Clinical trial NCT05856227
Conditions: Neonatal Sepsis
Keywords: Late-onset sepsis Neonates Infants
Sponsor: Basilea Pharmaceutica
Start date: 2023-08-06; Completion date: 2024-12-18
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluated the safety, pharmacokinetics and efficacy of ceftobiprole in term and pre-term newborn babies and infants up to 3 months of age with late-onset sepsis (LOS). Ceftobiprole is an antibiotic which belongs to a group of medicines called 'cephalosporin antibiotics'. It is approved for its use to treat adults and children with pneumonia in many European and non-European countries.

Detailed description:
This was a multicenter, open-label, single-arm, multiple-dose study of intravenous (IV) ceftobiprole medocaril (prodrug of the active moiety ceftobiprole). It could be combined with ampicillin and/or an aminoglycoside based on the Investigator's judgement according to manufacturer's instructions and/or local standard of care.

Following screening, ceftobiprole was administered as a 2-hour infusion at a dose of 7.5 mg/kg every 12 hours to 15 mg/kg every 8 hours, depending on age and weight.

The target treatment duration was 3-10 days, which could be extended to 14 days if considered clinically necessary by the Investigator.

Arms: arm 1: Ceftobiprole medocaril: 7.5 mg/kg to 15 mg/kg
Interventions: intervention 1: Ceftobiprole medocaril
Intervention descriptions: intervention 1: Ceftobiprole medocaril: 7.5 mg/kg every 12 hours to 15 mg/kg every 8 hours, administered IV as a 2-hour infusion.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
BPR-PIP-003
A multicenter, open-label, single-arm, multiple-dose study to evaluate the safety, 
pharmacokinetics, and efficacy of ceftobiprole medocaril in term and pre-term 
neonates and infants up to 3 months of age with late-onset sepsis
Protocol number / Version
BPR-PIP-003 / 5.0
Compound
Ceftobiprole medocaril
Phase of development
Phase 3
IND number
64,407
EudraCT number
2022-001837-35
Date
9 July 2024
Project Physician
Project Statistician
Sponsor
Basilea Pharmaceutica International Ltd, Allschwil
Hegenheimermattweg 167b
4123 Allschwil, Switzerland
Confidentiality statement
All information contained in this document is confidential and proprietary information of Basilea 
Pharmaceutica International Ltd, Allschwil (‘Basilea’). This information is provided to you on a 
confidential basis as an Investigator or potential Investigator, for review by you, and for potential future 
discussion with an applicable Independent Ethics Committee / Institutional Review Board as needed. It 
may otherwise not be disclosed by you to any third party other than those members of your staff who have 
a need to know, without prior written authorization from Basilea, except to the extent necessary to obtain 
informed consent from potential participants in the clinical study to which the document refers. If it is 
determined that disclosure to another third party is required by applicable law or regulations, the person 
to whom the information is disclosed must be informed that the information is confidential, and that it 
may not be further disclosed without prior written authorization from Basilea.
Note: This is an electronically controlled document
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Ceftobiprole medocaril
Clinical Study Protocol
BPR-PIP-003
Version 5.0
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PROTOCOL SYNOPSIS
TITLE:
A multicenter, open-label, single-arm, multiple-dose study to 
evaluate the safety, pharmacokinetics, and
efficacy of 
ceftobiprole medocaril in term and pre-term neonates and infants 
up to 3 months of age with late-onset sepsis
PROTOCOL NUMBER / 
VERSION:
BPR-PIP-003 / 5.0
SPONSOR:
Basilea Pharmaceutica International Ltd, Allschwil
STUDY PHASE:
Phase 3
INDICATION:
Treatment of late-onset sepsis in term and pre-term neonates and 
infants up to 3 months of age
IND NUMBER:
64,407
EUDRACT NUMBER:
2022-001837-35
DATE:
9 July 2024
OBJECTIVES 
Primary objectives
To characterise the safety profile of ceftobiprole medocaril in term and pre-term neonates and 
infants up to 3 months of age with late-onset sepsis (LOS).1
Secondary objectives
To assess in term and pre-term neonates and infants up to 3 months of age with LOS treated with 
ceftobiprole medocaril:

Pharmacokinetics (PK) of ceftobiprole

Clinical response

All-cause mortality

Microbiological response
STUDY OVERVIEW
Study design
This is a multicenter, open-label, single-arm, multiple-dose study of intravenous (IV) ceftobiprole
medocaril in term and pre-term neonates and infants up to 3 months of age with LOS. Ceftobiprole 
may be combined with ampicillin and/or an aminoglycoside based on the Investigator’s judgement, 
local standard of care, and/or isolated or presumed pathogens.
                                                
1 Ceftobiprole medocaril is the water-soluble prodrug of the active moiety ceftobiprole. Unless referring specifically to 
the prodrug, the term ‘ceftobiprole’ is used throughout the remainder of this protocol, and all doses are of ceftobiprole 
equivalents.
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Ceftobiprole medocaril
Clinical Study Protocol
BPR-PIP-003
Version 5.0
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PATIENT POPULATION
At least eight patients, at least two term (gestational age ≥37 weeks) and at least six pre-term 
(gestational age ≥24 to 36 weeks), with post-natal age ranging from ≥3 days to ≤3 months. 
INVESTIGATIONAL PRODUCT(S)
Ceftobiprole medocaril powder for concentrate for solution for infusion.
NUMBER OF SITES/LOCATIONS
Approximately ten sites in Europe and USA, with additional sites and locations possible.
DOSE / ROUTE / REGIMEN
Ceftobiprole medocaril: 7.5 mg/kg every 12 hours to 15 mg/kg every 8 hours, (depending on age 
and weight) administered IV as a 2-hour infusion, with dose adjusted according to gestational and 
post-natal ages. Neonates and infants with a body weight < 4 kg will receive a maximum of 
10 mg/kg/dose. The duration of treatment with ceftobiprole is 3–10 days, but may be extended to 
14 days if considered clinically necessary by the Investigator.
Ampicillin and/or an aminoglycoside (gentamicin, tobramycin, or amikacin), if applicable: dosage 
and administration according to manufacturer’s instructions and/or local standard of care. The 
treatment duration of ampicillin and/or the aminoglycoside, if added, is at the discretion of the 
Investigator.
KEY INCLUSION CRITERIA
(The full list of inclusion criteria is provided in Section 4.2 of the protocol.)

Informed consent from parent(s) or other legally-acceptable representative (LAR) to participate
in the study

Male or female, with a gestational age of ≥24 weeks and a post-natal age ranging from ≥3 days
to ≤3 months

Diagnosis of documented or presumed bacterial LOS requiring administration of systemic
antibiotic treatment

Sufficient vascular access to receive study drug and to allow blood sampling at a site separate
from the study drug infusion line
KEY EXCLUSION CRITERIA
(The full list of exclusion criteria is provided in Section 4.3 of the protocol.)

