerated in clinical pharmacology studies. 
There were no treatment-related or dose-dependent trends in vital sign measurements, 
electrocardiogram (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 and 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 associated with linear PK, has a relatively short apparent terminal half-life 
(t1/2,z), and is primarily excreted unchanged in the urine. A summary of the PK profile for 
cefiderocol is provided; additional details are provided in the current version of the IB.  
 After administration of a single 2000-mg dose of cefiderocol infused over 
3 hours, the geometric mean and coefficient of variation (CV% of geometric 
mean) of cefiderocol maximum plasma concentration (Cmax) and area under the 
concentration-time curve (AUC) extrapolated to infinity (AUC0-inf) were 
89.7 µg/mL (20.5%) and 386.1 µg·hr/mL (17.2%), respectively. The Cmax and 
AUC increased in a dose-proportional manner within the dose range from 100 to 
2000 mg and 2000 to 4000 mg. 
 After administration of 1000- and 2000-mg doses of cefiderocol every 8 hours 
(q8h), no accumulation for the Cmax (ratio of Cmax [Day 10/Day 1]: 1.07 to 
1.08-fold) or AUC over the dosing interval τ (AUC0-τ) (ratio of AUC0-τ 
[Day 10/Day 1]: 1.05 to 1.16-fold) was observed. Steady state was attained within 
1 day after the start of multiple dose administration. 
 After administration of a single 1000-mg dose of [14C]-cefiderocol infused over 
1 hour, the majority of total radioactivity in plasma was accounted for intact drug. 
Additionally, 98.6% and 2.8% of the administered dose was excreted in urine and 
feces, respectively, with an overall recovery of total radioactivity (urine and feces 
combined) of 101.4% of the administered dose. More than 90% of the dose was 
excreted as unchanged cefiderocol in urine. 
 After administration of a single 2000-mg dose of cefiderocol infused over 
3 hours, the apparent terminal elimination half-life (t1/2,z) of cefiderocol was 
2.4 hours. A similar t1/2,z of 2.74 hours was estimated after administration of a 
single 2000-mg dose of cefiderocol infused over 1 hour (Study 1203R2111).  
 Cefiderocol did not increase the Cmax or AUC of furosemide (for OAT1 and 
OAT3) and metformin (for OCT1, OCT2, and MATE2-K). Cefiderocol increased 
the Cmax and AUC of rosuvastatin (for OATP1B3) by 1.28-fold (90% CI, 1.12 to 
1.46) and 1.21-fold (1.08 to 1.35), respectively (Study 1521R2115). These results 
suggest no clinically significant drug-drug interaction potential via these 
transporters. 

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 There was no clinically meaningful effect of age, sex, race, or body weight on the 
PK of cefiderocol based on a population PK analysis. No dose adjustment of 
cefiderocol based on demographic characteristics is considered to be necessary. 
 A dedicated study to assess the potential effect of hepatic impairment on the PK 
of cefiderocol was not conducted. However, the need for a dose adjustment in 
subjects with hepatic impairment is not expected considering the primary route of 
elimination for cefiderocol is renal excretion. 
 After administration of a single 1000-mg dose of cefiderocol infused over 1 hour, 
the geometric least squares mean ratios (GMRs) [renal impairment/normal renal 
function] and their 90% CIs for the AUC0-inf of cefiderocol for subjects with mild, 
moderate, severe and end-stage renal disease (ESRD) requiring hemodialysis 
(HD) were 1.0 (0.8 to 1.3), 1.5 (1.2 to 1.9), 2.5 (2.0 to 3.3), and 4.1 (3.3 to 5.2), 
respectively. Dose adjustment of cefiderocol in subjects with renal impairment or 
augmented renal clearance is recommended.  
 The 3- to 4-hour HD removed approximately 60% of cefiderocol dose. A 
supplemental dose immediately following HD is therefore recommended. 
 In a thorough QT/QTc study (Study 1603R2116), after administration of single 
2-g (therapeutic) and 4-g (supra-therapeutic) doses, cefiderocol did not prolong 
the QT interval to a level of regulatory concern and met the criteria stipulated in 
the FDA E14 Guidance for Industry [6] associated with a negative thorough 
QT/QTc study. 
Phase 2 and 3 Studies 
A Phase 2 study (Study 1409R2121) in patients with complicated urinary tract infections 
(cUTI), with or without pyelonephritis or acute uncomplicated pyelonephritis, to assess 
the composite outcome of clinical response and microbiologic eradication of cefiderocol 
compared with IPM/CS in subjects at risk for MDR Gram-negative pathogens has been 
conducted. Subjects with infections due to known carbapenem-resistant (CR) pathogens 
were excluded from participation in the study. The study was a multicenter, randomized, 
double-blind, active-controlled, parallel-group study in which a total of 452 hospitalized 
subjects were randomized (2:1) to receive IV cefiderocol 2000 mg or IPM/CS 1000 mg 
administered over 1 hour, 3 times daily at 8-hour intervals for 7 to 14 days. Subjects were 
evaluated daily for clinical response and safety during hospitalization and periodically 
during follow-up for up to approximately 42 days from the time of randomization. The 
recommended duration of treatment with IV study antibiotics was 7 to 14 days. If in the 
opinion of the investigator it became in the subject’s best interest, then treatment could 
have been stopped after a minimum of 5 days. Safety assessments included AE 
monitoring, clinical laboratory safety tests (hematology, chemistry, endocrinology, and 
urinalysis), vital sign measurements, physical examinations, and 12-lead ECG recordings. 
The safety population consisted of all randomized subjects who received at least 1 actual 
dose of the study drug (448 subjects; 300 in the cefiderocol treatment group and 148 in the 
IPM/CS group). 
The response rate for the primary endpoint of the composite of microbiological 
eradication and clinical response at Test of Cure (TOC) for cefiderocol was not only 

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noninferior to IPM/CS (72.6% versus 54.6% of subjects in the cefiderocol and IPM/CS 
groups, respectively, with an adjusted treatment difference [cefiderocol - IPM/CS] of 
18.58% [95% CI; 8.23%, 28.92%], based on the prespecified noninferiority margins 
of -20% and −15%), but also was consistent with superiority. 
The most frequently observed AE was diarrhea, which was reported by 4.3% 
(13/300 subjects) in the cefiderocol treatment group and 6.1% (9/148 subjects) in the 
IPM/CS group. Serious AEs were reported in 4.7% (14/300 subjects) in the cefiderocol 
group compared with 8.1% (12/148 subjects) in the IPM/CS group. One death 
(cardiorespiratory arrest, considered unrelated to study drug) was reported in a subject 
treated with cefiderocol. The ECG analysis did not demonstrate a significant effect of 
study drug on QTcF duration or other ECG parameters.  
Cefiderocol was generally well tolerated, with more than 90% of subjects completing 
treatment (similar to those in the IPM/CS group). Overall AE rates were generally similar 
between the 2 treatment groups (40.7% [122/300] of subjects in the cefiderocol group 
compared with 51.4% [76/148] of subjects in the IPM/CS group. The observed safety 
profile of cefiderocol is as expected for a β-lactam antibiotic, and no unexpected safety 
concerns were identified.  
A pathogen-based Phase 3 study in subjects with evidence of CR, Gram-negative 
infections at various infection sites (CREDIBLE-CR, Study 1424R2131) and a Phase 3 
study in subjects with nosocomial pneumonia (NP; APEK-NP, Study 1615R2132) were 
completed. In the CREDIBLE study, the primary endpoints of the study showed that 
clinical and microbiological outcomes were comparable between the cefiderocol and best 
available therapy treatment groups. In the APEKS-NP study, cefiderocol was noninferior 
to high-dose extended infusion meropenem in the treatment of subjects with documented 
nosocomial pneumonia caused by Gram-negative bacteria for all-cause mortality at 
Day 14. Please refer to the current IB for a summary of the results. 
On 14 Nov 2019, Shionogi received FDA approval of cefiderocol, for the treatment of 
subjects 18 years of age or older with cUTI including kidney infections caused by 
susceptible Gram-negative microorganisms, who have limited or no alternative treatment 
options. On 28 Apr 2020, Shionogi received European Commission marketing 
authorization for cefiderocol for the treatment of infections due to aerobic Gram-negative 
bacteria in adult patients with limited treatment options. On 28 Sep 2020, Shionogi 
received FDA approval of cefiderocol for the treatment of patients 18 years of age or 
older with hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial 
pneumonia (VABP) caused by susceptible Gram-negative microorganisms.  
1.3 
Rationale for Study 
The primary purpose of the proposed study is to provide safety data commensurate with 
the intended duration of treatment clinically and to obtain PK data that will be used to 
confirm dosing recommendations to support the safe and effective use of cefiderocol in 
paediatric subjects 3 months to < 18 years of age with suspected or confirmed aerobic 
Gram-negative infections. The PK for cefiderocol from this study will be used for 

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modeling and simulations performed to estimate the probability of target attainment 
(PTA) for a percentage of time that free drug concentrations in plasma exceed the 
minimum inhibitory concentration (MIC) over the dosing interval (%fT>MIC) of ≥ 75%, 
which has been identified as the pharmacodynamic (PD) parameter associated with 
efficacy for cefiderocol. Using this approach, a potentially efficacious dose (and dosing 
regimen) of cefiderocol can be estimated and will therefore confirm the dosing 
recommendations for the age range included in the proposed study. 
The PD parameter of %fT>MIC is considered to be a reliable estimate of efficacy 
considering that the effectiveness of β-lactam antibiotics, including cephalosporins such 
as cefiderocol, is directly linked to the duration of time above the MIC of the bacterial 
pathogen being treated, and therefore plasma drug exposures drive clinical efficacy for 
most infection types. Specifically, β-lactam antibiotics, as a result of their relatively slow 
bactericidal action, exhibit time-dependent bactericidal activity with minimal increases in 
bactericidal activity with concentrations greater than the point of maximal killing (or 
4 times the MIC) [7]. Therefore, clinical efficacy of β-lactam antibiotics is dependent on 
the duration of time that free drug concentrations are above the MIC (or fT>MIC), which is 
used, along with the drug half-life, to develop dosing recommendations (dose and 
frequency of administration) such that the fT>MIC is optimized. It is generally accepted 
that clinically effective dosing regimens provide drug concentrations that exceed the MIC 
of the causative pathogen for a minimum of 40% to 50% of the dosing interval [7]. The 
fT>MIC for β-lactam antibiotics is a well-established PD parameter and has been 
incorporated into the PK/PD model for cefiderocol using a target value derived from 
nonclinical models of infection. Hence, PK/PD modeling and simulations based on 
predictive PK and human exposure data, a well-established PD parameter associated with 
clinical efficacy for β-lactam antibiotics, and nonclinical data supporting the target value 
for %fT>MIC provide a reliable approach to support dosing recommendations for 
cefiderocol in the paediatric population.  
1.4 
Overall Paediatric Program 
Three months to < 18 years 
Due to the different indications being pursued globally and the different health authority 
requirements for the conditions to be studied, the evaluation of paediatric subjects is 
being assessed in more than 1 study in subjects 3 months to < 18 years of age. This study 
will enroll subjects with aerobic Gram-negative pathogens (including but not limited to 
cUTI, complicated intra-abdominal infections [cIAI], hospital-acquired pneumonia 
[HAP]/ventilator-acquired pneumonia [VAP], and sepsis or bloodstream infections 
[BSI]) in the single-dose and multiple-dose phase. Another paediatric study will 
investigate cefiderocol in paediatric subjects with a variety of infections including but not 
limited to cUTI, cIAI, HAP/VAP, BSI, and sepsis in the single-dose phase, with the 
multiple-dose phase specific to subjects with cUTI and HAP/VAP. 
< 3 months 
A third study to investigate cefiderocol in subjects < 3 months is also planned. 

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2. STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
 
To assess the safety and tolerability of 
cefiderocol after single-dose administration in 
hospitalized paediatric subjects 3 months to 
< 18 years of age with suspected or confirmed 
aerobic Gram-negative bacterial infections 
 
To assess the PK of cefiderocol after single-
dose administration of cefiderocol in 
hospitalized paediatric subjects 3 months to 
< 18 years of age with suspected or confirmed 
aerobic Gram-negative bacterial infections 
 
To assess the safety and tolerability of 
cefiderocol after multiple-dose administration 
in hospitalized paediatric subjects 3 months to 
< 12 years of age with suspected or confirmed 
aerobic Gram-negative bacterial infections 
 
To assess the PK of cefiderocol after multiple-
dose administration in hospitalized paediatric 
subjects 3 months to < 12 years of age with 
suspected or confirmed aerobic Gram-
negative bacterial infections 
 
Adverse events 
 
Vital signs 
 
Physical examinations 
 
Clinical laboratory assessments 
 
Cmax, AUC0-inf, and t1/2 after single dose 
 
Cmax, AUC0-τ, and t1/2 after a minimum of 
4 doses 
Secondary 
 
 
Multiple-dose phase only: Whenever 
cefiderocol is administered alone, to assess 
the clinical response at the Posttreatment visit 
(7 [±◦4] days following End of Treatment 
[EOT]) and at the End-of-study (EOS) visit, 
AND to assess the microbiological response 
at the Posttreatment visit (7 [±◦4] days) 
following EOT and EOS (if available) 
 
Clinical outcome 
 
Microbiological outcome 
Exploratory 
 
 
To estimate the PTA for percent of time that 
free drug concentrations in plasma exceed the 
MIC over the dosing interval (%fT>MIC) of 
≥ 75% with infections caused by pathogens 
with MICs ≤ 4 µg/mL 
 
Multiple-dose phase only: To describe the 
clinical outcome of cefiderocol when given 
alone or in combination with standard of care 
(SOC) antibiotics to treat infections caused by 
aerobic Gram-negative pathogens in 
hospitalized paediatric subjects 3 months to 
< 12 years of age at the Posttreatment visit, 
EOT, and EOS 
 
Multiple-dose phase only: To describe the 
microbiological outcome of cefiderocol when 
given alone or in combination with SOC 
antibiotics to treat infections caused by 
 
Clinical outcome 
 
Microbiological outcome 
 
%fT>MIC for causative pathogens 
 
PTA for 75% fT>MIC 

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aerobic Gram-negative pathogens in 
hospitalized paediatric subjects 3 months to 
< 12 years of age at the Posttreatment visit, 
EOT, and EOS. 
 