Refractory septic shock not responding to 60 minutes of vasopressor treatment within 48 hours
before enrollment

Proven ventilator-associated pneumonia

Proven central nervous system infection (e.g., meningitis, brain abscess)

Proven osteomyelitis, infective endocarditis, or necrotising enterocolitis

Impaired renal function or known significant renal disease, as evidenced by an estimated
glomerular filtration rate (using the Schwartz formula or other applicable formula) calculated
to be less than 2/3 of normal for the applicable age group, OR urinary output < 0.5 mL/kg/h
(measured over at least 8 hours), OR requirement for dialysis

Progressively fatal underlying disease, or life expectancy < 30 days

Use of systemic antibacterial therapy for longer than 72 hours within 7 days before start of
study medication
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Clinical Study Protocol
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Version 5.0
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
Participation in another clinical study with an investigational product within 30 days of 
enrollment in the current study
MAIN STUDY ENDPOINTS
Primary endpoint

Safety and tolerability (Safety population):

Adverse events (AEs), serious AEs, deaths, and discontinuations due to AEs during 
treatment with ceftobiprole and at the end-of-treatment (EOT), test-of-cure (TOC), and last 
follow-up (LFU) visits

Clinical laboratory tests, vital signs, and physical examination findings
Secondary endpoints

Pharmacokinetics (PK population):

Plasma levels of ceftobiprole, ceftobiprole medocaril, and open-ring metabolite

Efficacy:

Clinical cure rate at the EOT and TOC visits (ITT and CE populations)

All-cause mortality through Day 28 (ITT population)

Microbiological eradication or presumed eradication rate at the EOT and TOC visits (mITT 
and ME populations)

Improved signs and symptoms of LOS at the Day 3, EOT, and TOC visits (ITT and CE 
populations)
STATISTICAL ANALYSIS
Key analysis populations
Intent-to-treat (ITT) population / Safety population
All patients enrolled in the study who received at least one dose of ceftobiprole.
Clinically Evaluable (CE) population
Patients in the ITT population who received at least 48 hours of study drug
(i.e., four or six infusions of ceftobiprole as applicable) and had a completed overall clinical 
outcome assessment at the TOC visit, no major protocol deviations, and no concomitant systemic 
non-study antibiotic therapy.
Microbiological Intent-to-treat (mITT) population
All patients in the ITT population with a valid pathogen identified at baseline.
Microbiologically Evaluable (ME) population
All patients in the CE analysis population with a valid pathogen identified at baseline and a 
microbiological outcome assessment at the TOC visit.
Pharmacokinetics (PK) population
All patients who received at least one dose of ceftobiprole and had at least one sample of plasma 
concentration measurement obtained by the appropriate methodology.
Analyses
There will be no formal hypothesis testing. Descriptive statistics will be applied to the primary 
and secondary endpoints as follows: number, mean, standard deviation, median, minimum, 
and maximum will be provided for continuous variables, and frequency distributions (counts and 
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percentages) will be shown for categorical variables. All variables will be summarised overall 
and by gestational and post-natal ages as appropriate. Variables may be compared to baseline where 
applicable. Listings of individual patients’ data will also be produced.
ASSESSMENTS
Safety/tolerability
Safety will be assessed through summaries of AEs, clinical laboratory tests, vital signs, and physical 
examination findings. All safety analyses will be based on the safety population.
Pharmacokinetics
Plasma concentrations of ceftobiprole, ceftobiprole medocaril, and open-ring metabolite. 
Descriptive analyses of these concentrations will be summarised by timepoint for term and pre-term 
neonates with post-natal age up to 3 months.
Clinical effect
The following efficacy assessments will be analysed using descriptive statistics:

Clinical and microbiological outcome assessments at the EOT and TOC visits (Section 5.6)