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3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, single-arm, open-label, single- and multiple-dose study to assess the 
safety, tolerability, and PK of cefiderocol in hospitalized paediatric subjects 3 months to 
< 18 years of age with a suspected or confirmed aerobic Gram-negative bacterial 
infection (including but not limited to cUTI, cIAI, HAP/VAP, and sepsis or BSI) caused 
by a suspected or confirmed aerobic Gram-negative pathogen requiring systemic 
antibiotics for an expected 5 to 14 days. 
The study will consist of 4 separate cohorts of paediatric subjects grouped according to 
age range (Table 3-1). 
Table 3-1 
Cohort Description 
Cohort 
Age Range 
Single-dose Phase 
(minimum per cohort) 
Multiple-dose Phase 
(minimum per cohort) 
1a 
12 to < 18 yrs 
N = 6 
Cohort 1 not applicable in 
multiple-dose phase 
2a,b  
6 to < 12 yrs 
N = 6 
N = 10 
3a,b 
2 to < 6 yrs 
N = 6 
N = 10 
4c 
3 mos to < 2 yrs 
N = 6 
N = 10 
mos = months; PK = pharmacokinetic; yrs = years 
a 
Cohorts 1, 2, and 3 single-dose phase will be initiated in parallel. 
b 
The multiple-dose phase (Cohorts 2, 3, and 4) will begin after safety and PK data from 6 subjects 
in the corresponding single-dose cohort have been assessed. 
c 
Cohort 4 (single dose) will begin after safety and PK data from at least 6 subjects from single-
dose Cohorts 1, 2, and 3 (with a minimum of 3 subjects from Cohort 3) have been assessed. 
 
The single-dose phase (in all 4 cohorts) will enroll subjects with Gram-negative bacterial 
infection and will confirm cefiderocol exposures in a minimum of 6 subjects prior to 
conducting a multiple-dose phase (in Cohorts 2, 3, and 4) in additional subjects. 
Cohort 1 will consist of a single-dose phase only. 
Cohorts 2, 3, and 4 will each consist of both a single-dose phase and a multiple-dose 
phase (an expected 5 to 14 days). Note: a minimum of 6 doses will be permissible if, in 
the opinion of the investigator, it is in the subject’s best interest. 
The single-dose phase of Cohorts 1, 2, and 3 will be initiated in parallel. Within the 
single-dose Cohorts 2, 3, and 4, the PK of cefiderocol will be determined in all subjects 
prior to initiating enrollment of subjects in the multiple-dose phase of each respective 
cohort.  
Single-dose Cohort 4 (the youngest age group) will begin after safety and PK data is 
evaluated from a minimum of 6 subjects from the single-dose Cohorts 1, 2, and 3 (with a 

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minimum of 3 subjects from Cohort 3). Multiple-dose cohorts will begin after analyzing 
safety and PK data from 6 subjects in the corresponding single-dose cohort.  
Enrollment will be stopped for the applicable cohort to allow for analysis of the PK data 
prior to moving from single-dose to multiple-dose in Cohorts 2, 3, and 4. Sites that are 
activated for enrollment will be instructed via email or a phone call from the sponsor or 
clinical research organization (CRO) to pause enrollment in the relevant age cohort, until 
the available data have been processed and evaluated; additionally, interactive response 
technology (IRT) will be de-activated to prevent enrollment until data have been 
evaluated. The phone call will be followed by written notification via “Dear Dr. Letter”. 
In the single-dose phase, each of the 4 cohorts will include a minimum of 6 paediatric 
subjects (at least 24 subjects total).  
In the multiple-dose phase (Cohorts 2, 3, and 4), each cohort will include a minimum of 
10 paediatric subjects (at least 30 subjects total).  
Overall, it is expected that at least 54 evaluable paediatric subjects will be enrolled in the 
study across all 4 cohorts.  
For summary of plasma cefiderocol concentrations, evaluable subjects in the single-dose 
phase will include those who have received 1 dose of cefiderocol and who have at least 
1 PK blood sample above the limit of quantification. In the multiple-dose phase, 
evaluable subjects will include those who have received ≥ 4 doses of cefiderocol and who 
have at least 1 PK blood sample above the limit of quantification. 
Screening will occur within 4 days prior to Treatment Day 1 or on Treatment Day 1 in 
both the single- and multiple-dose phase. Prior to Screening, sites will be asked to send a 
Permission to Screen Form to Shionogi’s medical monitor for evaluation and agreement. 
The purpose of the form is to check the eligibility of potential subjects being enrolled into 
the study.    
In the single-dose phase, cefiderocol will be administered (in addition to SOC) at any 
time during the SOC treatment regimen. In the multiple-dose phase, cefiderocol will be 
administered on Day 1 (in addition to SOC), within 72 hours of the start of potentially 
effective treatment with SOC antibiotics for infection. Subjects will subsequently receive 
cefiderocol every 8 hours (q8h) for an expected 5 to 14 days; the total duration of 
cefiderocol administration will be determined by the investigator based on clinical 
assessment of each subject’s infection status. Each dose of cefiderocol will be 
administered IV over 3 hours. The infusion may be shortened if this is in the best interest 
of the subject and if approved by the sponsor via the Request for Shortened Infusion 
Duration Form. The single-dose phase will include only those subjects with normal renal 
function or mild renal impairment. The dose of cefiderocol for the single-dose phase will 
be determined based on body weight only; the maximum dose to be administered is not to 
exceed 2000 mg. The dose for the multiple-dose phase will be determined based on both 
body weight and renal function; the maximum dose to be administered is not to exceed 
2000 mg. The SOC administered will be selected by the investigator based on the 

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suspected or confirmed pathogen(s) for the infection in accordance with local standards 
and can be modified at any time during the subject’s participation in the study at the 
investigator’s discretion. In the multiple-dose phase, if the subject’s infection is 
confirmed to be Gram negative only before starting treatment, monotherapy with 
cefiderocol may be allowed. 
End-of-treatment (EOT) assessments will occur within 24 hours after administration of 
cefiderocol (single-dose phase) or within 24 hours after administration of the last dose of 
study treatment (multiple-dose phase), or at early termination. A further clinical 
assessment will occur at a Posttreatment visit 7 (± 4) days after EOT (multiple-dose 
phase), which is analogous to a TOC and EOS time point, if microbiological samples are 
available. The EOS visit will occur 28 (+ 7) days after administration of cefiderocol in 
the single-dose phase or 28 (+ 7) days after administration of the last dose of study 
treatment in the multiple-dose phase; this visit may be performed on-site or via phone 
call. The study schematic including a schedule of assessments is provided in Figure 3-1 
and Table 3-2. 
The total duration of cefiderocol administration will be determined by the investigator 
based on clinical assessment of each subject’s infection status but should be expected (at 
time of enrollment) to be 5 to 14 days. Note: a minimum of 6 doses will be permissible if, 
in the opinion of the investigator, it is in the subject’s best interest. In special 
circumstances, treatment beyond 14 days may be allowed following review and approval 
of individual cases by the Shionogi medical monitor via the Treatment Extension Form. 
The dose of cefiderocol administered to each subject will be determined by the 
investigator based on dosing recommendations (Section 5.2).  
Figure 3-1 
Study Schematic 
 
PK = pharmacokinetic 
Cohort 1 is not applicable in the multiple-dose phase. 
Multiple-dose Cohorts 2, 3, and 4 will begin after PK analyses are complete. 

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Table 3-2 
Study Schedule of Assessments 
Study Phase 
Screening 
Cefiderocol 
Administration 
End-of-
Treatment 
(EOT) 
Post-
treatment 
Visit 
End-of-Study 
(EOS) Visit 
Single-dose 
Within 4 days 
prior to 
Treatment 
Day 1 or on 
Treatment 
Day 1 
1 day 
Within 24 hours 
after last dose of 
study treatment 
(or early 
termination) 
NA 
28 (+ 7) days 
after single dose 
of cefiderocol 
Multiple-dose 
5 to 14 days 
7 (± 4) 
days after 
EOT 
28 (+ 7) days 
after last dose of 
study treatment 
NA = not applicable 
 
Safety assessments including physical examinations, vital sign measurements, and 
clinical laboratory tests will be performed at prespecified time points during Screening, 
during study treatment, and after administration of study treatment within 24 hours. In 
addition, safety data will be captured at various time points during the study from safety 
assessments performed as part of routine patient care (Section 7.5). Adverse events will 
be collected and monitored from the time signed informed consent/assent is obtained 
through the end of study (EOS) visit or 28 (+ 7) days after administration of cefiderocol 
in the single-dose phase or 28 (+ 7) days after administration of the last dose of study 
treatment in the multiple-dose phase. 
Blood samples for determination of plasma cefiderocol concentrations will be collected 
from each subject at prespecified time points during and/or after the cefiderocol infusion 
(Section 7.4). Cefiderocol PK will be determined in the single-dose phase in each of the 
cohorts; cefiderocol dose recommendations may be revised by the sponsor prior to 
initiating enrollment of subjects in the multiple-dose phase of each respective cohort. 
In the multiple-dose phase only, clinical outcome data and microbiological outcome data 
will be obtained. Clinical and microbiological outcome assessments will be performed at 
EOT, at the Posttreatment visit (7 ± 4 days after EOT), and EOS if available. Data from 
assessments performed prior to, during, and after treatment with SOC antibiotics as part 
of routine patient care will be captured as study data. The time points for collection of 
microbiological specimens are otherwise not prespecified by the protocol (Posttreatment 
Visit, EOT, and EOS, if available; Section 7.6). In subjects where it is not possible to 
obtain a posttreatment culture and/or EOS culture, determination of presumed 
microbiological eradication may be made based on resolution of all presenting clinical 
sign and symptoms of the infection (clinical cure). 
3.2 
Rationale for Study Design and Control Group 
The proposed study is a nonrandomized, open-label study and will consist of 4 separate 
cohorts grouped by age (Section 3.1).  
The doses used in this study have been selected from estimates based on modeling and 
simulation of adult population PK data. Because these doses have not yet been studied in 
children, the single-dose phase of cefiderocol will be used to confirm the exposure prior 

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to initiating multiple dosing. Once the safety and PK data have been confirmed in 
subjects in the single-dose cohorts, the corresponding multiple-dose cohort will begin. If 
the exposures in the single-dose arms are not as predicted, adjustments to the dosing 
regimen will be made by the sponsor prior to initiating the multiple-dose phase of the 
respective cohorts. Dose adjustments at a subject level should be made by the investigator 
reflecting the current creatinine clearance level (CrCL) as described in Table 5-1,  
Table 5-2, and Table 5-3.  
The single-dose phase for Cohorts 1, 2, and 3 will initiate at the same time because renal 
maturation has occurred in these subjects and clearance is expected to be predictable. 
Cohort 4 single-dose phase will only occur after exposures have been analyzed and 
confirmed in at least 6 subjects total from the single-dose Cohorts 1, 2, and 3 (with a 
minimum of 3 subjects from Cohort 3), as the subjects in Cohort 4 have not achieved 
renal maturation and their clearance is less predictable. If the exposures in Cohorts 1, 2, 
and 3 are as expected, then Cohort 4 single-dose will commence; otherwise, the dosing 
regimen may be adjusted by the sponsor for Cohort 4. 
Multiple dosing is being investigated in Cohorts 2, 3, and 4 to confirm safety, since these 
subjects may respond differently from adults. As discussed and agreed with the European 
Medicines Agency’s (EMA’s) Paediatric Committee (PDCO), Cohort 1 (adolescents) will 
not participate in the multiple-dose phase because it is considered appropriate to 
extrapolate adolescent PK data from available and adequate adult PK data. Nevertheless, 
it should be noted that in the overall paediatric development program for cefiderocol, 
adolescents’ PK information from multiple dose regimens using the same dose 
recommendation as in the current protocol will be available from another parallel 
paediatric study agreed with the FDA for the paediatric development in the US. 
Cefiderocol will be added to SOC in both the single- and multiple-dose phase of this 
study (however, monotherapy with cefiderocol may be allowed in the multiple-dose 
phase if the subject’s infection is confirmed to be aerobic Gram-negative only before 
starting treatment). This is considered appropriate in the single-dose phase because a 
single dose of cefiderocol will not be effective in treating the underlying infection, 
whereas addition to SOC allows assessment of cefiderocol PK and safety while 
maintaining effective therapy in the subject and not restricting entry criteria to a 
particular baseline regimen. The use of SOC regimen is considered appropriate as each 
institution will likely have a different preferred antibiotic regimen and subjects will have 
different susceptibility profiles. It is well established that enrollment in paediatric studies 
is difficult when treatment options exist. By allowing any baseline treatment option (ie, 
SOC), enrollment will not be hindered and safety of cefiderocol can be assessed. 
An open-label design is considered appropriate because placebo fluids would need to be 
administered for a blinded design and this would not be recommended nor ethical in a 
paediatric population. A double-blind design requires placebo administration of all 
possible formulation types, which practically and operationally would be impossible.  

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3.3 
Study Duration 
3.3.1 
Study Duration for Individual Subjects 
Screening can last up to 4 days for the single-dose and multiple-dose phases. 
In the single-dose phase, the maximum duration of study participation for a subject from 
Treatment (Day 1) to the EOS visit (28 [+ 7] days after administration of the single dose 
of cefiderocol), is 28 days. 
In the multiple-dose phase (administration for 5 to 14 days), the maximum duration of 
study participation for a subject from Treatment (Day 1) to the EOS visit (28 [+ 7] days 
after administration of the last dose of study treatment), is 42 days (assuming 14 days of 
treatment). Note: a minimum of 6 doses will be permissible if, in the opinion of the 
investigator, it is in the subject’s best interest. 
3.3.2 
Study End 
The end of the study is defined as the last visit of the last subject. The estimated time for 
study completion, from first subject in to last subject last visit is approximately 2 years 
and 9 months.  

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4. STUDY ENROLLMENT AND WITHDRAWAL 
4.1 
Study Population 
Male and female paediatric subjects who fulfill the following eligibility criteria will be 
enrolled in the study.   
4.2 
General Inclusion Criteria 
Subjects who fulfill the following criteria will be included in the study. 
1. Subject’s parent(s) or legally authorized representative (LAR) provides written 
informed consent in accordance with regional and country-specific laws and 
regulations. 
2. Subject provides written informed assent, when feasible (age of assent to be 
determined by institutional review boards/independent ethics committees 
[IRB's/IEC's] or be consistent with local legal requirements). 
3. Hospitalized subject is 3 months to < 18 years of age at the time written informed 
consent/assent is obtained for the single-dose phase. Hospitalized subject is 
3 months to < 12 years of age at the time written informed consent/assent is 
obtained for the multiple-dose phase. Premature babies will not be restricted, but 
the subject must have an adjusted or postnatal age of 3 months.  
4. Subject has a suspected or confirmed infection (including but not limited to cUTI, 
cIAI, HAP/VAP, sepsis, or BSI) that requires hospitalization for treatment with 
IV antibiotics.  
5. If subject is a sexually active female of childbearing potential and has reached 
menarche or Tanner stage 3, subject agrees to use barrier contraception (including 
condom, diaphragm, or cervical cap) with spermicide or agrees to use a highly 
effective method of contraception (including contraceptive implant, injectable 
contraceptive, combination oral contraceptive, or an intrauterine [IUD] 
contraceptive device) from Screening up to 28 days after administration of the last 
dose of cefiderocol. 
4.3 
General Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Subject has a documented history of any hypersensitivity or allergic reaction to 
any β-lactam antibiotic (Note: for β-lactams, a history of a mild rash followed by 
uneventful re-exposure is not a contraindication to enrollment). 
2. Multiple-dose only: Subject has an infection caused only by a confirmed Gram-
positive pathogen. 
3. Subject has a suspected or confirmed central nervous system (CNS) infection 
(eg, meningitis, brain abscess, shunt infection) or osteomyelitis (which would 
require prolonged antibiotic therapy). 
4. Subject has cystic fibrosis. 