All-cause mortality through Day 28

Signs and symptoms of LOS at the Day 3, EOT, and TOC visits (Section 5.6)
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TABLE OF CONTENTS
PROTOCOL SYNOPSIS....................................................................................................3
TABLE OF CONTENTS ....................................................................................................8
LIST OF TABLES ............................................................................................................13
LIST OF FIGURES...........................................................................................................13
LIST OF APPENDICES ...................................................................................................13
LIST OF ABBREVIATIONS ...........................................................................................14
1
INTRODUCTION ......................................................................................................16
1.1
Disease characteristics and study drug.................................................................16
1.1.1
Disease characteristics....................................................................................16
1.1.2
Study drug ......................................................................................................16
1.2
Nonclinical studies with ceftobiprole...................................................................17
1.2.1
Nonclinical pharmacodynamics and activity of ceftobiprole.........................17
1.2.2
Nonclinical pharmacokinetics ........................................................................17
1.2.3
Nonclinical toxicology ...................................................................................18
1.3
Clinical studies with ceftobiprole.........................................................................19
1.3.1
Completed Phase 3 clinical studies in adult patients......................................19
1.3.2
Completed studies in pediatric patients..........................................................20
1.3.2.1 Study CSI-1006.........................................................................................20
1.3.2.2 Study BPR-PIP-001..................................................................................21
1.3.2.3 Study BPR-PIP-002..................................................................................22
1.3.3
Benefit-risk assessment ..................................................................................23
1.4
Study rationale .....................................................................................................23
1.4.1
Summary of study design...............................................................................24
1.4.2
Study design rationale ....................................................................................24
1.4.3
Dose rationale.................................................................................................24
2
OBJECTIVES OF THE STUDY................................................................................25
2.1
Primary objective .................................................................................................25
2.2
Secondary objectives............................................................................................26
3
STUDY DESIGN .......................................................................................................26
3.1
Overview of study design and dosing regimen....................................................26
3.2
Endpoints..............................................................................................................28
3.2.1
Primary endpoint ............................................................................................28
3.2.2
Secondary endpoints.......................................................................................28
3.3
Treatment plan .....................................................................................................28
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3.3.1
Dose modifications.........................................................................................28
3.3.2
Duration of treatment .....................................................................................28
3.3.3
Missed-dose management ..............................................................................29
3.3.4
Overdose.........................................................................................................29
3.4
Data and Safety Monitoring Board ......................................................................29
3.5
Definition of the end of the study ........................................................................29
4
STUDY POPULATION.............................................................................................30
4.1
Target population .................................................................................................30
4.2
Inclusion criteria...................................................................................................30
4.3
Exclusion criteria .................................................................................................31
4.4
Patient withdrawal................................................................................................32
4.5
Replacement of patients.......................................................................................33
4.6
Study discontinuation...........................................................................................33
5
SCHEDULE OF ASSESSMENTS AND PROCEDURES........................................33
5.1
Summary of schedule of assessments ..................................................................33
5.2
Study visits...........................................................................................................37
5.2.1
Screening visit / Baseline (Day −2 to Day 1).................................................37
5.2.2
Active treatment visits....................................................................................38
5.2.3
End-of-treatment visit.....................................................................................39
5.2.4
Test-of-cure visit ............................................................................................39
5.2.5
Last follow-up visit.........................................................................................40
5.3
Medical history and concomitant medications.....................................................40
5.3.1
Medical history...............................................................................................40
5.3.2
Prohibited concomitant medications ..............................................................40
5.3.3
Permitted concomitant medications ...............................................................41
5.4
Microbiology assessments ...................................................................................41
5.5
Safety assessments ...............................................................................................41
5.5.1
Adverse event monitoring ..............................................................................41
5.5.2
Physical examination......................................................................................41
5.5.3
Vital signs and pulse oximetry .......................................................................42
5.5.4
Laboratory parameters and PK sampling .......................................................42
5.5.5
Pregnancy testing............................................................................................43
5.6
Efficacy assessments............................................................................................43
5.6.1
Overall clinical outcome.................................................................................43
5.6.2
All-cause mortality.........................................................................................44
5.6.3
Microbiological outcome................................................................................44
5.6.4
Relapse at LFU...............................................................................................45
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5.6.5
Signs and symptoms of LOS ..........................................................................45
5.7
Pharmacokinetic assessments...............................................................................45
6
STUDY TREATMENT..............................................................................................46
6.1
Blinding................................................................................................................46
6.2
Randomization .....................................................................................................46
6.3
Packaging and labelling .......................................................................................46
6.4
Shipping and storage conditions ..........................................................................46
6.5
Preparation, presentation, and stability of study drug..........................................46
6.6
Dosage and administration of study drug.............................................................46
6.7
Compliance and drug-supply accountability........................................................47
6.7.1
Drug disposal..................................................................................................47
7
SAFETY .....................................................................................................................48
7.1
Warnings and precautions....................................................................................48
7.1.1
Ceftobiprole....................................................................................................48
7.1.2
Ampicillin / aminoglycosides.........................................................................48
7.1.3
Contraception and pregnancy.........................................................................48
7.2
Definitions............................................................................................................48
7.2.1
Adverse event .................................................................................................48
7.2.2
Serious adverse event .....................................................................................49
7.2.3
Adverse drug reaction.....................................................................................50
7.2.4
Suspected unexpected serious adverse reaction .............................................50
7.2.5
Adverse events of special interest ..................................................................50
7.2.6
Further adverse event definitions ...................................................................51
7.2.7
Special Situations ...........................................................................................51
7.3
Evaluation of adverse events................................................................................51
7.3.1
Grading of severity.........................................................................................51
7.3.2
Assessment of causality..................................................................................51
7.4
Handling of safety information and collection periods........................................53
7.4.1
Responsibilities and procedures .....................................................................53
7.4.2
Handling of safety data during the pre-treatment period................................53
7.4.3
Handling of safety data during the treatment period and up to the last 
scheduled follow-up .......................................................................................53
7.4.3.1 Reporting procedures for adverse events that do not meet seriousness 
criteria .......................................................................................................54
7.4.3.2 Reporting procedures for serious adverse events .....................................55
7.4.4
Follow-up of adverse events...........................................................................56
7.4.5
Handling of post-study safety data.................................................................56
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Ceftobiprole medocaril
Clinical Study Protocol
BPR-PIP-003
Version 5.0
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7.4.6
Reporting and handling of pregnancies..........................................................56
7.5
Adverse events associated with an overdose or any other Special Situation.......56
8
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN........................57
8.1
Study endpoints....................................................................................................57
8.1.1
Primary endpoint ............................................................................................57
8.1.2
Secondary endpoints.......................................................................................57
8.2
Analysis populations ............................................................................................57
8.2.1
Intent-to-treat (ITT) population / Safety population ......................................57
8.2.2
Clinically Evaluable (CE) population ............................................................57
8.2.3
Microbiological Intent-to-treat (mITT) population........................................57
8.2.4
Microbiologically Evaluable (ME) population ..............................................57
8.2.5
Pharmacokinetics (PK) population.................................................................58
8.3
Sample size considerations ..................................................................................58
8.4
Statistical and analytical methods........................................................................58
8.4.1
Primary endpoint analysis ..............................................................................58
8.4.1.1 Safety/tolerability analysis........................................................................58
8.4.2
Secondary endpoint analyses..........................................................................58
8.4.2.1 Pharmacokinetic analysis..........................................................................58
8.4.2.2 Efficacy analyses ......................................................................................59
8.4.3
Study drug exposure and compliance.............................................................59
8.4.4
Prior and concomitant treatments...................................................................59
8.4.5
Handling of missing data and discontinuations..............................................59
9
STUDY ADMINISTRATION AND REGULATORY ASPECTS............................59
9.1
Study records........................................................................................................59
9.1.1
Investigator Site File.......................................................................................59
9.1.2
Case report forms ...........................................................................................59
9.1.3
Patient source documents ...............................................................................60
9.1.4
Document retention and archiving .................................................................60
9.2
Clinical monitoring ..............................................................................................60
9.3
Audits and inspections .........................................................................................61
9.4
Protocol amendments...........................................................................................61
9.5
Premature termination of the study......................................................................61
9.6
Publication policy.................................................................................................61
10 ETHICS AND GOOD CLINICAL PRACTICE ........................................................62
10.1 Good clinical practice ..........................................................................................62
10.2 Informed consent..................................................................................................62
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Ceftobiprole medocaril
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Version 5.0
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10.3 Patient confidentiality and data protection...........................................................63
10.4 Independent Ethics Committees / Institutional Review Boards...........................63
11 PROTOCOL VERSION HISTORY...........................................................................64
12 REFERENCES ...........................................................................................................65
13 APPENDICES ............................................................................................................67
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Ceftobiprole medocaril
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LIST OF TABLES
Table 1
Key completed Phase 3 clinical studies in adult patients ...................19
Table 2
Completed clinical studies in pediatric patients .................................20
Table 3
Schedule of assessments.....................................................................34
Table 4
Local laboratory parameters ...............................................................43
Table 5
Ceftobiprole dosing regimen for the treatment of neonates and 
infants with LOS.................................................................................47
LIST OF FIGURES
Figure 1
Overview of study design...................................................................27
LIST OF APPENDICES
Appendix 1 Renal function.....................................................................................67
Appendix 2 Investigator’s protocol signature page................................................69
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Version 5.0
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LIST OF ABBREVIATIONS
% fT > MIC
Percentage of the dosing interval that free-drug 
concentrations are above the minimum inhibitory 
concentration
ABSSSI
Acute bacterial skin and skin structure infection
ADR
Adverse drug reaction
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
CABP
Community-acquired bacterial pneumonia
CE
Clinically Evaluable
CI
Confidence Interval
Cmax
Maximum concentration
CoNS
Coagulase-negative staphylococci
CRO
Contract Research Organization
DSMB
Data and Safety Monitoring Board 
EC
Ethics Committee
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EOT
End-of-treatment
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
HABP
Hospital-acquired bacterial pneumonia
IB
Investigator’s Brochure
ISF
Investigator Site File
ITT
Intent-to-treat
IV
Intravenous
LAR
Legally-acceptable representative
LFU
Last follow-up
LOS
Late-onset sepsis
ME
Microbiologically Evaluable
MIC
Minimum inhibitory concentration
mITT
Microbiological Intent-to-treat
MRSA
Methicillin-resistant Staphylococcus aureus
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Ceftobiprole medocaril
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Version 5.0
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NOAEL
No-observed-adverse-effect level
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
q12h
Every 12 hours
q8h
Every 8 hours
SAP
Statistical Analysis Plan
SAR
Serious adverse reaction
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reaction
T > MIC
Time above the minimum inhibitory concentration
TOC
Test-of-cure
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Ceftobiprole medocaril
Clinical Study Protocol
BPR-PIP-003
Version 5.0
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1
INTRODUCTION
1.1
Disease characteristics and study drug
1.1.1
Disease characteristics
The incidence of neonatal sepsis is estimated at 2,824 cases per 100,000 live births (95% 
CI 1,892–4,194) and is inversely related to birth weight and gestational age, with a higher 
burden in low- and middle-income countries and a mortality ranging from 10.3% to 28.6%
(Fleischmann 2021). Neonatal sepsis may be categorised as early onset (day of life 0–3) or 
late onset (day of life 4 or later) (Dong 2015). Early-onset sepsis is associated with 
acquisition of infection from the mother, mainly ascending from the cervix, or less 
commonly via hematogenous or transplacental spread. Late-onset sepsis (LOS) is 
attributed to organisms acquired from the environment, including coagulase-negative 
staphylococci (CoNS), Staphylococcus aureus, Enterobacterales, and Pseudomonas
species (Dong 2015, Shane 2017). Empirical antibiotic treatment of LOS is typically 
guided by the antimicrobial resistance patterns of bacterial isolates commonly detected in 
the neonatal intensive care unit or in community settings. Given the increasing resistance 
among pathogens, alternative antibiotic treatments are needed.
1.1.2
Study drug
Ceftobiprole 
medocaril2
is 
the 
water-soluble 
prodrug 
of
ceftobiprole, 
an 
advanced-generation intravenous (IV) cephalosporin with bactericidal activity against a 
broad spectrum of Gram-positive (including CoNS and methicillin-resistant S. aureus
[MRSA]) and Gram-negative (including Enterobacterales and P. aeruginosa) pathogens.
Ceftobiprole medocaril is approved for the treatment in adults of hospital-acquired 
pneumonia (excluding ventilator-associated pneumonia) and community-acquired 
pneumonia in many European and non-European countries. It is currently under 
investigation to support a New Drug Application in the United States for the treatment in 
adults of acute bacterial skin and skin structure infections (ABSSSIs) and S. aureus
bacteremia, including right-sided infective endocarditis.
In the context of the agreed European Paediatric Investigation Plan, three pediatric clinical 
studies were completed including a study to evaluate the single-dose safety and 
pharmacokinetics (PK) of ceftobiprole in neonates and infants up to 3 months of age. The 
purpose of the current study is to evaluate the safety, PK and efficacy of ceftobiprole, which 
may be combined with ampicillin and/or an aminoglycoside, in neonates and infants up to 
3 months with LOS.
                                                
2 Unless referring specifically to the prodrug, the term ‘ceftobiprole’ is used throughout the remainder of this protocol, 
and all doses are of ceftobiprole equivalents
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Ceftobiprole medocaril
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Version 5.0
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1.2
Nonclinical studies with ceftobiprole
A comprehensive summary of nonclinical studies is provided in the Investigator’s 
Brochure (IB).
1.2.1
Nonclinical pharmacodynamics and activity of ceftobiprole
Dose fractionation studies showed that the time above the minimum inhibitory 
concentration (T > MIC) is the pharmacokinetic-pharmacodynamic (PK-PD) index that 
correlated best with ceftobiprole activity, which is consistent with the beta-lactam class of 
antibiotics. In a neutropenic mouse thigh infection model, the %fT > MIC values 
required for the bacteriostatic doses were 14 to 28% for S. aureus (including MRSA) and 
Streptococcus pneumoniae, and 36 to 47% for Enterobacterales and P. aeruginosa
(Craig 2008). The mean %fT > MIC for the 2-log kill dose for the strains of S. pneumoniae
and S. aureus was 26% and 29%, respectively, while for the strains of Enterobacterales it 
was 65%. Ceftobiprole showed activities in the lung model similar to those in the thigh 
model.
The probability of target attainment was estimated by Monte Carlo simulation based on 
data from 150 adult subjects enrolled in Phase 1 and 2 studies analysed by using population 
PK modelling (Lodise 2007). For ceftobiprole 500 mg q8h administered as a 2-hour 
IV infusion, the probabilities of achieving 40% and 60% fT > MIC exceeded 90% for MICs 
< 4 and < 2 µg/mL, respectively. The probability of achieving a nearly maximal 
bactericidal effect (50% fT > MIC) exceeded 90% for S. aureus (including MRSA). For 
Gram-negative pathogens, the probability of achieving a nearly maximal bactericidal effect 
(60% fT > MIC) exceeded 90% for non-AmpC-producing isolates. This dose regimen was 
selected for the Phase 3 studies in adults with pneumonia and adults with ABSSSIs.
1.2.2
Nonclinical pharmacokinetics
In animal PK, toxicological, and infection model studies, IV ceftobiprole medocaril was 
rapidly hydrolyzed in plasma to the active moiety ceftobiprole by multiple enzymes,
including plasma esterases, and also non-enzymatically. The volume of distribution of 
ceftobiprole was restricted to the extracellular compartment, and its elimination occurred 
predominantly by passive glomerular filtration of unchanged ceftobiprole. The beta-lactam 
open-ring was the main metabolic product.
In rats, excretion was almost complete within 4 days after IV administration of 
ceftobiprole medocaril. Penetration of ceftobiprole into lungs and brain in infected animals 
was demonstrated.
Based on cytochrome P450 inhibition data, the potential of ceftobiprole to exhibit 
clinically relevant drug-drug interactions is small. Protein binding of ceftobiprole in 
plasma of rats, rabbits, marmosets, cynomolgus monkeys, and dogs was low 
(approximately 10% to 45%) and concentration-independent. Plasma protein binding in 
humans was also low (approximately 16%) and concentration-independent.
Toxicokinetic monitoring during toxicity studies in rats, rabbits, marmosets, cynomolgus 
monkeys, and dogs demonstrated high and approximately dose-proportional exposures to 
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ceftobiprole in all species, exceeding the expected human therapeutic exposure at the 
no-observed-adverse-effect level (NOAEL). There were no relevant indications of 
accumulation, differences related to sex, or time-dependent PK.
In neonates and juveniles male and female rats administered daily from Day 1 post-partum
until Day 49, which covers the human age range from neonates up to teenagers, 
dose-proportional exposure of the pups and decreased half-life and exposure to ceftobiprole 
with increasing age was demonstrated, as a consequence of increased renal clearance. 
There were no gender-differences. This study provides a safety margin of 2 to 6 for 
pediatric patients (neonates up to < 18 years) with the optimized dosing regimens.
1.2.3
Nonclinical toxicology
The toxicological profile of ceftobiprole was characterised in an extensive repeated-dose 
toxicity program that included systemic toxicity studies up to 13 weeks in rats, dogs and 
primates; reproductive toxicity; genotoxicity; local tolerability; and special studies to 
address the antigenic, phototoxic and nephrotoxic potential. In addition, juvenile toxicity 
was assessed in rats.
In rats, the primary targets of toxicity were the kidneys and the infusion site. Signs of 
vascular irritation at the IV infusion site were likely related to the large size of the catheter 
relative to that of the venous lumen. Vascular irritation by the test article was largely 
confined to the region of the vein damaged by the catheter, with little or no effect distal to 
the infusion site where the vein was exposed to the test article but not to the catheter. 
Toxicity to the kidneys was observed at doses ≥250 mg/kg, and was associated with the 
precipitation of drug-like material in the distal part of the nephron.
In dogs, reddening of the skin and mucous membranes was attributed to histamine release. 
No other relevant findings were observed.
In marmosets, thromboembolic effects secondary to infusion site reactions were observed, 
including thrombus formation at the catheter tip. Signs of vascular irritation at the 
IV infusion site were consistent with respective effects noted in rats, and were likely related 
to technical challenges inherent to chronic IV dosing in small animals. Findings in the 
kidneys were reversible and not associated with microscopic lesions. There were 
no indications of kidney toxicity related to precipitation as seen in rats.
Ceftobiprole medocaril was neither teratogenic nor embryotoxic in rats or cynomolgus 
monkeys, and had no effect on fertility and early embryonic development in rats. In a 
pre- and post-natal development study in rats, slight maternal toxicity was seen at high 
doses, but there were no direct effects on pups.
No mutagenic potential was seen in the Ames test or in the Chinese hamster ovarian assay.
Ceftobiprole medocaril exhibited low irritancy potential in rabbit local tolerance studies. 
No phototoxic potential was seen, and no hemolysis or precipitation was observed at 
concentrations ≤1.25%.
The toxicity of ceftobiprole medocaril in neonatal and juvenile rats was investigated in a 
study with 7-week once daily subcutaneous administration starting on Day 1 post-partum. 
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At the highest dose of 250 mg/kg/day (187.5 mg/kg/day ceftobiprole), effects on clinical 
condition and reduced body weight prior to weaning were seen. Differences in crown to 
rump and bone measurements were considered related to the lower body weight. Gross 
pathological and histopathological changes at the injection site were noted, and 
microscopic changes in the kidneys were seen at the end of treatment. Based on these 
findings, the NOAEL in juvenile rats was 100 mg/kg/day (75 mg/kg/day ceftobiprole).
In summary, the nonclinical toxicology profile of ceftobiprole is consistent with that seen 
with antibiotics of the beta-lactam class, and the observations in juvenile animals were 
similar to those seen in adult animals.
1.3
Clinical studies with ceftobiprole
The ceftobiprole clinical development program includes 32 completed studies: 21 Phase 1 
studies in adult subjects, two Phase 1 studies (CSI-1006 and BPR-PIP-001) in pediatric
patients, two Phase 2 studies in adult patients, five Phase 3 studies in adult patients, and 
one Phase 3 study (BPR-PIP-002) in pediatric patients.
One Phase 3 study (BPR-CS-009) in adult patients with S. aureus bacteremia is currently 
ongoing (Hamed 2020).
1.3.1
Completed Phase 3 clinical studies in adult patients
Table 1 gives an overview of key completed Phase 3 clinical studies in adult patients.
Table 1
Key completed Phase 3 clinical studies in adult patients
Study number /
NCT number
(Reference)
Study title
Number of patients
Study start 
Study end
BAP248/307 /
NCT00210964
(Awad 2014)
A Phase 3, randomized, double-blind study of 
ceftobiprole medocaril versus linezolid plus 
ceftazidime in the treatment of nosocomial 
pneumonia
N=781
Ceftobiprole (n=391) 
Comparator (n=390)
06 Apr 2005 
22 May 2007
CAP-3001 /
NCT00326287
(Nicholson 2012)
Randomized, double-blind, multicenter study of 
ceftobiprole medocaril versus ceftriaxone 
with/without linezolid in treatment of subjects 
hospitalised with community-acquired 
pneumonia
N=638
Ceftobiprole (n=314) 
Comparator (n=324)
05 Jun 2006 
19 Jul 2007
BPR-CS-008 /
NCT03137173
(Overcash 2021)
A randomized, double-blind, multicenter study to 
establish the safety and efficacy of ceftobiprole 
medocaril compared with vancomycin plus 
aztreonam in the treatment of acute bacterial skin 
and skin structure infections
N=679
Ceftobiprole (n=335) 
Comparator (n=344)
19 Feb 2018 
22 Apr 2019
In studies BAP248/307, CAP-3001, and BPR-CS-008, ceftobiprole was administered as a 2-hour 500 mg IV infusion 
every 8 hours.
In all completed Phase 3 studies in adult patients, the non-inferiority of ceftobiprole to 
comparator antibiotics was demonstrated within the pre-specified non-inferiority margin 
for the primary efficacy endpoint in each study.
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Safety findings in the ceftobiprole clinical development program are consistent with the 
cephalosporin class effects and the underlying disease. Overall, treatment with ceftobiprole 
is well tolerated, with a manageable AE profile.
1.3.2
Completed studies in pediatric patients
Table 2 outlines completed clinical studies in pediatric patients.
Table 2
Completed clinical studies in pediatric patients
Study number / 
NCT number
(Reference)
Study title
Phase Number of patients
Study start
Study end
CSI-1006 / 
NCT01026636
(Rubino 2021a)
An open-label study to evaluate the 
single-dose pharmacokinetics and safety 
of ceftobiprole in pediatric subjects ≥3 
months to < 18 years of age undergoing 
treatment with systemic antibiotics
1
N=64
08 Nov 2007 
02 Apr 2010
BPR-PIP-001 / 
NCT03439124
(Rubino 2021b)
An open-label study to evaluate the 
single-dose pharmacokinetics and safety 
of ceftobiprole in neonate and infant 
patients aged up to 3 months undergoing 
treatment with systemic antibiotics
1
N=15
22 Nov 2016 
07 Jul 2020
BPR-PIP-002 / 
NCT02527681
(Bosheva 2021)
A multicenter, randomized, Investigator-
blind, active-controlled study to evaluate 
the safety, tolerability, pharmacokinetics 
and efficacy of ceftobiprole versus 
intravenous standard-of-care 
cephalosporin treatment with or without 
vancomycin in pediatric patients aged 
from 3 months to less than 18 years with 
hospital-acquired pneumonia or 
community-acquired pneumonia 
requiring hospitalisation
3
N=138 
Ceftobiprole (n=94) 
Comparator (n=44)
27 Nov 2017 
16 Mar 2020
1.3.2.1
Study CSI-1006
The primary objective of study CSI-1006 was to characterise the PK of ceftobiprole when 
administered as a 2-hour single-dose infusion in pediatric patients aged ≥3 months to 
< 18 years, who required therapeutic or prophylactic therapy with systemic antibiotics. The 
secondary objective was to evaluate the safety and tolerability of ceftobiprole in this study 
population.
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This was a multicenter, open-label, single-dose, Phase 1 study that enrolled 64 pediatric
patients in the following four age groups with documented or presumed, or at risk for, 
bacterial infections, and receiving systemic antibiotic therapy:

3 months to < 2 years (18 patients, 15 mg/kg)

2 years to < 6 years (15 patients, 15 mg/kg)

6 years to < 12 years (15 patients, 10 mg/kg)

12 years to < 18 years (16 patients, 7 mg/kg)
1.3.2.1.1
Pharmacokinetic results
Of the 62 patients who completed the study, 61 were included in the descriptive statistics 
of the ceftobiprole plasma concentrations, and 55 were included in the estimation of the 
plasma PK and exploratory PD parameters.
Overall, at the doses administered to patients aged < 12 years (15 mg/kg for patients aged 
< 6 years and 10 mg/kg for patients aged 6 years to < 12 years), the single-dose PK were 
generally within the range of what was previously observed in healthy adult subjects after 
a single ceftobiprole 500 mg dose. At the dose administered to patients aged 12 years to 
< 18 years (7 mg/kg, up to a maximum of 500 mg), the systemic exposure was substantially 
lower than that achieved in adults after a single ceftobiprole 500 mg dose.
1.3.2.1.2
Safety results
The safety assessments in this pediatric study showed that single-dose administration of 
ceftobiprole was safe and well tolerated by patients aged ≥ 3 months to < 18 years. No new 
or unexpected safety signals associated with ceftobiprole were detected.
1.3.2.2
Study BPR-PIP-001
The primary objective of study BPR-PIP-001 was to characterise the PK of ceftobiprole 
when administered as a 4-hour single-dose (7.5 mg/kg) infusion in neonates and infants 
aged ≤ 3 months. The secondary objective was to evaluate the safety and tolerability of 
ceftobiprole in this study population.
This was a multicenter, open-label, single-dose, Phase 1 study that planned to enroll 
45 patients who had documented, or were presumed to be at risk of, bacterial infections, 
and who were already receiving systemic antibiotic therapy. This study enrolled 15 term 
neonates (gestational age ≥37 weeks).
1.3.2.2.1
Pharmacokinetic results
While all 15 patients enrolled in the study had measurable plasma concentrations, 
two patients had insufficient PK data for the non-compartmental analysis, and were 
therefore excluded from the PK analysis population.
Overall, exposure to the active moiety ceftobiprole was substantially higher than that for 
the prodrug ceftobiprole medocaril and the open-ring metabolite. The median maximum 
plasma concentration (Cmax) was highest for ceftobiprole (11.2 μg/mL) compared to 
ceftobiprole medocaril (0.107 μg/mL) and the open-ring metabolite (0.644 μg/mL). 
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Ceftobiprole time to maximum concentration was reached at the end of infusion (i.e., at 
4 hours) in all patients.
1.3.2.2.2
Safety results
The safety assessments in this pediatric study showed that single-dose administration of 
ceftobiprole at 7.5 mg/kg was safe and well tolerated by the neonate and infant population 
aged ≤3 months. No new or unexpected safety signals associated with ceftobiprole were 
detected.
1.3.2.3
Study BPR-PIP-002
The primary objective of study BPR-PIP-002 was to evaluate the safety profile of 
ceftobiprole in pediatric patients aged 3 months to < 18 years with hospital-acquired 
bacterial pneumonia (HABP) or community-acquired bacterial pneumonia (CABP)
requiring hospitalisation and IV antibiotic therapy.
The secondary objectives were to characterise the PK of ceftobiprole and to evaluate the
efficacy 
of 
ceftobiprole 
versus 
IV 
standard-of-care 
cephalosporin 
treatment 
(± vancomycin) in this patient population.
This was a multicenter, randomized (2:1), Investigator-blind, active-controlled study that 
enrolled 138 patients (94 in the ceftobiprole group and 44 in the comparator group).
Patients randomized to ceftobiprole received IV infusions every 8 hours (q8h) at 
ageadjusted doses and infusion durations as follows:

3 months to < 2 years (12 patients, 20 mg/kg as 4-hour infusions)

2 years to < 6 years (37 patients, 20 mg/kg as 2-hour infusions)

6 years to < 12 years (27 patients, 15 mg/kg as 2-hour infusions)

12 years to < 18 years (18 patients, 10 mg/kg as 2-hour infusions)
1.3.2.3.1
Pharmacokinetic results
The PK population comprised 33 patients who received at least one dose of ceftobiprole 
and had at least one ceftobiprole plasma concentration measurement obtained. Of these, 
plasma concentration-time data were available for 29 patients. Exposure to ceftobiprole 
was substantially higher than that for the prodrug ceftobiprole medocaril and the open-ring 
metabolite. Ceftobiprole peaked at the end of infusion (4 hours for patients < 2 years and 
2 hours for all other age groups).
In general, patients under 6 years of age (i.e., those who received ceftobiprole 20 mg/kg 
q8h) had higher ceftobiprole exposure and slightly longer half-life compared to patients 
aged 6 years or older. Mean Cmax and area under the plasma concentration-time curve 
time zero to tau estimates were ~40% greater and half-life was ~16% longer in patients 
aged under 6 years compared to those 6 years or older (Cmax: 33.3 versus 23.7 µg/mL;
AUCtau: 108 versus 77.6 h.µg/mL, respectively).
1.3.2.3.2
Safety results
The safety and tolerability of ceftobiprole in this study were consistent with the established 
safety profile for ceftobiprole in adults and with those of the cephalosporin class of 
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antibiotics. No new or unexpected safety signals associated with ceftobiprole were 
detected.
1.3.2.3.3
Efficacy results
Although the study was not powered to compare efficacy, this was the only pediatric study 
to-date that included efficacy objectives. The early clinical response rate at Day 4 was 
slightly higher in the ceftobiprole group than in the comparator group for both the 
intent-to-treat (ITT) and Clinically Evaluable (CE) populations, and at the test-of-cure 
(TOC) visit, the clinical cure rate was above 90% in both treatment groups, although lower 
in the ceftobiprole group than in the comparator group for both populations.
1.3.3
Benefit-risk assessment
Data from the clinical studies show that ceftobiprole can be safely administered to adult 
and pediatric (neonates to < 18 years of age) patients. Completed Phase 3 studies 
demonstrated the safety and efficacy of ceftobiprole in the adult population for various 
indications (HABP, CABP, and ABSSSI), and in the pediatric population the safety and 
efficacy in patients with bacterial pneumonia were similar to those observed in adult 
patients. One Phase 3 study is currently ongoing to evaluate the safety and efficacy of 
ceftobiprole for the treatment of S. aureus bacteremia in adult patients.
The potential benefit to patients participating in this study is receiving antibiotic therapy 
for their infection, and the potential benefit of this study in general is the identification of 
a new addition to the available antibiotic therapy that is safe and effective for the treatment 
of LOS. It is possible that ceftobiprole will not prove to be a sufficiently effective treatment 
for LOS. This risk is mitigated by the optional addition of ampicillin and/or an 
aminoglycoside, by close monitoring of study patients, and by management with 
appropriate therapies as determined by the Investigator. The risk considerations for this 
study encompass the known and potential risks for ceftobiprole, as well as those risks 
associated with other treatments that may be administered (i.e., ampicillin and/or an 
aminoglycoside) as described in their respective prescribing information.
1.4
Study rationale
This study is part of a pediatric clinical development program to evaluate the use of 
ceftobiprole in patients < 18 years of age. Three completed pediatric studies, two Phase 1 
and one Phase 3, are described in Section 1.3.2. Study BPR-PIP-001 assessed the PK and 
safety of single-dose ceftobiprole in term neonates and infants aged ≤3 months.
LOS is a major cause of morbidity and mortality among neonates and young infants. 
Pathogens responsible for LOS include CoNS, S. aureus, Enterobacterales, and 
P. aeruginosa. Ceftobiprole has a broad-spectrum bactericidal activity against most of
these organisms, and was well tolerated in adult and pediatric clinical studies with a safety
profile consistent with that of available cephalosporins. Therefore, ceftobiprole has the
potential to become a therapeutic option in the treatment of LOS.
The purpose of this study is to assess the safety, tolerability, PK, and clinical effect of 
ceftobiprole, possibly combined with ampicillin and/or an aminoglycoside, in neonates and 
young infants up to 3 months of age with LOS.
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1.4.1
Summary of study design
This is a multicenter, open-label, single-arm, multiple-dose study of IV ceftobiprole in term 
and pre-term neonates and infants up to 3 months of age with LOS. Ceftobiprole may be 
combined with ampicillin and/or an aminoglycoside based on the Investigator’s judgement, 
local standard of care, and/or isolated or presumed pathogens. At least eight patients, at 
least two term (gestational age ≥37 weeks) and at least six pre-term (gestational age ≥24 
to 36 weeks), with post-natal age ranging from ≥3 days to ≤3 months will be enrolled.
The DSMB will review data on a regular basis to assess the safety of all patients enrolled 
in this study (see Section 3.4).
1.4.2
Study design rationale
A single-arm study design is based on practical considerations, mainly the feasibility of 
recruitment and study evaluation of pre-term and term neonates and young infants with 
LOS. As the incidence of LOS is inversely proportional to gestational age (i.e., almost 
double in pre-term neonates ≤32 weeks as compared to term neonates [Dong 2015]), twice 
as many pre-term neonates than term neonates will be enrolled.
Immediate administration of empiric antibiotic therapy with broad-spectrum bactericidal 
activity is critical in neonates and young infants with LOS, in order to prevent morbidity 
and decrease mortality. The optional combination with ceftobiprole of ampicillin and/or an 
aminoglycoside allows for maximal coverage of Gram-positive and Gram-negative 
pathogens of LOS, particularly during initial empiric treatment, and in accordance with 
local pathogen epidemiology and local standard of care.
1.4.3
Dose rationale
A three-compartment pediatric population PK model with linear elimination, clearance 
dependent on glomerular filtration, and other PK parameters scaled to body weight using 
a fitted coefficient consistent with allometric scaling principles, provided a robust fit to 
pooled data from studies CSI-1006, BPR-PIP-001, and BPR-PIP-002. Pre-defined model 
qualification procedures indicated that the final population PK model was expected to 
provide reliable estimates of ceftobiprole plasma exposure in the pediatric patients enrolled 
in these studies, and that the model was appropriate for the conduct of model-based 
simulations designed to identify appropriate ceftobiprole dosing regimens in pediatric 
patients (Rubino 2021a).
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Model-based simulation analyses conducted using the final population PK model suggest 
that the following dosing regimens are predicted to result in consistent ceftobiprole 
exposure and adequate PK-PD target attainment for pathogens with a ceftobiprole MIC of 
4 µg/mL (≥97.1% of the pediatric population with a %fT>MIC above 40%):