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5.  Single-dose phase: Subject has moderate or severe renal impairment based on 
estimated glomerular filtration rate (eGFR) (based on the Schwartz equation [10] 
if ≥ 3 months to < 1 year of age and modified Bedside Schwartz equation [11] if 
≥ 1 to < 18 years of age) of < 60 mL/min/1.73 m2 at Screening. 
Multiple-dose phase: Subject has an eGFR (based on the Schwartz equation [10] 
if ≥ 3 months to < 1 year of age and modified Bedside Schwartz equation [11] if 
≥ 1 to < 18 years of age)) of < 15 mL/min/1.73 m2 at Screening.  
See Section 7.5.3.1.2 for eGFR calculations and ranges. 
6. Subject has ESRD, is on hemodialysis (HD), or receiving continuous venovenous 
hemofiltration (CVVH). 
7. Subject has experienced shock in the prior month or is in shock at the time of 
Screening.  
8. Subject has severe neutropenia or is severely immunocompromised. 
9. Subject has multiorgan failure. 
10. Subject has a life expectancy of < 30 days due to severity of a concurrent illness. 
11. Subject is a female who has a positive pregnancy test at Screening. 
12. Subject is a female who is breastfeeding. 
13. Subject has received any other investigational medicinal product (IMP) within 
30 days. 
14. 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, 
including acute trauma to the pelvis or urinary tract. 
15. Subject is receiving vasopressor therapy at Screening. 
The suspected or confirmed aerobic Gram-negative infection type (including but not 
limited to cUTI, cIAI, HAP/VAP, and sepsis or BSI) will be specified and recorded in the 
electronic case report form (eCRF).  
A cUTI is defined as a clinical syndrome characterized by pyuria and a microbial 
pathogen in the urine in the context of the following underlying features: recurrent 
urinary tract infections (2 or more in a 12-month period); obstructive uropathy; a 
functional or anatomical abnormality of the urinary tract, including anatomical 
malformations or neurogenic bladder; vesicoureteric reflux; urinary tract catheterization; 
an invasive urogenital procedure, such as cystoscopy or urogenital surgery; or azotemia 
caused by intrinsic renal disease. In addition, pediatric subjects should have at least 2 of 
the following signs and symptoms depending on their age: 
For subjects < 2 years of age 
Fever defined as body temperature ≥ 38.0°C, failure to thrive, recent weight loss, 
irritability, poor feeding, lack of normal level of activity, abdominal pain/tenderness on 
physical examination, vomiting, or jaundice 

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For subjects ≥ 2 to < 18 years 
Fever defined as body temperature ≥ 38.0°C, chills or rigors, dysuria, urinary urgency, 
urinary frequency, new-onset urinary incontinence, suprapubic pain, flank pain, 
abdominal pain, pelvic pain, suprapubic tenderness or costovertebral angle tenderness on 
physical examination, nausea, or vomiting 
Hospital-acquired pneumonia is defined as an acute infection of the pulmonary 
parenchyma associated with clinical signs and symptoms, such as fever or hypothermia, 
chills, rigors, cough, purulent sputum production, chest pain, or dyspnea, accompanied by 
the presence of a new or progressive infiltrate on a chest radiograph in a patient 
hospitalized for more than 48 hours or developing within 7 days after discharge from a 
hospital. Patients with HAP may or may not require intubation and mechanical 
ventilation. 
Ventilator-associated pneumonia is defined as an acute infection of the pulmonary 
parenchyma associated with clinical signs and symptoms, such as fever or hypothermia, 
chills, rigors, purulent respiratory secretions, and increased oxygen requirements. These 
signs and symptoms are in addition to laboratory abnormalities, such as leukocytosis 
accompanied by the presence of a new or progressive infiltrate on a chest radiograph in a 
patient on mechanical ventilation for a minimum of 48 hours. 
4.4 
Screen Failures 
Screen failures are defined as subjects who provide assent and/or whose parent(s)/LAR(s) 
provide consent to participate in the study but the subject participating in the study did 
not meet the inclusion/exclusion criteria. Minimal information will be collected on 
subjects who fail screening requirements: informed consent/assent date, baseline subject 
characteristics, all of eligibility criteria not met, reasons for screen failure, any AEs that 
lead to discontinuations during screening, and any SAEs. This information will be 
entered in the eCRF. 
Subjects who do not meet the criteria for participation in the study may be rescreened, 
after discussion with the sponsor/medical monitor. Rescreened subjects will be assigned a 
new screening number. 
4.5 
Withdrawal of Subjects from the Study or Discontinuation from 
Study Treatment 
Withdrawal or discontinuation is defined as subjects who provide assent and/or whose 
parent(s)/LAR(s) provide consent to participate in the study but, the subject or 
parent/LAR wish to stop their participation in the study, or in the investigator’s opinion, 
the safety of the subject is at risk.   
The investigator will make every reasonable attempt to complete the study for each study 
subject. A subject may withdraw assent to participate in the study or a subject’s 
parent(s)/LAR may withdraw consent for the subject’s participation in the study at any 
time, for any reason.  

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The investigator or subinvestigator may discontinue a subject from study treatment 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 treatment  
 Progression of the study-qualifying infection (poor or no response, aggravation, or 
relapse of current infection) for which the investigator considers that the subject 
should discontinue study treatment  
 The subject recovers from the infection and antibiotic treatment is no longer 
required 
 The subject is proven to be ineligible for the study after dosing/entry into the 
study 
 The investigator or subinvestigator determines that the subject should be 
discontinued from the study treatment based on the management and 
discontinuation criteria for abnormal liver function tests (Appendix 2) 
 The study is prematurely terminated 
 The investigator or subinvestigator determines that the subject should be 
discontinued from study treatment for any other reasons 
In the event a subject withdraws assent, and/or a subject’s parent(s)/LAR withdraws 
consent, the subject will be discontinued from the study and no further assessments will 
be done. However, in the event a subject is prematurely discontinued from study 
treatment by the investigator or subinvestigator but assent and consent from the study 
have not been withdrawn, EOT (or early termination) procedures including physical 
examination, vital sign measurements, and clinical laboratory tests will be performed and 
the reporting of AEs will be obtained until the EOS visit (28 [+ 7] days after 
administration of the last dose of study treatment).  
Subjects with ongoing AEs will be monitored until either resolution or stabilization is 
achieved, the subject is referred for continued care to another health care professional, or 
until a determination of the cause being unrelated to the study treatment or procedure is 
made or the subject is lost to follow-up. Investigator causality must be included with all 
SAEs reported to the sponsor. Serious AEs with missing investigator causality will be 
followed up by the CRO urgently until a response is provided to the sponsor. 
The date of withdrawal or discontinuation and reason for withdrawal or discontinuation 
will be entered in the eCRF.  

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5. STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Test Drug 
Cefiderocol powder for solution for infusion will be supplied in vials containing the 
equivalent of 1 g cefiderocol as a white to off-white cake or powder manufactured by 
Shionogi & Co., Ltd. Each cefiderocol vial will be reconstituted in 0.9% sodium chloride 
(normal saline) injection, 5% dextrose injection, 0.45% sodium chloride (half-normal 
saline) injection, or water for injection to produce a clear solution and then extracted for 
further dilution in one of the following: normal saline for injection, 5% dextrose 
injection, or half-normal saline for injection to prepare an infusion solution with a final 
concentration of approximately 20 mg/mL for IV administration.  
Each dose of cefiderocol will be prepared by the study pharmacist or qualified designee 
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. 
For reconstitution and dilution instructions, follow the directions in the pharmacy 
manual. 
5.1.2 
Standard of Care 
The SOC antibiotics administered will be selected by the investigator based on the 
suspected or confirmed pathogen(s) for the infection in accordance with local standards 
and can be modified at any time during the subject’s participation in the study at the 
investigator’s discretion. 
5.2 
Treatments to be Administered 
The single-dose phase will include only those subjects with normal renal function or mild 
renal impairment. The dose of cefiderocol for the single-dose phase will be determined 
based on body weight only; the maximum dose to be administered is not to exceed 
2000 mg. The dose for the multiple-dose phase will be determined based on both body 
weight and renal function; the maximum dose to be administered is not to exceed 
2000 mg. Sites will be instructed to monitor renal function as per their routine 
practice/guidelines and to change doses immediately if renal function changes. Dosing 
recommendations for subjects with normal renal function or mild renal impairment and 
subjects with moderate or severe renal impairment (multiple-dose phase only) are 
provided in Table 5-1, Table 5-2, and Table 5-3, respectively. Shorter infusion times may 
be allowed in the multiple-dose phase if agreed by the sponsor via the Request for 
Shortened Infusion Duration Form, and if in the best interest of the subject. If shorter 
infusion times are needed, refer to the Pharmacy Manual for adjusted PK scheduling. 
Infusion time must be 3 hours in the single-dose phase. For all subjects enrolled in the 
multiple-dose phase of the study, cefiderocol doses may be adjusted based on changes in 
renal function as assessed (using the Schwartz equation [10] if ≥ 3 months to < 1 year of 
age and modified Bedside Schwartz Equation [11] if ≥ 1 to < 18 years of age) and 
according to the dosing recommendations for subjects with moderate or severe renal 
impairment (Table 5-3). See Section 7.5.3.1.2 for eGFR calculations and ranges. 

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After review of data from administration of cefiderocol in the single-dose phase, dosing 
recommendations for cefiderocol may be adjusted by the sponsor prior to administration 
in the multiple-dose phase or for the next subsequent cohort based on ongoing assessment 
of PK data. All revised dosing recommendations will be provided by the sponsor, 
discussed with the investigator, and documented.  
Single-dose Phase (Cohorts 1, 2, 3, and 4): On Day 1 of the single-dose phase, subjects 
will be administered a single dose of cefiderocol infused IV over 3 hours. Cefiderocol 
will be administered at any time during the SOC treatment. The dose of cefiderocol 
administered to each subject will be based on body weight (Table 5-1). No more than 
2000 mg of cefiderocol should be administered. 
Multiple-dose Phase (Cohorts 2, 3, and 4): In the multiple-dose phase, subjects will be 
administered doses of cefiderocol infused IV over 3 hours, q8h, beginning on Day 1 and 
continuing for an expected 5  to 14 days (in addition to SOC), within 72 hours of the start 
of potentially effective treatment with SOC antibiotics for infection. The total duration of 
treatment with cefiderocol will be determined by the investigator based on clinical 
assessment of each subject’s infection status. The dose of cefiderocol administered to 
each subject will be based on both body weight and renal function (Table 5-2). No more 
than 2000 mg of cefiderocol should be administered. After initiation of cefiderocol 
administration, cefiderocol doses may be adjusted based on changes in renal function as 
assessed by eGFR (using the Schwartz equation [10] if ≥ 3 months to < 1 year of age and 
modified Bedside Schwartz equation [11] if ≥ 1 to < 18 years of age) and according to the 
dosing recommendations for subjects with moderate or severe renal impairment 
(Table 5-3). See Section 7.5.3.1.2 for eGFR calculations and ranges.  
Shorter infusion times may be allowed in the multiple-dose phase if agreed on by the 
sponsor via the Request for Shortened Infusion Duration Form, and if in the best interest 
of the subject. Infusion volume adjustments by age will be provided in the pharmacy 
manual. 
In special circumstances, treatment beyond 14 days may be allowed following review and 
approval of individual cases by the Shionogi medical monitor. To apply for this, a 
Treatment Extension Form should be completed and submitted to the Shionogi medical 
monitor on Day 12 or earlier (if over the weekend) to ensure continuity of treatment. 
In the multiple-dose phase, if the subject’s infection is confirmed to be Gram-negative 
only before starting treatment, monotherapy with cefiderocol may be allowed. 

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Table 5-1 
Dosing Limits for Cefiderocol in Single-dose Phase: 
Subjects with Normal Renal Function or Mild Renal 
Impairment 
Cohort 
Single-dose Phase Dose 
Infusion Time 
Body Weight 
≥ 34 kg 
< 34 kg 
1 (12 to < 18 years of age) 
2000 mg 
60 mg/kg* 
3 hours 
2 (6 to < 12 years of age) 
2000 mg 
60 mg/kg* 
3 hours 
3 (2 to < 6 years of age) 
2000 mg 
60 mg/kg* 
3 hours 
4 (3 months to < 2 years of age) 
2000 mg 
60 mg/kg* 
3 hours 
* 
No more than 2000 mg of cefiderocol should be administered.  
The single-dose phase will include only those subjects with normal renal function (estimated 
glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2) or mild renal impairment (eGFR 60 to 
< 90 mL/min/1.73 m2). See Section 7.5.3.1.2 for eGFR calculations and ranges. 
 
Table 5-2 
Dosing Limits for Cefiderocol in Multiple-dose Phase: 
Subjects with Normal Renal Function or Mild Renal 
Impairment 
Cohort 
Multiple-dose Phase Dose 
Frequency 
Infusion 
Time 
Body Weight 
≥ 34 kg 
< 34 kg 
1 (12 to < 18 years of age) 
Cohort 1 not applicable in multiple-dose phase 
2 (6 to < 12 years of age) 
2000 mg 
60 mg/kg* 
q8h 
3 hours 
3 (2 to < 6 years of age) 
2000 mg 
60 mg/kg* 
q8h 
3 hours 
4 (3 months to < 2 years of age) 
2000 mg 
60 mg/kg* 
q8h 
3 hours 
q8h = every 8 hours 
* 
No more than 2000 mg of cefiderocol should be administered. 
Shorter infusion times may be allowed in the multiple-dose phase if agreed by the sponsor via the 
Request for Shortened Infusion Duration Form and if in the best interest of the subject. Infusion 
volume adjustments by age and weight will be provided in the pharmacy manual.  
See Section 7.5.3.1.2 for estimated glomerular filtration rate calculations and ranges. 
 

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Table 5-3 
Dosing Limits for Cefiderocol in Multiple-dose Phase: 
Subjects with Moderate or Severe Renal Impairment 
Renal Function 
Multiple-dose Phase Dose 
Body Weight ≥ 34 kg 
Body Weight < 34 kg 
Dose 
(mg) 
Frequency 
Infusion 
Time 
Dose 
(mg/kg) 
Frequency 
Infusion 
Time  
Moderate renal impairment 
(eGFR 30 to 
< 60 mL/min/1.73 m2) 
1500 
q8h 
3 hours 
45 
q8h 
3 hours 
Severe renal impairment (eGFR 
15 to < 30 mL/min/1.73 m2) 
1000 
q8h 
3 hours 
30 
q8h 
3 hours 
eGFR = estimated glomerular filtration rate; q8h = every 8 hours 
Shorter infusion times may be allowed in the multiple-dose phase if agreed by the sponsor via the Request 
for Shortened Infusion Duration Form and if in the best interest of the subject. Infusion volume 
adjustments by age and weight will be provided in the pharmacy manual. 
Expected total duration of cefiderocol administration is 5 to 14 days. A minimum of 6 doses will be 
permissible if, in the opinion of the investigator, it is in the subject’s best interest. 
 
5.3 
Selection and Timing of Dose for Each Subject 
Dosing instructions were developed based on age-specific PK parameters estimated for 
paediatric subjects from a population PK model using PK data from adult subjects to 
target equivalent systemic exposure (AUC) to in paediatric subjects to those in adults. 
Specifically, a population PK model was developed based on the data obtained from adult 
subjects and has been modified for predicting PK in paediatric subjects. Total clearance 
and volume of distribution at steady state in paediatric subjects were scaled using 
allometric relationships developed for 15 parenteral β-lactam antibiotics including 
13 cephems (12 cephalosporins) and 2 carbapenems reported by Shimamura et al [7]. The 
maturation factor of the elimination-relevant organ (kidney) is also incorporated into the 
model to simulate PK in very young children whose glomeruli are immature (ie, neonates 
and infants). Plasma cefiderocol concentrations were simulated to calculate Cmax and 
AUC for paediatric subjects of all age groups. The dose for each age group was adjusted 
to provide exposure (AUC) comparable to that in adult subjects. The PTA for the fraction 
of time for which free plasma drug concentrations exceeds the MIC over the 8-hour 
dosing interval (fT>MIC) of 75% was calculated at the adjusted doses for a MIC range 
from 0.25 to 16 μg/mL. The results of the calculations suggest that similar drug 
concentration and efficacy observed in adults can be achieved in paediatric subjects. 
In the proposed study, ongoing assessment of PK parameters after single-dose 
administration in Cohorts 1, 2, 3, and 4 will be used to adjust the initial model-based PK 
parameter estimates to refine dosing recommendations, as necessary, before proceeding 
with multiple-dose administration in each respective cohort. The data used for this 
assessment will come from paediatric subjects receiving cefiderocol from this and/or 
other paediatric studies. 

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5.4 
Method of Assigning Subjects to Treatment Groups 
This study has a single-dose phase and a multiple-dose phase and will include 4 separate 
age-specific cohorts.  
In the single-dose phase, cefiderocol will be administered (in addition to SOC) at any 
time during the SOC treatment regimen.  
Subjects in the multiple-dose phase will receive cefiderocol and SOC combination or 
cefiderocol alone (if the subject’s infection is confirmed to be Gram-negative only before 
starting treatment). 
An IRT will be used to assign subjects to identification numbers for use in the study. 
When the centralized IRT has accepted and enrolled the subject, the dispensing study 
pharmacist or qualified designee will prepare the study drug according to the pharmacy 
manual.  
The process for subject number assignment is described in the IRT procedure documents. 
5.5 
Blinding 
This is an open-label study. 
5.6 
Packaging and Labeling 
Cefiderocol powder for solution for infusion will be provided in vials containing the 
equivalent of 1 g cefiderocol per vial. Each vial will be labeled with information 
including the name of the active ingredient, protocol number, dosage form, strength, 
storage conditions, sponsor’s name and address, and cautionary statements according to 
the required country regulations. 
5.7 
Storage and Accountability 
Cefiderocol powder for solution for infusion vials must be stored according to the 
product label at 2oC to 8oC (36oF to 46oF) protected from light. 
The investigator will ensure that the cefiderocol drug supply is stored and dispensed in 
accordance with the pharmacy manual. All cefiderocol supplies must be kept in a secure 
locked area with access limited to those authorized by the investigator. 
The study pharmacist or qualified designee will maintain accurate records on the 
following information: receipt and condition of the cefiderocol drug supply, date of the 
receipt, when and how much cefiderocol 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 cefiderocol will be 
performed. Cefiderocol must not be used for any purpose other than the present study.   

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5.8 
Investigational Product Retention at Study Site 
At the completion of the study, all the unused cefiderocol must be returned to the sponsor 
(or designee) as per the sponsor’s written instructions or destroyed as per the CRO's 
standard operating procedures (SOPs) and a destruction certificate will be provided as 
needed.  
5.9 
Treatment Compliance 
The IV catheter used for administration of cefiderocol should be flushed with normal 
saline prior to administration of cefiderocol to confirm that the catheter is functioning 
and/or patency of the IV line and to remove traces of drugs previously administered 
through the line; flushing after each infusion is not necessary. Each subject will receive 
cefiderocol by IV infusion using an IV infusion pump to ensure delivery of the complete 
dose over 3 hours. Three (3) hours is the required duration to ensure adequate time over 
MIC for multidrug resistant Gram-negative infections. Shorter infusion times may be 
allowed in the multiple-dose phase if agreed on by the sponsor via the Request for 
Shortened Infusion Duration Form, and if in the best interest of the subject. Infusion time 
must be 3 hours in the single-dose phase. 
The date, start and infusion duration of each cefiderocol IV infusion will be recorded in 
the eCRF. Any interruption in the infusion or adjustment in the rate of infusion should be 
recorded and should not exceed 5 to 10 minutes.  

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6. RESTRICTIONS 
6.1 
Prior Therapy 
Prior antibiotic therapy is defined as any antibiotic administered for current infection. 
Prior therapy is defined as any therapy administered within 14 days prior to the first dose 
of study treatment.  
Any prior therapy (prescription drugs, nonprescription drugs, procedures [eg, surgical or 
nonsurgical] with or without any medication) taken by the subject within 14 days prior to 
the first dose of study treatment in the study will be recorded in the eCRF and the 
information will include the name of drug used or procedures done, duration of treatment, 
and reason for use. If a drug is administered, dose, dosing frequency, and route of 
administration will also be included. 
6.2 
Concomitant Therapy 
Concomitant therapy is defined as any therapy other than study treatment administered 
after the first dose of study treatment in the study. Concomitant medication information 
will be collected until the end of the study visit (EOS) in both phases of the study.  
Concomitant therapy, including prescription or nonprescription medications and 
procedures, will be recorded in the eCRF and include the following information:   
 Name of medication or procedure  
 Start date 
 Stop date 
 Dose, dosing frequency, route of administration 
 Reason for use 
A concomitant antibiotic is defined as any antibiotic used to treat an infection other than 
the qualifying Gram-negative infection. 
6.2.1 
Prohibited Therapy 
There are no prohibited medications in this study. Hemodialysis is an exclusion criterion 
(Section 4.3); therefore, if initiated during the study, should lead to subject withdrawal.  

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7. STUDY PROCEDURES AND METHODS OF ASSESSMENTS 
The study procedures and the times procedures are to be performed are summarized in 
the Time and Events Schedule in Appendix 1. 
7.1 
Informed Consent 
The investigator or subinvestigator will fully explain the nature of the study to the subject 
and subject’s parent(s)/LAR by using the IRB/IEC-approved informed consent form 
(ICF) and assent form, if applicable. Prior to the initiation of any study procedures, 
informed consent will be obtained from the subject’s parent(s)/LAR by the signing and 
dating of the ICF prior to the initiation of any study procedures. Subjects will be 
informed about the nature and duration of the study with written age-appropriate 
information, in language and terms they can understand. When appropriate, subjects must 
sign an assent form (age of assent to be determined by IRB/IEC or be consistent with 
local legal requirements). A copy of the signed and dated ICF and assent form will be 
given to the subject and subject’s parent(s)/legal guardian. The signed and dated original 
consent and assent forms, if applicable, will be retained by the investigator.  
The investigator or subinvestigator is responsible for ensuring that the subject 
understands the risks and benefits of participating in the study, including answering any 
questions the subject and subject’s parent(s)/LAR 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 
Medical History, Demographics, and Baseline Characteristic 
A complete medical history, including prior or concomitant therapies (including 
prescription and nonprescription medications), will be taken at Screening. Medical 
history will include previous significant medical conditions (eg, cancer, inherited 
conditions), any concurrent medical conditions, surgical history, history of diagnosis, and 
history of treatment of current infection or other infections requiring antibiotic therapy. 
Demographics and baseline characteristics, including date of birth (month and year), if 
permitted according to local requirements, sex, ethnicity, race, body weight, and height 
will be recorded in the eCRF.   
7.3 
Enrollment in the Study and Dispensing Study Drug 
After a subject is determined to be eligible according to the inclusion/exclusion criteria, 
the investigator or qualified designee will contact the IRT system for a subject 
identification number and provide the required information for study enrollment. If 
accepted, the subject will be enrolled in the study. After the subject is enrolled in the 
study, the investigator, subinvestigator, study pharmacist, or qualified designee will 
dispense the study treatment as specified in Section 5.  
Pharmacokinetic assessments will be performed for all subjects. Enrollment will be 
stopped for the applicable cohort to allow for analysis of the PK data prior to moving from 
single-dose to multiple-dose in Cohorts 2, 3, and 4. Sites that are activated for enrollment 

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will be instructed via email or a phone call from the sponsor or CRO to pause enrollment 
in the relevant age cohort, until the available data have been processed and evaluated; 
additionally, IRT will be de-activated for that cohort to prevent further enrollment until 
data have been evaluated.  
The phone call will be followed by written notification via “Dear Dr. Letter”. 
7.4 
Pharmacokinetic Assessments 
Pharmacokinetic studies in the paediatric population are generally conducted in patients 
with the disease to obtain data that better reflect clinical use of cefiderocol. The PK 
analyses in this study are mandatory and are being performed to determine PK 
parameters in different age groups to support cefiderocol dosing recommendations.  
The total volume of blood withdrawn per subject in this study has been kept at a 
minimum by using micro tubes. The PK sampling schedule also allows for some 
flexibility in Cohorts 1 and 2, in terms of number of samples (3 to 5 samples, See 
Table 7-2 for PK sampling times).  
Several approaches will be used to minimize the amount of blood drawn and/or the 
number of venipunctures: 
 Due to the use of a sensitive assay for cefiderocol, the volume of blood required 
per sample is 180 µL, ie, 0.18 mL (0.36 mL in total for primary sample and back-
up) 
 To minimize discomfort of blood sampling, sites will be encouraged to use topical 
anesthesia to place IV catheters, to use indwelling catheters rather than repeated 
venipunctures for blood sampling, and to collect PK blood samples at the same 
time as routine, clinical blood samples are obtained, when possible 
 The study uses PK and central laboratories experienced in handling small 
volumes of blood for PK analyses and for laboratory safety studies 
At each PK sampling time point, up to 0.4 mL of blood (but no less than 180 µL, ie, 
0.18 mL) will be obtained, adding up to the maximum volumes shown in Table 7-1: 
Table 7-1 
Total PK Blood Sample Volumes 
Cohorts 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohorts 1 and 2 
Flexible Sampling 
Age 
12 years to 
< 18 years 
6 years to 
< 12 years 
2 years to 
< 6 years 
3 months to 
< 2 years 
3-point 
design 
4-point 
design 
Number of samples 
5 samples 
5 samples 
3 samples 
3 samples 
3 samples 
4 samples 
Total PK Blood 
volume 
2.0 mL 
2.0 mL 
1.2 mL 
1.2 mL 
1.2 mL 
1.6 mL 
PK = pharmacokinetic 

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Cohorts 1 and 2: A total of 5 blood samples for determination of plasma cefiderocol 
concentrations will be collected from each subject as specified in Table 7-2. In the 
multiple-dose phase, sampling will be done during one of the dosing intervals from the 
6th to the 12th dose of cefiderocol. In the multiple-dose phase of the study in Cohort 2, if 
approved by the sponsor and is in the subject’s best interests, it is acceptable adjust the 
sampling time points to a minimum of 3 or 4 samples (versus ideally 5 samples).  
Cohorts 3 and 4: A total of 3 blood samples for determination of plasma cefiderocol 
concentrations will be collected from each subject as specified in Table 7-2 in the 
multiple-dose phase during one of the dosing intervals from the 6th to the12th dose of 
cefiderocol (multiple-dose phase).  
The option to use an indwelling catheter to facilitate blood sampling or application of a 
topical anesthetic cream prior to venipuncture is allowed. 
Table 7-2 
Blood Sampling Times after Start of Infusion 
Cohort 
Sampling Time Points (hours) After Start of Infusion 
1 
3* 
3.5 
5 
8 
Single-dose Phase 
Cohort 1 
X 
X 
X 
X 
X 
Cohort 2 
X 
X 
X 
X 
X 
Cohort 3 
 
X 
 
X 
X 
Cohort 4 
 
X 
 
X 
X 
Multiple-dose Phase 
Cohort 1 
NA 
NA 
NA 
NA 
NA 
Cohort 2 
X 
X 
X 
X 
X 
Cohort 3 
 
X 
 
X 
X 
Cohort 4 
 
X 
 
X 
X 
NA = not applicable 
* 
Within 15 minutes prior to the end-of-infusion using a separate line or immediately after the end of 
infusion using the same line and with proper flushing. 
If using a 3-point design, sampling times after the start of infusion are: 3, 5, and 8 hours. If using a 
4-point design, sampling times after the start of infusion are: 3, 5, and 8 hours, and 1 or 3.5 hours. 
For each blood sample collected, the actual sampling time will be recorded in the eCRF. 
In the event that shorter infusion times are approved by the sponsor, the PK sampling 
time points will need to be adjusted as described in the laboratory manual. See the 
laboratory manual for more details on PK sampling and management. 
If the line for PK sampling is the same line used for drug administration, the line needs to 
be flushed with normal saline to avoid mixing with the infused drug solution.  
7.5 
Safety Assessments 
All safety assessments will be performed at prespecified time points per the Time and 
Events schedule in Appendix 1. All results will be entered in the eCRF. 

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7.5.1 
Physical Examination 
Prior to administration of cefiderocol on Day 1 (single- and multiple-dose phases), body 
weight only will be measured to determine the appropriate dose of cefiderocol to be 
administered (Section 5.3).  
In the multiple-dose phase, in addition to prespecified time points, data from physical 
examinations performed at other time points as part of routine patient care will be 
collected during administration of cefiderocol until the last dose of study treatment. The 
physical examination should be performed according to the normal practice of the clinical 
study site by the investigator or subinvestigator. 
7.5.2 
Vital Sign Measurements 
Vital sign measurements include blood pressure (systolic and diastolic), pulse rate, 
respiratory rate, and body temperature. In the multiple-dose phase, in addition to 
prespecified time points, data from vital sign measurements performed at other time 
points as part of routine patient care will be collected once daily during Screening and at 
least 3 times per day starting on Day 1 of the infusion and continuing during 
administration of study treatment until the last dose of study treatment. 
7.5.3 
Clinical Laboratory Tests 
This is a safety and PK study; therefore, clinical laboratory tests are mandatory and will 
be performed for all subjects in both the single- and multiple-dose phase. The laboratory 
tests listed in Table 7-3 must be performed at Screening and within 24 hours of the 
cefiderocol infusion in the single-dose phase and at Screening, during cefiderocol 
treatment, and within 24 hours of the last dose of cefiderocol in the multiple-dose phase. 
Full details are listed in the Time and Events schedule in Appendix 1. In the 
multiple-dose phase, 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 as 
clinically indicated during administration of study treatment until the last dose of study 
treatment. If clinically indicated, and if part of routine patient care, eGFR should be 
checked daily to determine whether dose adjustments should be made. See 
Section 7.5.3.1.2 for eGFR calculations and ranges. 
7.5.3.1 
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 RRs are implemented during the study conduct. 
The investigator or subinvestigator will assess whether any abnormal changes from 
Screening (within 4 days prior to the administration of the first dose of study treatment) 
or previous visit results, are clinically significant. The date of specimen collection 
(whether or not specimen was collected) will also be entered in the eCRF. 