ceftobiprole 10 mg/kg infused over 2 hours and administered q12h in neonates and 
infants aged < 3 months with a body weight < 4 kg

ceftobiprole 15 mg/kg infused over 2 hours and administered q12h in neonates and 
infants aged < 3 months with a body weight ≥ 4 kg

ceftobiprole 15 mg/kg infused over 2 hours and administered q8h in infants and 
children aged ≥ 3 months to < 12 years with a body weight < 33 kg 

ceftobiprole 10 mg/kg infused over 2 hours and administered q8h in adolescents aged 
≥ 12 to < 18 years with a body weight < 50 kg 

ceftobiprole 500 mg infused over 2 hours and administered q8h in children with a body 
weight ≥ 33 kg and adolescents with a body weight ≥ 50 kg
Model-based simulations also indicated that the dose should be adjusted based on body 
weight or maximum allowable dose to avoid overly high exposures in the lightest infants 
(< 4 kg), children ≥ 33 kg, and adolescents ≥ 50 kg.
Extrapolation of the model to pre-term neonates and young infants was deemed appropriate 
given the dependence of ceftobiprole PK on glomerular filtration rate and body weight, 
which are both well described in this population. Glomerular filtration rate was assigned 
using a standard equation that assumed normal renal function, adjusted for age and body 
surface area using fat-free mass (Rhodin 2009). Body weight and height were assigned 
using a set of polynomial longitudinal growth equations, which define body weight and 
height over time based on gender, gestational age, and post-natal age (Troutman 2018).
Model-based simulation analyses to assist in the ceftobiprole dose selection for the 
treatment of LOS in pre-term and term neonates and young infants assessed several dose 
regimens before identification of an optimal regimen (Table 5). The optimal dose regimen, 
with dose adjustment according to gestational and post-natal ages, was predicted to result 
in a consistent ceftobiprole exposure and adequate PK-PD target attainment similar to those 
in adults and older pediatric patients. In general, the median predicted AUC0–24 values 
fall within the mean two standard deviations from the adult Phase 1 exposures from the 
multiple-ascending dose study. The 90% prediction intervals fall outside the range but 
remain acceptable. In contrast, ceftobiprole Cmax estimates were predicted to be lower 
than those observed in healthy adults, with the exception of the patients in the oldest 
gestational age group (≥ 37 weeks), which are similar to adults.
2
OBJECTIVES OF THE STUDY
2.1
Primary objective
To characterise the safety profile of ceftobiprole in term and pre-term neonates and infants 
up to 3 months of age with LOS.
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2.2
Secondary objectives
To assess in term and pre-term neonates and infants up to 3 months of age with LOS treated 
with ceftobiprole:

PK of ceftobiprole

Clinical response

All-cause mortality

Microbiological response
3
STUDY DESIGN
This is a multicenter, open-label, single-arm, multiple-dose study of IV ceftobiprole in term 
and pre-term neonates and infants up to 3 months of age with LOS. At least eight patients, 
at least two term (gestational age ≥ 37 weeks) and at least six pre-term (gestational age 
≥24 to 36 weeks), with post-natal age ranging from ≥ 3 days to ≤ 3 months will be enrolled
at approximately ten sites in Europe and USA, with additional sites and locations possible.
Study therapy consists of IV ceftobiprole medocaril for 3–10 days, which may be extended 
to 14 days if considered clinically necessary by the Investigator. Ceftobiprole may be 
combined with ampicillin and/or an aminoglycoside based on the Investigator’s judgement, 
local standard of care, and/or isolated or presumed pathogens. If added, the treatment 
duration of ampicillin and/or an aminoglycoside is at the discretion of the Investigator.
Each patient is expected to complete the study in approximately 5–7 weeks, including 
screening, an estimated treatment duration of 3–10 days with possible extension up to 
14 days, end-of-treatment (EOT) visit, TOC visit 7–14 days after last ceftobiprole dose, 
and a last follow-up (LFU) visit 28–35 days after last ceftobiprole dose.
Safety assessments will be done throughout the study. Specimens for microbiological 
assessment will be obtained as clinically indicated in accordance with local standard of 
care. Blood samples for PK analysis will be collected on Day 3. Efficacy outcomes will be 
assessed at the EOT, TOC, and LFU visits.
The DSMB will review data on a regular basis to assess the safety of all patients enrolled 
in this study (see Section 3.4).
3.1
Overview of study design and dosing regimen
An overview of the study design is provided in Figure 1.
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3.2
Endpoints
3.2.1
Primary endpoint
The primary endpoint is safety and tolerability in the Safety population, as assessed by 
AEs, SAEs, deaths, and discontinuations due to AEs during treatment with ceftobiprole 
and at the EOT, TOC, and LFU visits, as well as clinical laboratory tests, vital signs, and 
physical examination findings.
3.2.2
Secondary endpoints
Pharmacokinetics

Plasma levels of ceftobiprole, ceftobiprole medocaril, and the open-ring metabolite in 
the PK population
Efficacy

Clinical cure rate at the EOT and TOC visits (ITT and CE populations)

All-cause mortality through Day 28 (ITT population)

Microbiological eradication or presumed eradication rate at the EOT and TOC visits
(mITT and ME populations)