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7.5.3.1.1 
Clinical Laboratory Tests 
Mandatory hematology, blood chemistry, and urinalysis parameters that will be assessed 
are presented in Table 7-3.  
Table 7-3 
Mandatory Laboratory Tests 
Category 
Evaluation Parameters 
Hematology tests 
Hematocrit 
Hemoglobin 
Platelet count 
White blood cell count 
Differential white blood cell count 
Blood chemistry 
tests 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma glutamyltransferase  
Alkaline phosphatase 
Total bilirubin 
Total protein 
Albumin 
Blood urea nitrogen 
Serum creatinine 
Blood glucose 
Sodium 
Potassium 
Urinalysis 
(dipstick)a 
Protein 
Glucose 
Bilirubin 
Urobilinogen 
Occult blood 
Leukocyte esterase 
a  
If the subject has a complicated urinary tract infection, urine microscopy and Gram stain should be 
performed if the local laboratory has capability (see Section 7.5.3.2). Dipstick is not required if microscopy 
is performed. Dipstick for leukocyte esterase is not required if urine microscopy shows white cells. If urine 
microscopy shows white cells and is cultured, no further characterization is needed. 
 
The total volume to be drawn in the study may vary based on local/regional specific 
laboratory requirements and the clinical requirements for the individual subject. 
According to central laboratory, Eurofins, the average blood volume drawn for routine 
laboratory testing is 3.5 mL (minimum 1 mL, maximum 3.5 mL). As a general rule, total 
blood volume (including PK sampling) should not exceed 3% of the total blood volume 
over a period of 4 weeks, and should not exceed 1% at any single time. This 
recommendation leads to the allowable sample volumes, indicated in Table 7-4 below: 
Table 7-4 
Maximum Allowable Research-related Blood Sample 
Volumes 
Body weight 
(kg) 
Circulating total 
blood volume (mL) 
Maximum allowable 
sample volume over 
4 weeks (mL) – 3% of total 
blood volume 
Maximum allowable 
sample volume at single 
time (mL) – 1% of total 
blood volume 
2.5 to 5 
250 to 500 
7.5 to 15 
2.5 to 5 
5 to 12 
480 to 960 
14.4 to 28.8 
4.9 to 9.6 
12 to 20 
960 to 1600 
28.8 to 48 
9.6 to 16 
20 to 30 
1600 to 2400 
48 to 72 
16 to 24 
30 to 70 
2400 to 5600 
72 to 168 
24 to 56 
Source: Ethical considerations for clinical trials on medicinal products conducted with minors [9]. 
The estimated total amount of blood per cohort is listed in Table 7-5. The estimate is 
based on assumptions of 10 routine blood draws during the study. Fewer or more draws 
may be required based on clinical considerations. 

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Table 7-5 
Total Average Blood Volume (Multiple-dose Phase) 
Cohorts 
1 
2 
3 
4 
Age 
12 years to 
< 18 years 
6 years to 
< 12 years 
2 years to 
< 6 years 
3 months to 
< 2 years 
Total blood volume for PK samples 
2.0 mL 
2.0 mL 
1.2 mL 
1.2 mL 
Assumed number of routine blood 
samples 
10 
10 
10 
10 
Assumed amount per routine blood 
sample 
3.5 mL 
2.5 mL 
1.5 mL 
1.0 mL 
Total blood volume for routine lab 
tests 
35 mL 
25 mL 
15 mL 
10 mL 
Total blood volume  
37 mL 
27 mL 
16.2 mL 
11.2 mL 
PK = pharmacokinetics 
 
7.5.3.1.2 
Estimated Glomerular Filtration Rate 
Estimated GFR will be measured at Screening for subjects in the single-dose phase. In 
the multiple-dose phase, eGFR should be estimated at Screening and daily during 
treatment, if clinically indicated. Dose adjustments should be made reflecting the current 
CrCL (Section 5.2).  
For ages ≥ 3 months to < 1 year, the eGFR will be based on the Schwartz equation [10]: 
eGFR = 0.45 × (height/Scr), if height is expressed in centimeters 
For ages ≥ 1 year to < 18 years, the eGFR will be based on the modified Bedside 
Schwartz equation [11]: 
eGFR = 0.413 × (height/Scr), if height is expressed in centimeters 
OR 
41.3 × (height/Scr), if height is expressed in meters 
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
Scr (standardized serum creatinine) = mg/dL 
Renal function ranges are provided in Table 7-6. 

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Table 7-6 
Renal Function Ranges  
Renal Impairment 
Estimated Glomerular Filtration Rate (eGFR) 
None (normal) 
≥ 90 mL/min/1.73 m2 
Mild 
60 to < 90 mL/min/1.73 m2 
Moderate  
30 to < 60 mL/min/1.73 m2 
Severe 
15 to < 30 mL/min/1.73 m2 
The single-dose phase will enroll subjects with an eGFR of ≥ 60 mL/min/1.73 m2. 
The multiple-dose phase will enroll subjects with an eGFR of ≥ 15 mL/min/1.73 m2. 
7.5.3.1.3 
Pregnancy Test 
A urine pregnancy test will be performed for females of childbearing potential only. 
7.5.3.2 
Microbiologic Cultures 
Appropriate clinical specimens (eg, urine, blood, sputum, swabs) should be obtained if 
possible from all subjects prior to the start of any antibiotic treatments and also prior to 
starting study treatment. Clinical specimens for microbiologic cultures are to be sent to 
the local laboratory for identification of all pathogens causing the infection. Urine should 
be grown quantitatively with appropriate method-specific dilutions. Blood cultures 
should be collected if clinically indicated and sent to the local laboratory. After initiation 
of study treatment in the multiple-dose phase, clinical specimens should be obtained 
where possible, if clinically indicated. Culture results obtained prior to informed 
consent/assent, but directly related to the current infection, should be recorded and may 
form the basis for subject inclusion in the study. 
Local culture results for subjects enrolled in the single-dose phase should be recorded in 
the subject medical records, and local culture results for subjects enrolled in the multiple-
dose phase should be recorded in the eCRF. Identified isolates from subjects in the 
multiple-dose phase should be sent to the central laboratory. 
If possible, all baseline microbiological specimens should also have a Gram stain 
performed. In addition, quantification results for cultures will be collected. The high-
power microscopic view of the Gram stain can be used to characterize the general type of 
bacteria causing the infection (eg, a Gram-positive or a Gram-negative bacterial 
pathogen). A report of both inflammatory cells and bacteria is necessary. A Gram stain 
result showing the presence of Gram-negative bacteria is a primary indication of the 
infection that will be most appropriate for this study. 
Inappropriate clinical specimens should not be used for confirmatory culture 
identification of causative pathogens. 
All isolated pathogens will be frozen and stored for later shipping to the central 
laboratory. Detailed procedures for sample collection, handling, labeling, storage, and 
shipping will be provided in the separate study laboratory manual. Shipping labels, 
instructions for shipping, and courier service will be provided from the sponsor or CRO. 

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7.5.3.3 
Sample Collection, Storage, and Shipping 
Clinical specimens 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. 
7.5.4 
Adverse Events Assessments 
7.5.4.1 
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 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 or subject’s parent(s)/LAR 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 progression of the study qualifying infection (poor or no response, aggravation, or 
relapse of current infection) is not an AE (unless the outcome is serious) in the study. 
This statement applies until the Posttreatment visit. Any aggravation or relapse of the 
study qualifying infection after the Posttreatment visit should be considered an AE. 
New onset infection involving another site such as BSI is considered an AE. 
Hospitalizations for preplanned or elective procedures to treat a preexisting condition that 
did not worsen after study start will not be considered AEs or SAEs. The exception is 
when the subject experiences another event or has an outcome that is fatal, life-
threatening, leads to prolonged hospitalization, or is considered to be clinically 
significant during/following the procedure. 
The investigator or subinvestigator is responsible for assessing AEs. Adverse events 
should be fully investigated and recorded in detail including onset date, end date, date of 
outcome assessment (if outcome is other than not recovered, recovering, or unknown), 
severity, seriousness with a category of seriousness, causal relationship with the study 
treatment, action taken to manage the AE, and outcome of the AE in the eCRF. 
7.5.4.2 
Assessment Period 
Adverse events will be collected and monitored from the time signed informed 
consent/assent is obtained through the end of study (EOS) visit or 28 (+ 7) days after 
administration of cefiderocol in the single-dose phase or 28 (+ 7) days after 
administration of the last dose of study treatment (cefiderocol and SOC combination, 

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cefiderocol alone [if Gram-negative infection confirmed in the multiple-dose phase]) in 
the multiple-dose phase. If a subject withdraws early from the study or is prematurely 
discontinued from study treatment by the investigator, the investigator will make an 
effort to collect AEs for 28 (+ 7) days after administration of the last dose of study 
treatment. Subjects with ongoing AEs will be monitored until either resolution or 
stabilization is achieved, the subject is referred for continued care to another healthcare 
professional or until a determination of the cause being unrelated to the study treatment 
or study procedure is made, or the subject is lost to follow-up. Investigator causality must 
be included with all SAEs reported to the sponsor. Serious AEs with missing investigator 
causality will be followed up by the CRO urgently until a response is provided to the 
sponsor. 
Serious adverse events occurring after the subject’s completion of the study (EOS) are 
addressed in Section 7.5.4.7.2. 
7.5.4.3 
Severity 
The severity of an event will be graded by the investigator or subinvestigator according to 
the following definitions: 
● Mild: A finding or symptom is minor and does not interfere with usual daily 
activities. 
● 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. 
All severity grades identified during the period in which the AE occurred will be 
recorded in the eCRF. 
7.5.4.4 
Relationship to the Study Treatment 
The causal relationship of an event to cefiderocol will be determined by the investigator 
or subinvestigator according to the following criteria: 
 Related: An AE which can be reasonably explained as having been caused by 
cefiderocol. For example, the occurrence of the AE can be explained by any of the 
following: a pharmacological effect of cefiderocol (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 which cannot be reasonably explained as having been caused 
by cefiderocol. 
Related events are defined as those events that are treatment related and treatment 
emergent. 

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7.5.4.5 
Expectedness 
Expected AEs for cefiderocol are listed under Expected Adverse Reactions in Section 
“Undesirable Effects” of the “Summary of Data and Guidance for Investigators” in the 
current IB for cefiderocol.  
7.5.4.6 
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 cefiderocol from baseline, the investigator or subinvestigator will 
consider whether those results are clinically significant. Abnormal laboratory test results 
are defined as values outside the RR. For test results which 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 which are considered to be clinically significant by the investigator or 
subinvestigator are to be recorded as AEs. 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 (Section 7.5.4.7.1). 
 Clinical laboratory test results that lead to a change in dosing of study treatment 
or discontinuation from the study. 
 Clinical laboratory test results that lead to a concomitant drug 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 2. 
In addition, when any test result meets the management and discontinuation criteria for 
liver function abnormalities or transaminase elevations (Appendix 2), the results of 
further assessments and required follow-up should be recorded in the Liver Event Form 
in the eCRF. 

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7.5.4.7 
Serious Adverse Events 
7.5.4.7.1 
Definition 
An SAE is defined by regulation as any AE occurring at any dose that results in any of 
the following outcomes: 
 Death 
 Life-threatening condition 
 Hospitalization or prolongation of existing hospitalization for treatment 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 Other medically important condition 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. Abnormal liver function tests and the 
process to deal with then are described in Appendix 2. The investigator or subinvestigator 
will determine the seriousness of an AE.  
An elective procedure, identified at baseline, not associated with a worsening of a known 
underlying medical condition is not considered an AE, and therefore will not be 
considered an SAE despite requiring hospitalization. However, complications of a 
procedure will be considered an AE and may be considered an SAE if hospitalization is 
prolonged (or any other SAE criteria is met). A hospitalization or prolongation of a 
hospitalization for reasons other than an AE would not be considered an SAE. 
7.5.4.7.2 
Reporting Serious Adverse Events 
All SAEs must be reported to the clinical research organization (CRO)/sponsor in 
detail in the eCRF SAE Form in the electronic data capture (EDC) within 24 hours 
from the time the investigator first becomes aware of the SAE. 
 
All SAEs must be reported regardless of causal relationship to cefiderocol and the 
reporter must provide a causality assessment. When reporting SAEs, the investigator 
should record the diagnosis whenever possible. If no diagnosis is available at the time of 
reporting, individual signs and symptoms can be reported. 
 
In rare and exceptional circumstances, such as unavailability of EDC system, for 
reports occurring in subjects who consented but were screening failures, or for reporting 
instances of partner pregnancy of a male subject; sites may submit paper reports to the 
CRO via email or fax, within 24 hours of awareness to 
 Global Safety and 
Pharmacovigilance group: 

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Fax: 
 
Email: 
 
A template of the paper SAE Form and further instructions can be found in the Site 
Regulatory Binder.  
Once EDC is functional again, sites must enter reports previously sent via fax or email 
into EDC. 
If the sponsor requires a follow-up assessment, the investigator should provide new 
information to the CRO as it becomes available via EDC by adding the follow-up 
information to the SAE EDC Form. 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.  
Appropriate remedial measures should be taken by the investigator using his/her best 
medical judgment to treat the SAE. These measures and the subject’s response to these 
measures should be recorded. Clinical, laboratory, and diagnostic measures should be 
employed by the investigator as needed to adequately determine the etiology of the event.  
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation (EOS visit). However, if the investigator learns of SAEs occurring after the 
AE assessment period specified in Section 7.5.4.2, considered related to cefiderocol by 
the investigator, the SAEs must be reported to the CRO/sponsor via email or fax at the 
same fax and email for reporting SAE information above in this section. Investigator 
assessment of causality must be included with all SAEs reported to the sponsor. Serious 
adverse events with missing investigator causality will be followed up by the CRO 
urgently until response is provided to the sponsor. 
The sponsor will be responsible for reporting SAEs to the regulatory authorities as 
required by the applicable regulatory requirements. 
7.5.4.8 
Special Situations - Abuse, Misuse, Overdose, and Medication Error 
All Special Situations must be reported to the CRO/sponsor’s medical monitor in detail in 
the eCRF Special Situations Report Form in EDC as soon as possible from the time the 
investigator first becomes aware of the Special situation. In the event that EDC is not 
available, sites may submit paper reports to the CRO via email or fax at the same fax and 
email for reporting SAE information in Section 7.5.4.7.2.  
Abuse, misuse, overdose, or medication error of cefiderocol (as defined below) must be 
reported to the CRO or sponsor by the investigator using a Special Situations Report 
Form as soon as possible. If there is an associated AE, the investigator will enter the 
information in the eCRF and no SAE submission is required. If there are associated 
SAEs, the investigator will complete and submit an SAE Form in EDC as well.  

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 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.  
 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.  
7.5.4.9 
Pregnancy 
If a female subject becomes pregnant during the study, the investigator (or 
subinvestigator) will immediately discontinue the study treatment. Instances of pregnancy 
of a female subject must be reported to the CRO in detail in the eCRF Pregnancy Test 
(Urine) Form in EDC within 24 hours from the time the investigator first becomes aware 
of the pregnancy of the female subject. Additionally, the investigator (or subinvestigator) 
will need to also report the completed Pregnancy paper Form via email or fax, within 
24 hours of awareness, to 
 Global Safety and Pharmacovigilance group 
using the same fax and email procedures for SAE reporting in Section 7.5.4.7.2. 
Pregnancy complications and elective terminations for medical reasons must also be 
reported as an AE or sponsor 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, if there is an issue preventing submission to 
the CRO. 
Furthermore, the investigator must attempt to collect pregnancy information on any 
female partners of male subjects, who become pregnant during the study. A specific 
pregnant partner consent form for the pregnant partner of a male subject is available 
according to local regulations and must be completed prior to reporting to the sponsor 
information on the pregnant partner and child. Instances of pregnancy of a female partner 
of a male subject must be reported to the CRO via email or fax, within 24 hours of 
awareness, to the CRO. 
Instances of pregnancy of a female partner of a male subject must be reported to the CRO 
at the fax number or email for SAE reporting in Section 7.5.4.7.2 using the Pregnancy 
Form found in the Site Regulatory Binder. Pregnant Partner and Child reports must not 
be reported in EDC, as they pertain to individuals who are not study subjects. 
Cefiderocol is not genotoxic; therefore, no requirements for male subjects to use barrier 
contraceptives exist. 

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7.5.4.10 
Treatment-emergent Adverse Events 
Adverse events reported after the initial dose of cefiderocol will be considered treatment-
emergent AEs (TEAEs).   
7.6 
Efficacy Assessments (Multiple-dose Phase Only)  
Microbiological response will be characterized based on microbiological laboratory 
results and clinical response will be characterized based on an evaluation of clinical signs 
and symptoms by the investigator or designee. 
7.6.1 
Physician Clinical Response 
For the primary analysis, the clinical response will be a dichotomy (cure or failure) based 
on the clinical outcome as assessed by the investigator, taking into consideration 
objective data (eg, body temperature, white blood cell count, urinalysis). 
7.6.1.1 
Clinical Outcomes 
The following clinical outcomes in the multiple-dose phase will be characterized at EOT, 
at the Posttreatment visit, and at EOS (conducted on site or as a phone call). 
7.6.1.1.1 
HAP/VAP/cIAI 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms of pneumonia/cIAI. 
 Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms of pneumonia/cIAI; reappearance of signs and/or 
symptoms of pneumonia/cIAI; development of new signs and/or symptoms of 
pneumonia/cIAI requiring antibiotic therapy other than, or in addition to, study 
treatment therapy; progression of chest radiographic abnormalities; or death due 
to pneumonia/cIAI. 
 Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 
7.6.1.1.2 
Complicated Urinary Tract Infection 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms of cUTI, or return to preinfection baseline if known, such that no 
antibiotic therapy is required for the treatment of the current infection. 
 Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms of cUTI; or reappearance of signs and/or 
symptoms of cUTI; development of new signs and/or symptoms of cUTI 
requiring antibiotic therapy other than, or in addition to, study treatment therapy; 
or death due to cUTI. 
 Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 

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7.6.1.1.3 
BSI/Sepsis 
 Clinical Cure: Resolution or substantial improvement of baseline signs and 
symptoms. Subjects with bacteremia must have eradication of bacteremia caused 
by the Gram-negative pathogen. 
 Clinical Failure: No apparent response to therapy; persistence or worsening of 
baseline signs and/or symptoms, reappearance of signs and/or symptoms; 
development of new signs and/or symptoms requiring antibiotic therapy other 
than, or in addition to, study treatment therapy; or death due to BSI/sepsis. 
 Indeterminate: Lost to follow-up such that a determination of clinical 
cure/failure cannot be made. 
7.6.2 
Microbiological Response 
An overall per-subject microbiological response will be determined at the Posttreatment 
Visit (7 [± 4] days) following EOT and EOS (if available) based on available information 
provided by the site’s SOC for this population.  
7.6.2.1 
Microbiological Outcomes 
An overall per-subject microbiological outcome for the specimens collected and obtained 
at any time after initiation of study treatment will be determined based on the individual 
microbiological outcomes for each baseline Gram-negative pathogen. The 
microbiological outcomes determined by investigator will also be entered in the eCRF. 
Emergent (ie, nonbaseline) pathogens are considered separately, and do not affect the 
per-subject microbiological outcome. 
7.6.2.1.1 
HAP/VAP/cIAI and BSI/Sepsis 
 Eradication: Absence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. If it is not possible to obtain an appropriate clinical 
culture and the subject has a successful clinical outcome, the response will be 
presumed to be eradication. 
 Persistence: Continued presence of the baseline Gram-negative pathogen from an 
appropriate clinical specimen. 
 Indeterminate: No culture obtained from an appropriate clinical specimen or 
additional antibiotic therapy for the treatment of the current infection including 
missed sampling. 
7.6.2.1.2 
cUTI 
 Eradication: A urine culture shows the baseline Gram-negative uropathogen 
found at entry at ≥ 105 colony forming units (CFU)/mL are reduced to 
< 103 CFU/mL. 
 Persistence: A urine culture shows that the baseline Gram-negative uropathogen 
found at entry at ≥ 105 CFU/mL grows ≥ 103 CFU/mL. 

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 Indeterminate: No urine culture obtained or additional antibiotic therapy for the 
treatment of the current infection including missed sampling. 
7.7 
Appropriateness of Measurements 
The proposed safety assessment (physical examinations, vital sign measurements, and 
clinical laboratory tests) and timing of assessments are considered appropriate to 
adequately monitor and assess the safety of cefiderocol in paediatric subjects 3 months to 
< 18 years of age. The assessments of safety are typical for research studies in adults and 
therefore are also considered to be appropriate to provide a comprehensive assessment of 
safety in the paediatric population. Because cefiderocol is not associated with a risk for 
QTcF prolongation based on a negative thorough QT/QTc study (Study 1603R2116), 
ECGs will not be performed in the current study.   
The proposed blood sampling scheme for determination of plasma cefiderocol 
concentrations is considered sufficiently accurate to estimate PK parameters in the 
paediatric population using a population PK model. 
Efficacy parameters are exploratory study objectives, considering that the primary 
objectives of the current study are safety and PK (to confirm dosing recommendations) in 
paediatric subjects 3 months to < 18 years of age. Additionally, because the study is open 
label and because cefiderocol will be administered concurrently with SOC antibiotics, 
efficacy assessments will intentionally be not rigorous, but rather obtained to provide 
supplemental information regarding the use of cefiderocol in the paediatric population 
clinically.  
7.8 
Acceptable Time Windows 
Measurements for safety, PK, and efficacy endpoints will be performed according to the 
schedule of assessments in Appendix 1. The time windows displayed in Table 7-7 are the 
acceptable time windows for information collection; time windows for analyses will be 
stated in the statistical analysis plan (SAP). The actual sampling date and time will be 
recorded in the eCRF. 

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Table 7-7 
Acceptable Time Windows 
Study Activity 
Time Points 
Acceptable Time Window 
Screening 
Can be Treatment Day 1 
Within 4 days prior to Treatment Day 1 
Enrollment 
Treatment Day 1 
--- 
Drug infusion 
See Appendix 1 
± 15 minutes 
Dosing interval 
See Appendix 1 
± 15 minutes 
Pharmacokinetic 
blood sampling 
Cohorts 1 and 2 
1 hour after start of 
infusion 
± 15 minutes 
3 hours after start of 
infusion 
Within 15 minutes prior to the end of 
infusion using a separate line or 
immediately after the end of infusion 
using the same line and with proper 
flushing 
3.5 hours after start 
of infusion 
± 15 minutes 
5 and 8 hours after 
start of infusion 
± 30 minutes 
Cohorts 3 and 4 
3 hours after start of 
infusion  
Within 15 minutes prior to the end of 
infusion using a separate line or 
immediately after the end of infusion 
using the same line and with proper 
flushing 
5 and 8 hours after 
start of infusion 
± 30 minutes 
EOT 
Within 24 hours after last day of study 
treatment  
As soon as possible after last dose 
(same calendar day) 
Posttreatment 
7 days after EOT 
± 4 days 
EOS 
28 days after last dose of study treatment 
+ 7 days 
EOS = End of Study; EOT = End of Treatment 

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8. STUDY ACTIVITIES  
Study activities are presented in Section 7 and in the Time and Events Schedule in 
Appendix 1. The activities related to collection of study information and samples should 
not impair the normal SOC of the individuals consenting to be in the study. 

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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 an SAP and PK analysis plan 
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 finalized before database lock. As this is an 
open-label study, any changes made to the SAP after the first draft may be based on 
unblinded data. 
Unless otherwise noted, continuous variables will be summarized by 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 by using the frequency count and the percentage of subjects in each category 
as summary statistics.  
For summary of plasma cefiderocol concentrations, evaluable subjects in the single-dose 
phase will include those who have received 1 dose of cefiderocol study drug and who 
have at least 1 PK blood sample above the limit of quantification. In the multiple-dose 
phase, evaluable subjects will include those who have received ≥ 4 doses of cefiderocol 
study drug and who have at least 1 PK blood sample above the limit of quantification. 
No inferential statistical testing will be performed in this study. 
In general, all tables will be presented by cohort and treatment regimen (ie, single-dose or 
multiple-dose). Individual subject data, PK data, and any derived data will be presented 
and listed by subject. All analyses and tabulations will be performed by using both the 
SAS Version 9.4 or higher and/or WinNonlin Version 6.2.1 or higher. 
9.2 
Determination of Sample Size 
The design and the sample size of this study have been discussed with and agreed to by 
the Paediatric Committee [PDCO] (the EMA’s scientific paediatric committee) prior to 
study initiation. This study’s primary purpose is to assess the PK and safety of 
cefiderocol in paediatric subjects 3 months to < 18 years of age with suspected or 
confirmed aerobic Gram-negative infections. Efficacy is not a primary endpoint; 
therefore, the sample size calculations do not take into account efficacy endpoints.  
The design of the paediatric study and the number of subjects included in each cohort and 
overall was discussed, agreed and approved by PDCO and is in line with the 
CHMP/PDCO scientific advice Shionogi received in 2016 (Procedure No.: 
EMEA/H/SA/3435/1/2016/PED/III). It also reflects the requirements in the current draft 
Addendum to the guideline on the evaluation of medicinal products indicated for 
treatment of bacterial infections to address paediatric-specific clinical data requirements. 

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9.3 
Analysis Populations 
The following analysis populations will be analyzed for this study based on enrolled 
subjects with good clinical practice (GCP) compliance. The Intent-to-treat (ITT) and 
Microbiological ITT (MITT) populations will be defined only for subjects in the 
multiple-dose phase.  
 Safety population includes all enrolled subjects who receive at least 1 dose of 
cefiderocol.  
 Pharmacokinetic Concentration population includes all enrolled subjects who 
have received at least 1 dose of cefiderocol and have at least 1 PK blood sample. 
This population will be used for the concentration listing.  
 Pharmacokinetic Concentration Summary population includes all enrolled 
subjects who have received 1 dose of cefiderocol in the single-dose phase and 
≥ 4 doses of cefiderocol in the multiple-dose phase of the study and those who 
have at least 1 PK blood sample above the limit of quantification. This population 
will be used for the concentration summary as well as for plotting the 
concentration-time data and the concentration data summary. 
 ITT population includes all enrolled subjects who receive at least 1 dose of 
cefiderocol 
 MITT population includes all ITT subjects who have a baseline Gram-negative 
pathogen in the multiple-dose phase 
9.4 
Handling of Missing Data 
Handling of missing data will be specified in the SAP.   
9.5 
Subject Disposition 
Among the enrolled subjects, 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 for each cohort and treatment regimen. The number of subjects included in 
each analysis population and the percentage of subjects enrolled to cohort will also be 
presented. 
9.6 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized with summary statistics by 
cohort and treatment regimen for the Safety, ITT, and MITT populations using summary 
statistics. 
9.7 
Extent of Exposure and Treatment Compliance 
Exposure to the cefiderocol will be listed and summarized.   

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9.8 
Prior Therapies 
Prior therapies for drugs will be coded using the World Health Organization (WHO) 
Drug Dictionary. All prior therapy(ies) will be listed and summarized 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 and summarized for the Safety 
population. 
9.10 Pharmacokinetic Analysis 
Individual plasma concentrations of cefiderocol will be listed and summarized by cohort, 
phase (single- and multiple-dose phases), infusion time (1, 2, and 3 hours), and nominal 
sampling time using descriptive statistics 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 (Min) and maximum 
(Max) 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. The time course of individual and mean plasma concentrations 
will be presented by appropriate graphics.  
Population PK analyses will be performed using nonlinear mixed effects model approach 
and will be planned and reported separately by the Clinical Pharmacology & 
Pharmacokinetics of Shionogi & Co., Ltd. NONMEM Version 7.3 or higher will be used 
for the analyses.  
9.11 Safety Analysis 
9.11.1 
Adverse Events 
Adverse events will be classified by system organ class and preferred term using Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs will be used 
for the safety analyses (Section 7.5.4.10) and are referred to as an AE in this section. The 
number of subjects who experience at least 1 TEAE, treatment-emergent SAE, significant 
TEAE, and TEAE leading to withdrawal will be counted. The number of TEAEs, which 
are counted by cases reported, will also be presented. Treatment-related AEs will be 
summarized by the same as TEAE category of overall summary.  
A summary of TEAE by MedDRA system organ class and preferred term will be 
presented. The summary for severity and outcome will be presented by system organ 
class and preferred term.  
All AEs will be listed. 

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9.11.2 
Vital Signs 
Summary statistics for vital sign measurements will be presented for each scheduled time 
point and for the change from baseline to each time point. Baseline will be the last value 
obtained prior to study treatment administration within each respective study part. 
9.11.3 
Clinical Laboratory Analysis 
Summary statistics for select laboratory parameters will be presented for each scheduled 
time point measured and for the change from baseline to each time point. Baseline will be 
the last value obtained prior to study treatment administration within each respective 
phase of the study. 
9.11.4 
Physical Examination 
All physical examination data will be listed by subject. 
9.12 Efficacy Analyses 
Efficacy analyses will be performed only for subjects in the multiple-dose phase of the 
study for the MITT and ITT analysis populations.  
9.12.1 
Efficacy Endpoints 
The efficacy endpoints include the following variables: 
 Clinical outcome 
 Microbiological outcome per pathogen/subject 
9.12.2 
Analyses of Efficacy Endpoints 
 Clinical outcome: the number and proportion of subjects in each category will be 
calculated for each time point.  
 Microbiological outcome: the number and proportion of subjects in each category 
will be calculated for each time point.  
In addition, efficacy endpoints will be analyzed by cefiderocol alone and cefiderocol in 
combination with SOC. 
9.13 Data Review 
The decision to move to the next cohort will be based on the review of results of the PK 
analysis. Details will be specified in the PK analysis plan. 
Data analysis for data safety monitoring board (DSMB) will also be performed as 
specified in the DSMB charter. 

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10. 
ADMINISTRATIVE CONSIDERATIONS 
10.1 Study Administrative Structure 
Sponsor: 
Shionogi B.V.  
Kingsfordweg 151 
Amsterdam, 1043GR The Netherlands 
Tel: 
 
Sponsor's contact: 
 
 
Shionogi Inc. 
300 Campus Drive, Florham Park, NJ 07932 USA 
Tel: 
 
Sponsor's chief medical officer: 
 
Shionogi & Co., Ltd. 
Medical monitor: 
 
 
Shionogi Inc. 
300 Campus Drive, Florham Park, NJ 07932 USA 
Tel: 
 
Study monitoring: 
 
 
Central laboratory for North 
America and South America: 
Eurofins Central Laboratory 
2430 New Holland Pike 
Lancaster PA 17601 USA 
Tel: 
 
Fax: 
 
 
Clinical Laboratory for Europe:  
Eurofins Central Laboratory 
Bergschot 71 
4817 PA Breda 
The Netherlands 
Tel: 
 
Fax:
 
Clinical Laboratory for Asia- 
Pacific: 
Eurofins Central Laboratory 
1 International Business Park # 01-16 The Synergy 
609917 Singapore 
Tel: 
 
Fax: 
 

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Bioanalytical laboratory: 
Keystone Bioanalytical, Inc. 
501 Dickerson Road 
North Wales, PA 19454 USA 
Tel: 
 or 
  
Fax: 
 
 
Microbiological laboratory: 
International Health Management Associates, Inc. 
2122 Palmer Drive 
Schaumburg, IL 60173 USA 
Tel: 
  
Fax: 
 
 
10.2 Institutional Review Board or Independent Ethics Committee 
Approval 
The IRB/IEC 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/IEC. The IRB/IEC will be appropriately constituted in accordance 
with ICH GCP, and local requirements, as applicable. The study will be undertaken only 
after the IRB/IEC has given full approval and the investigator has received 
documentation of the approval.  
Amendments to the protocol will be subject to the same requirements as the initial 
review. The investigator will submit all periodic reports and updates as required by the 
IRB/IEC. The investigator will inform the IRB/IEC of any reportable AEs. 
10.3 Ethical Conduct of the Study 
The study will be conducted in accordance with all appropriate regulatory requirements 
and under the protocol approved by the IRB/IEC. The study will be conducted in 
accordance with current ICH GCP, all appropriate subject privacy requirements, and the 
ethical principles that are outlined in the Declaration of Helsinki.   
10.4 Informed Consent and Assent Process 
The investigator will generate informed consent/assent form(s) for the study that comply 
with the ICH GCP and regulatory requirements. The sponsor will review the proposed 
informed consent/assent form(s). The consent/assent form(s) will include all the elements 
required by the ICH GCP and any additional elements required by local regulations and 
will be reviewed and approved by the appropriate IRB/IEC before use. The sponsor must 
agree to any changes to the proposed ICF suggested by the investigator prior to 
submission to the IRB/IEC, and the IRB/IEC approved version must be provided to the 
site monitor after IRB/IEC approval.  

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The investigator or subinvestigator will explain the nature, purpose and methods, 
reasonable anticipated benefits and potential hazards of the study to the subject and 
subject’s parent(s)/LAR in simple terms by using the informed consent/assent form(s) 
approved by the IRB/IEC before the subject is entered the study. The method of 
obtaining and documenting informed consent/assent will comply with ICH GCP and all 
applicable regulatory requirement(s).   
10.5 Subject Confidentiality 
Procedures for protecting subject privacy must adhere to applicable data privacy laws and 
regulations. To maintain subject privacy, all eCRFs, cefiderocol accountability records, 
study reports, and communications will identify the subject by the subject 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 Information 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 is 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 protocol. The study monitoring will be 
performed by a representative of the sponsor through central, remote, and/or on-site 
monitoring as frequently as necessary and frequent communications (email, letter, 
telephone, and/or fax). The site monitor or representative of the sponsor will review data 
recorded in the eCRFs, verify the eCRFs entries with direct access to source documents, 
collect any safety/efficacy information on subjects, verify that amounts of unused 
cefiderocol are accurate, and check retention of source documents and essential 
documents. Remote source data verification may be implemented if applicable and 
according to local laws and regulations.  
10.7 Case Report Forms and Source Documents 
10.7.1 
Case Report Forms 
Electronic case report forms (eCRFs) will be created using an EDC system and made 
available for each subject with signed informed consent/assent into which the investigator 
will transcribe historical information and relevant data, as specified by the protocol. All 

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subject data from study visits must be legibly collected on source documents and 
promptly entered in the eCRF in accordance with the specific instructions in the eCRF 
Completion Guidelines. Data entry is performed by the investigator, subinvestigator, and 
study coordinator who are authorized in 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. 
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. However, the following data can be recorded directly 
on an eCRF as source data:  
 Reason for use of prior therapy or concomitant therapy 
 Severity and seriousness of an AE, and its causal relationship to the study 
treatment 
 Clinical comments to entries made in the eCRF 
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/IEC, 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 document within the study site. All source documents should meet 
Attributable, Legible, Contemporaneous, Original and Accurate (ALCOA) requirements. 
10.7.3 
External Data 
The following data will be reported in separate documents from eCRFs.  
 Concentration data of cefiderocol  
 Pharmacokinetic analyses results derived from concentration data  
 Central laboratory data 
 

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10.8 Committees 
10.8.1 
Data Safety Monitoring Board 
An evaluation of safety and efficacy data will be performed by the DSMB according to 
the DSMB charter. The DSMB will communicate their recommendations to the sponsor 
based on their data review. The recommendations may include, but are not limited to, 
continuing, stopping, or modifying the study; they will also provide the reason for each 
recommendation. 
10.9 Termination or Suspension of the Study 
10.9.1 
Termination or Suspension of the Entire Study 
The sponsor may prematurely terminate or suspend the study at any time for the 
following reasons:   
 Ensuring 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 efficacy/safety, inadequate recruitment of subjects) 
If the study is prematurely terminated or suspended, the sponsor should promptly inform 
the investigators. The investigator or subinvestigator should promptly inform the 
participating subjects and change the study treatment to other appropriate therapy(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 compliance 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/IEC 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/IEC 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/IEC approval/favorable opinion prior to implementation, except when the 

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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/IEC by the investigator 
and any deviations or modifications require expedited review and approval by the 
IRB/IEC. After the investigator obtained approval/favorable opinion from the IRB/IEC, 
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 
protocol must be fully documented on source documentation. 
10.11 Data Management 
The sponsor or designee will be responsible for data management. Procedures will be 
specified in study documents including but not limited to the Data Management Plan. 
10.12 Retention of Data 
The study records and documents, including ICFs, must be retained by the investigator as 
specified in the ICH GCP unless applicable local regulatory requirements require a longer 
retention period. 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 
retention requirements, whichever is latest 
However, the duration of retention may be prolonged in accordance with an agreement 
with the sponsor. In the event that the institution or investigator is unable or unwilling to 
retain study records as outlined in the clinical study agreement, the institution or 
investigator shall notify the sponsor, and the sponsor shall be entitled, at its expense, to 
take custody of the study records. In no event shall any study records be transferred to 
another location or be destroyed or disposed of without the prior written consent of the 
sponsor. 

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10.13 Quality Control and Assurance 
The sponsor or designee will implement and maintain quality control (QC) and quality 
assurance (QA) 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. 
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 
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. 
Information about this protocol will be posted in a publicly accessible database 
(clinicaltrials.gov) in accordance with all applicable regulatory requirements.  
10.15 Financial Disclosure 
The information on financial disclosure for investigators will be addressed in a separate 
agreement between the sponsor and the investigator. 

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11. 
REFERENCE LIST 
1. Diene SM, Rolain JM. Carbapenemase genes and genetic platforms in gram-negative 
bacilli: Enterobacteriaceae, Pseudomonas and Acinetobacter species. Clin Microbiol 
Infect. 2014;20(9):831-8. 
2. Livermore DM. Current epidemiology and growing resistance of gram-negative 
pathogens. Korean J Intern Med. 2012;27:128-42. 
3. Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in 
Gram-negative bacteria. Clin Microbiol Rev. 2015;28(2):337-418. 
4. Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing 
Enterobacteriacea. Emerg Infect Dis. 2011;17(10):1791-8. 
5. Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. Deaths attributable 
to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis. 
2014;20(7):1170-5. 
6. FDA Guidance for E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs (October 2005). 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM073153.pdf 
7. Shimamura K, Wajima T, Yano Y. Pharmacokinetic prediction for intravenous 
-lactam antibiotics in paediatric patients. J Pharm Sci. 2007;96(11):3125-39.  
8. FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation (July 2009). 
http://www.fda.gov/downloads/Drugs/Guidance/UCM174090.pdf 
9. Ethical considerations for clinical trials on medicinal products conducted with 
minors, Recommendations of the expert group on clinical trials for the 
implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal 
products for human use, Revision 1, 18 September 2017. 
10. Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in 
full-term infants during the first year of life. J Pediatr. 1984;104(6):849–54. 
11. Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in 
children with CKD. J Am Soc Nephrol. 2009;20(3):629-37. doi: 
10.1681/ASN.2008030287. Epub 2009 Jan 21. 
 

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Appendix 1 
Time and Events Schedule 
Single-dose Phase (Cohorts 1, 2, 3, and 4) 
Screeninga 
Treatment 
EOTb 
EOSc 
Day 
-4 to Start of 
Treatment  
1 
2 
28 
(+ 7) 
Days 
After 
Dosing 
Hour 
 
0 
1 
3 
3.5 
5 
8 
24 
 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Signs and symptoms 
X 
 
 
 
 
 
 
X 
 
Demographics & baseline characteristics 
X 
 
 
 
 
 
 
 
 
Review of prior/concomitant medications 
X 
 
X 
Clinical Procedures 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
X 
 
Vital sign measurements  
X 
 
X 
 
 
 
X 
X 
 
Mandatory clinical laboratory tests (see Table 7-3) 
X 
 
 
 
 
 
 
X 
 
eGFRe 
X 
 
 
 
 
 
 
 
 
Pregnancy testf (urine) 
X 
 
 
 
 
 
 
 
 
Adverse event monitoring 
X 
 
X 
Liver Event Form (if criteria in Appendix 2 are met) 
X 
 
X 
Study Treatments  
 
 
 
 
 
 
 
 
 
Administration of cefiderocol study drugg 
 
       X 
    X 
 
 
 
 
 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
Cohorts 1 and 2: Blood sample collectionh 
 
 
X 
X 
X 
X 
X 
 
 
Cohorts 3 and 4: Blood sample collectioni 
 
 
 
X 
 
X 
X 
 
 

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eGFR = estimated glomerular filtration rate; EOS = End of Study; EOT = End of Treatment; IV = intravenous 
a 
Screening will occur within 4 days prior to Treatment Day 1 or on Treatment Day 1. 
b 
EOT assessment will occur within 24 hours after administration of study treatment or at early termination.  
c 
EOS visit will occur 28 (+ 7) days after administration of study treatment, on-site or via telephone call.  
d 
Body weight measurement only at Screening. 
e 
eGFR (based on Schwartz equation [10] if ≥ 3 months to < 1 year of age and modified Bedside Schwartz equation [11] if ≥ 1 to < 18 years of age) will 
be estimated at Screening and predose (if more than 24 hours after Screening). See Section 7.5.3.1.2 for eGFR calculations and ranges. 
f 
Female subjects of childbearing potential only. 
g 
Cefiderocol administered as an IV infusion over 3 hours. Infusion time must be 3 hours in the single-dose phase, but may be shortened in the multiple-
dose phase. 
h 
Cohorts 1 and 2: Blood samples will be collected: 1, 3 (within 15 minutes prior to the end of infusion using a separate line or immediately after the end 
of infusion using the same line and with proper flushing), 3.5, 5, and 8 hours after the start of infusion. 
i 
Cohorts 3 and 4: Blood samples will be collected 3 (within 15 minutes prior to the end of infusion using a separate line or immediately after the end of 
infusion using the same line and with proper flushing), 5, and 8 hours after the start of infusion. 
 
 

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Multiple-dose Phase (Cohorts 2, 3, and 4) 
Screeninga 
Treatment Days 
EOTb 
Post-
treatment 
EOSc 
Study Day 
-4 to Start of 
Treatment 
1 
2 to 4 
5 to 14 
 
7 (± 4) 
days after 
EOT 
28 (+ 7) 
days after 
last dose 
Administrative Procedures 
 
 
 
 
 
 
 
Informed consent/assent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Signs and symptoms 
X 
 
 
 
X 
X 
 
Demographics & baseline characteristics 
X 
 
 
 
 
 
 
Review of prior/concomitant medications 
X 
 
 X 
Clinical Procedures 
 
 
 
 
 
 
 
Physical examination  
X 
Xd 
Xd 
Xd 
X 
 
 
Vital sign measurementsf  
X 
X 
X 
X 
X 
 
 
Mandatory clinical laboratory tests (see Table 7-3) 
X 
X 
X 
Xe 
Xe 
X 
 
eGFRg 
X 
X 
X 
X 
X 
 
 
Microbiologic culturesh 
X 
X 
X 
Xe 
Xe 
X 
 
Pregnancy testi (urine) 
X 
 
 
 
 
 
 
Adverse event monitoring 
X 
 
X 
Liver Event Form (if criteria in Appendix 2 are met) 
X 
 
X 
Study Treatments 
 
 
 
 
 
 
 
Administration of cefiderocol study drugj 
 
X 
X 
X 
 
 
 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
Cohort 2: blood sample collectionk 
 
 
X 
X 
 
 
 
Cohorts 3 and 4: blood sample collectionl 
 
 
X 
X 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
Clinical outcomem 
 
 
 
 
X 
X 
X 
Microbiological outcome (if available)n 
 
 
 
 
X 
Xn 
X 

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eGFR = estimated glomerular filtration rate; EOS = End of Study; EOT = End of Treatment; IV = intravenous; q8h = every 8 hours; SOC = standard of care 
a 
Screening will occur within 4 days prior to Treatment Day 1 or on Treatment Day 1. 
b 
EOT assessments will occur within 24 hours after administration of the last dose of study treatment or at early termination. 
c 
EOS visit will occur 28 (+ 7) days after administration of study treatment; on-site or via phone call. 
d 
Body weight measurement only, if clinically indicated and otherwise physical examinations should be symptom focused. 
e 
Clinical laboratory tests are mandatory at Screening, Day 1, one of the Days 2 to 4, one of the Days 5 to 14, and Posttreatment. If performed, as part of 
routine patient care, data from all additionally performed physical examinations and clinical laboratory will be collected during administration of study 
treatment until the last dose of study treatment. 
f 
Vital sign measurements will be taken 1 hour postdose, and prior to initiation of the next dose of study treatment. Data from vital sign measurements 
performed at other time points as part of routine patient care will be collected once daily during Screening and at least 3 times per day starting on Day 1 
and continuing during administration of study treatment until the last dose of study treatment. 
g 
eGFR (based on Schwartz equation [10] if ≥ 3 months to < 1 year of age and modified Bedside Schwartz equation [11] if ≥ 1 to < 18 years of age) will 
be estimated at Screening and daily during treatment if clinically indicated. See Section 7.5.3.1.2 for eGFR calculations and ranges. 
h 
Microbiologic samples should be obtained for all subjects before the first dose of study treatment; it’s allowed to use samples obtained prior to 
informed consent, but directly related to the current infection. After initiation of study treatment, urine, blood or other samples, should be obtained 
where possible if clinically indicated. Identified isolates from subjects in the multiple-dose phase should be sent to the central laboratory. 
i 
Female subjects of childbearing potential only. 
j 
Multiple doses of cefiderocol administered as an IV infusion over 3 hours, q8h, beginning on Day 1 and continuing for an expected 5 to 14 days. Note: 
Shorter infusion times may be allowed in the multiple-dose phase if agreed on by the sponsor and in the best interest of the subject via the Request for 
Shortened Infusion Duration Form. In special circumstances, treatment beyond 14 days may be allowed following review and approval of individual 
cases by the Shionogi medical monitor via the Treatment Extension Form. 
k 
Cohort 2: Blood samples will be collected once at each time point: at 1, 3 (within 15 minutes prior to the end of infusion using a separate line or 
immediately after the end of infusion using the same line and with proper flushing), 3.5, 5, and 8 hours after the start of infusion for the single dose and 
Cohort 2 for the multiple dose phase during one of the dosing intervals from the 6th to the 12th dose of cefiderocol. Pharmacokinetic sampling schedule 
is shown in Table 7-2. 
l 
Cohorts 3 and 4: Blood samples will be collected once at each time point at 3 (within 15 minutes prior to the end of infusion using a separate line or 
immediately after the end of infusion using the same line and with proper flushing), 5, and 8 hours after the start of infusion for the single dose and 
during one of the dosing intervals from the 6th to the 12th dose of cefiderocol during the multiple dose phase. Pharmacokinetic sampling schedule is 
shown in Table 7-2. 
m Clinical outcome assessments will be performed at EOT, Posttreatment, and EOS if available; additional clinical outcome assessments may be 
performed as part of routine patient care.  

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Clinical Study Protocol: 1802R2135 
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n 
Microbiological specimens may be collected as part of routine patient care and time points are not otherwise prespecified per protocol (EOT, 
Posttreatment Visit, and EOS, if applicable). In subjects where it is not possible to obtain a posttreatment culture and/or EOS culture, determination of 
presumed microbiological eradication maybe made based resolution of all presenting clinical sign and symptoms of the infection (clinical cure). 

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Clinical Study Protocol: 1802R2135 
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Appendix 2 
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: Jul 2009) 
[8]. 
Abnormal Liver Chemistry Criteria 
The investigator or subinvestigator must review study subject laboratories to identify if 
any levels meet the following criteria: 
a. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 × upper 
limit of normal (ULN) 
b. AST or ALT > 3 × ULN and total bilirubin (TBL) > 2 × ULN or PT-INR > 1.5, if 
PT-INR is measured 
c. AST or ALT > 3 × ULN with signs or symptoms compatible with hepatitis or 
hypersensitivity (eg, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, jaundice, fever, rash, eosinophilia [> 5%]) 
Action to be taken by Investigator 
If any one of abnormal liver chemistry criterion is met, the investigator or subinvestigator 
must do the following: 
 Subjects must be instructed to discontinue study immediately. The investigator or 
subinvestigator should not re-challenge the subject with the investigational 
product without consulting the sponsor. 
 Following the initial observed elevation, every effort should be made to have the 
subject reassessed within 48 to 72 hours to repeat liver function chemistries and 
for further hepatic evaluation.   
 Every effort should be made to have the subjects monitored 2 to 3 times per week 
until liver function chemistries (ALT, AST, alkaline phosphatase [ALP], TBL) 
resolve, stabilize, or return to within the normal range or to baseline levels. 
 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 in the eCRF.  
 Consultation with a specialist such as a hepatologist is considered. 
 Liver imaging (ie, ultrasound, magnetic resonance imaging (MRI), computerized 
tomography) is considered. 
For criterion b, the case must be reported as an SAE. 
If laboratory values are normalizing, follow-up reports with these values are required 
once the values have normalized. 
 

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Clinical Study Protocol: 1802R2135 
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If the laboratory values are significantly worsening, follow-up reports are required each 
time the subject is monitored for these values, ie, 2 to 3 times per week. 
 
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 in the 
eCRF: 
 Clinical signs and symptoms course 
 Alcohol use 
 Risk factors for nonalcoholic steatohepatitis such as diabetes, obesity and 
hypertriglyceridemia 
 Autoimmune hepatitis/cholangitis 
 Wilson's disease 
 Laboratory Assessments 
– Viral hepatitis serology 
– Hepatitis A immunoglobulin M (IgM) antibody 
– Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (IgM) 
– Hepatitis C RNA 
– Hepatitis E IgM antibody 
– Cytomegalovirus IgM antibody 
– Epstein-Barr viral capsid antigen IgM antibody 
– For subjects with TBL > 1.5 ULN, conjugated bilirubin should be measured. 
– Complete blood count with differential to assess for eosinophilia 
 

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Clinical Study Protocol: 1802R2135 
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Appendix 3 
Sponsor’s Signature 
Form 511-01 
Protocol Approval 
 
 
Product Name: Cefiderocol (S-649266) 
Study Protocol Title: A Single Arm, Open-label Study to Assess the Safety, 
Tolerability, and Pharmacokinetics of Single and Multiple Doses of Cefiderocol in 
Hospitalized Paediatric Subjects 3 Months to < 18 Years of Age with Suspected or 
Confirmed Aerobic Gram-negative Bacterial Infections 
Study Protocol Number: 1802R2135 
Version Number: Version 7 
Issue Date: 18 Nov 2021 
 
 
 
 
Sponsor signatory: 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor: 
 
 
Refer to electronic signature page  
 
Refer to electronic signature page 
 
 
Shionogi & Co., Ltd. 
ID: 
 
 
Date: day-month-year 
 

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Clinical Study Protocol: 1802R2135 
18 Nov 2021 
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Page 83 of 83 
Appendix 4 
Investigator’s Signature 
Study Title: 
A Single Arm, Open-label Study to Assess the Safety, 
Tolerability, and Pharmacokinetics of Single and 
Multiple Doses of Cefiderocol in Hospitalized 
Paediatric Subjects 3 Months to < 18 Years of Age 
with Suspected or Confirmed Aerobic Gram-negative 
Bacterial Infections 
Study Number: 
1802R2135 
Date of Protocol: 
10 Jul 2019  
Date of Latest 
Amendment: 
18 Nov 2021 
 
I have read the protocol described above. I agree to comply with all applicable 
regulations and to conduct the study as described in the protocol.  
 
Signed: 
 
 
 
 
 
 
Date:  
 
 
 
Printed Name: ____________________________ 
Title: ___________________________________ 
Affiliation: ______________________________ 
 

Electronic Signature Page for VV-CLIN-084521 v1.0
Electronic Signature Page for VV-CLIN-084521 v1.0
Final Approval
19-Nov-2021 00:34:00 GMT+0000

S-649266 (Cefiderocol)
Shionogi Inc. 
Clinical Study Protocol: 1802R2135
18 Nov 2021 
Confidential 
Page 1 of 5 
PROTOCOL VERSION 7, AMENDMENT 6 
SUMMARY OF CHANGES 
Study Title: A Single Arm, Open-label Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of Single and Multiple Doses of Cefiderocol in Hospitalized Paediatric 
Subjects 3 Months to < 18 Years of Age with Suspected or Confirmed Aerobic Gram-
negative Bacterial Infections 
Date of Amendment: 18 Nov 2021 
Version: 7 
Date of Previous Version: 04 Mar 2021 
Amendment Summary: Revisions to the protocol and the rationales for these revisions 
are provided by section below. The protocol was amended to allow treatment beyond 
14 days in special circumstances, following review and approval of individual cases by 
the Shionogi medical monitor. Strikethrough text was deleted, and underlined text was 
added. Minor editorial changes such as word changes, spelling, sentence structure, and 
document formatting revisions are not summarized.  
Section 
Revision 
Rationale 
Synopsis Study 
Design 
Subjects will subsequently receive 
cefiderocol every 8 hours (q8h) 
for an expected minimum of 
5 days to a maximum of 14 days 
total; the total duration of 
cefiderocol administration will be 
determined by the investigator 
based on clinical assessment of 
each subject’s infection status. 
To allow treatment beyond 
14 days in special 
circumstances 
Synopsis Criteria 
for Inclusion and 
Exclusion and 4.3 
General Exclusion 
Criteria 
Details on the underlying features 
and signs and symptoms of a cUTI 
were provided. 
Clarification 
NCT #: NCT04335539

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Section 
Revision 
Rationale 
Synopsis Duration 
of Treatment 
Multiple-dose phase: expected 
minimum of 5 days to a maximum 
of 14 days (a minimum of 6 doses 
will be permissible if, in the 
opinion of the investigator, it is in 
the subject’s best interest). In 
special circumstances, treatment 
beyond 14 days may be allowed 
following review and approval of 
individual cases by the Shionogi 
medical monitor. 
To allow treatment beyond 
14 days in special 
circumstances 
Synopsis Study 
Duration 
Study duration for individual 
subjects is approximately 28 days 
in the single-dose phase and 
42 days (or longer if treatment 
beyond 14 days is allowed by the 
Shionogi medical monitor) in the 
multiple-dose phase from the time 
of the first drug infusion. 
To allow treatment beyond 
14 days in special 
circumstances 
3.1 Overall Study 
Design and Plan 
Cohorts 2, 3, and 4 will each 
consist of both a single-dose phase 
and a multiple-dose phase (an 
expected 5 days to a maximum of 
14 days). 
To allow treatment beyond 
14 days in special 
circumstances 
Subjects will subsequently receive 
cefiderocol every 8 hours (q8h) 
for an expected minimum of 
5 days to a maximum of 14 days 
total; the total duration of 
cefiderocol administration will be 
determined by the investigator 
based on clinical assessment of 
each subject’s infection status. 
To allow treatment beyond 
14 days in special 
circumstances 
 
In special circumstances, 
treatment beyond 14 days may be 
allowed following review and 
approval of individual cases by the 
Shionogi medical monitor via the 
Treatment Extension Form. 
To allow treatment beyond 
14 days in special 
circumstances 

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18 Nov 2021 
 
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Section 
Revision 
Rationale 
3.3.1 Study 
Duration for 
Individual 
Subjects 
In the multiple-dose phase 
(administration for 5 to 14 days), 
the maximum duration of study 
participation for a subject from 
Randomization (Day 1) to the 
EOS visit (28 [+ 7] days after 
administration of the last dose of 
study treatment) is 42 days 
(assuming 14 days of treatment). 
To allow treatment beyond 
14 days in special 
circumstances 
5.2 Treatments to 
be Administered 
For all subjects enrolled in the 
multiple-dose phase of the study, 
cefiderocol doses may be adjusted 
based on changes in renal function 
as assessed by if clinically 
indicated, and if part of routine 
patient care, eGFR should be 
checked daily (using the Schwartz 
equation [10] if 
≥ 3 months to < 1 year of age and 
modified Bedside Schwartz 
Equation [11] if ≥ 1 to < 18 years 
of age) and according to the 
dosing recommendations for 
subjects with moderate or severe 
renal impairment (Table 5-3) to 
determine whether dose 
adjustments should be made. 
Clarification 
In the multiple-dose phase, 
subjects will be administered 
doses of cefiderocol infused IV 
over 3 hours, q8h, beginning on 
Day 1 and continuing for an 
expected minimum of 5 days to a 
maximum of 14 days total 
5 to14 days (in addition to SOC), 
within 72 hours of the start of 
potentially effective treatment 
with SOC antibiotics for cUTI, 
HAP, or VAP. 
To allow treatment beyond 
14 days in special 
circumstances 

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Clinical Study Protocol: 1802R2135 
18 Nov 2021 
 
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Page 4 of 5 
Section 
Revision 
Rationale 
 
In special circumstances, 
treatment beyond 14 days may be 
allowed following review and 
approval of individual cases by the 
Shionogi medical monitor. To 
apply for this, a Treatment 
Extension Form should be 
completed and submitted to the 
Shionogi medical monitor on Day 
12 or earlier (if over the weekend) 
to ensure continuity of treatment. 
To allow treatment beyond 
14 days in special 
circumstances 
7.5.2 Vital Sign 
Measurements 
In the multiple-dose phase, in 
addition to prespecified time 
points, data from vital sign 
measurements performed at other 
time points as part of routine 
patient care will be collected once 
daily during Screening and at least 
3 times per day at approximately 
evenly spaced intervals across the 
24-hour day starting on Day 1 of 
the infusion and continuing during 
administration of study treatment 
until the last dose of study 
treatment. 
Clarification 
7.5.3.1.1 Clinical 
Laboratory Tests 
Table 7-3 
a  If the subject has a complicated 
urinary tract infection, urine 
microscopy and Gram stain 
should be performed if the local 
laboratory has capability (see 
Section 7.5.3.2). Dipstick is not 
required if microscopy is 
performed. Dipstick for 
leukocyte esterase is not 
required if urine microscopy 
shows white cells. If urine 
microscopy shows white cells 
and is cultured, no further 
characterization is needed. 
Clarification 
7.8 Acceptable 
Time Windows 
Table 7-7 
Row added for Dosing interval 
± 15 minutes 
To allow for a 15-minute 
window between 8-hour 
dosing intervals 

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Section 
Revision 
Rationale 
Appendix 1 Time 
and Events 
Schedule 
d  Body weight measurement only 
at Screening. Vital signs as 
clinically indicated. 
Clarification 
j  Multiple doses of cefiderocol 
administered as an IV infusion 
over 3 hours, q8h, beginning on 
Day 1 and continuing for an 
expected minimum of 5 days to 
a maximum of 14 days. Shorter 
infusion times may be allowed in 
the multiple-dose phase if agreed 
to by the sponsor and in the best 
interest of the subject via the 
Request for Shortened Infusion 
Duration Form. In special 
circumstances, treatment beyond 
14 days may be allowed 
following review and approval 
of individual cases by the 
Shionogi medical monitor via 
the Treatment Extension Form. 
To allow treatment beyond 
14 days in special 
circumstances