Improved signs and symptoms of LOS at the Day 3, EOT, and TOC visits (ITT and 
CE populations)
3.3
Treatment plan
3.3.1
Dose modifications
The intended dose of IV ceftobiprole may not be modified. As patients with moderate or 
severe renal impairment will be excluded, no need for dose adjustment is expected. Study 
drug may be discontinued at any time at the Investigator’s discretion (see Section 4.4). If a 
patient’s estimated glomerular filtration rate (using the Schwartz formula or other 
applicable formula) decreases to less than two-thirds of normal for the applicable age 
group, or urinary output decreases to < 0.5 mL/kg/h (measured over at least 8 hours) during 
study drug treatment, ceftobiprole administration should be stopped and the patient should 
be switched to standard of care treatment. If continuation of ceftobiprole is considered 
necessary by the Investigator based on an individual medical benefit-risk assessment for a 
patient, then the implementation of real-time plasma level assessments of ceftobiprole is 
recommended.
If added, any dose modification for ampicillin and/or an aminoglycoside is at the discretion 
of the Investigator in accordance with local standard of care; aminoglycoside dose 
modification may be based on renal function or therapeutic drug monitoring.
3.3.2
Duration of treatment
The target treatment duration with IV ceftobiprole (administered as a 2-hour IV infusion 
according to the schedule in Table 5) is 3–10 days, which may be extended to 14 days if 
considered clinically necessary by the Investigator.
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If added, the treatment duration of ampicillin and/or an aminoglycoside is at the discretion 
of the Investigator in accordance with local standard of care.
3.3.3
Missed-dose management
If one or more doses of IV ceftobiprole are missed, no additional doses are to be 
administered other than in accordance with the schedule provided in Table 5. In such cases, 
the Investigator may consider exclusion of the patient from the study after discussion with 
the medical monitor.
For ampicillin and/or an aminoglycoside, if added, management of missed doses is at the 
discretion of the Investigator in accordance with local standard of care.
3.3.4
Overdose
There is no available information on overdose with ceftobiprole in humans. The highest 
daily dose administered in Phase 1 clinical studies in adults was 3,000 mg (1,000 mg q8h). 
The range of doses administered in the Phase 1 pediatric study BPR-PIP-001 was 17.6 to 
37.5 mg (5.8 to 7.5 mg/kg) in neonates and infants aged ≤ 3 months.
If an overdose occurs, it should be treated symptomatically. Symptomatic treatment may
include 
treatment 
of 
gastrointestinal 
or 
central-nervous-system 
side 
effects 
(e.g., convulsions) which may be related to peak ceftobiprole plasma concentrations. 
Monitoring of plasma levels of ceftobiprole should therefore be considered. Ceftobiprole 
half-life is approximately 3.5 hours and plasma concentrations can be reduced by 
haemodialysis.
For ampicillin and/or an aminoglycoside, if added, see the respective local labels.
3.4
Data and Safety Monitoring Board
The composition, roles and responsibilities, and schedule of data review meeting of the 
DSMB are described in the DSMB Charter. The DSMB will review patient data on an 
ongoing basis to determine whether any safety concerns are observed, and whether the 
study should be allowed to continue.
3.5
Definition of the end of the study
The end of the study is defined as the completion of the last study-related contact with the 
last participant in the study.
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4
STUDY POPULATION
4.1
Target population
Term (gestational age ≥37 weeks) and pre-term (gestational age ≥24 to 36 weeks) 
neonates and infants, with post-natal age ranging from ≥3 days to ≤3 months, meeting all 
of the inclusion criteria and none of the exclusion criteria are eligible for enrollment in this 
study.
4.2
Inclusion criteria
For inclusion in the study, patients must meet all of the following criteria:
1. Informed consent from parent(s) or other legally-acceptable representative (LAR) to 
participate in the study
2. Male or female, with a gestational age of ≥24 weeks and a post-natal age ranging from 
≥3 days to ≤3 months
3. Diagnosis of documented or presumed bacterial LOS requiring administration of IV
antibiotic treatment. 
Patients must present with at least two of the clinical criteria and at least one of the 
laboratory criteria listed below:
Clinical criteria (at least two):
a) Hypothermia (< 36.6 °C / 97.9 °F rectal; < 36.5 °C / 97.7 °F axillary; 
< 35.5 °C / 95.9 °F oral; < 35.8 °C / 96.4 °F tympanic) OR fever 
(> 38.0 °C / 100.4 °F rectal; > 37.5 °C / 99.5 °F axillary; > 37.5 °C / 99.5 °F oral; 
> 38.0 °C / 100.4 °F tympanic)
b) Bradycardia (< 100 beats/minute awake; < 80 beats/minute asleep) OR 
tachycardia (> 205 beats/minute awake; > 160 beats/minute asleep)
c) Urinary output 0.5–1 mL/kg/h OR hypotension OR signs of impaired peripheral 
perfusion, such as mottled skin, moist and cold skin, finger to forearm 
temperature gradient, or increased capillary refill time
d) Petechial rash OR sclerema neonatorum
e) New onset or worsening of apnea episodes OR tachypnea episodes OR increased 
oxygen requirements OR requirement for ventilatory support (excluding 
underlying ventilator-associated pneumonia; see exclusion criteria)
f)
Feeding intolerance OR poor sucking OR abdominal distension
g) Irritability
h) Lethargy
i)
Muscular hypotonia
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Laboratory criteria (at least one):
a) White blood cell count ≤4.0 × 109/L OR ≥20.0 × 109/L
b) Immature to total neutrophil ratio > 0.2
c) Platelet count ≤100 × 109/L
d) C-reactive protein > 15 mg/L OR procalcitonin ≥2 ng/mL OR Interleukin-6
(IL-6) elevated according to local laboratory thresholds
e) Hyperglycemia OR hypoglycemia
f)
Metabolic acidosis
4. Sufficient vascular access to receive study drug and to allow blood sampling at a site
separate from the study drug infusion line
4.3
Exclusion criteria
Patients who meet any of the following criteria must be excluded from the study:
1. History of a previous clinically relevant hypersensitivity or serious adverse reaction
to beta-lactam antibiotics, or to aminoglycosides if intended to be used in
combination with ceftobiprole
2. Viral, fungal, or parasitic pathogen as the sole reason for infection, OR known
resistance of the causative bacterial pathogens to ceftobiprole
3. Refractory septic shock not responding to 60 minutes of vasopressor treatment within
48 hours before enrollment
4. Proven ventilator-associated pneumonia
5. Proven central nervous system infection (e.g., meningitis, brain abscess)
6. Proven osteomyelitis, infective endocarditis, or necrotising enterocolitis
7. Impaired renal function or known significant renal disease, as evidenced by an
estimated glomerular filtration rate (using the Schwartz formula or other applicable
formula) calculated to be less than 2/3 of normal for the applicable age group, OR
urinary output < 0.5 mL/kg/h (measured over at least 8 hours), OR requirement for
dialysis
8. Significant laboratory abnormalities, including:
a) Hematocrit < 20%
b) Absolute neutrophil count < 0.5 × 109/L
c) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 8 × the
age-specific upper limit of normal
9. Progressively fatal underlying disease, or life expectancy < 30 days
10. Documented history of convulsions
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11. Severe immunodeficiency (congenital or acquired)
12. Use of systemic antibacterial therapy for longer than 72 hours within 7 days before
start of study medication
13. Any condition including antepartum / peripartum factors or procedures, which would, 
in the opinion of the Investigator, make the patient or caregiver unsuitable for the 
study, putting the patient at risk or compromising the quality of the data
14. Participation in another clinical study with an investigational product within 30 days 
of enrollment in the current study
4.4
Patient withdrawal
Parents or LARs may voluntarily withdraw consent for the patient’s participation in the 
study at any time for any reason. The Investigator may also withdraw a patient from the 
study for reasons which may include adverse reactions (including but not limited to 
allergic-type reactions, infusion site reactions, or clinically relevant changes in vital signs), 
apparent infant distress, or at the request of the parent or the LAR.
If patients are withdrawn, the date of withdrawal and the reason for withdrawal must be 
recorded in the electronic case report form (eCRF).
If a patient who has received at least one dose of study drug discontinues treatment at any 
time for reasons other than withdrawal of consent, every effort must be made to complete 
the EOT and LFU visits.
Reasons for discontinuation of study treatment must be recorded, and may include:

Adverse event

Abnormal laboratory value

Abnormal test procedure result

Intercurrent illness that prevents further administration of treatment

Diagnosis of any of the following conditions after enrollment in the study: 
ventilator-associated pneumonia, meningitis, brain abscess, osteomyelitis, infective 
endocarditis, or necrotising enterocolitis

Confirmation of reduced susceptibility to ceftobiprole of any pathogen isolated

Death

Withdrawal of consent

Withdrawn from the study at the Investigator’s discretion

Protocol deviation/non-compliance

Lost to follow-up

Administrative reasons
The reasons for discontinuation of study treatment must be recorded in the eCRF.
For all patients who discontinue study treatment, AE monitoring must be continued up to 
and including the LFU visit. For patients who fail to return for the LFU visit, the 
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Investigator must make every effort to contact the parent(s) or LAR (by telephone or mail 
correspondence). The outcome of this contact must be documented by the Investigator and 
filed in the Investigator Site File (ISF).
4.5
Replacement of patients
Patients failing screening procedures are to be replaced.
Patients who for any reason discontinue participation in the study after enrollment but prior 
to receiving the first dose of study drug are to be replaced.
Patients who for any reason discontinue participation in the study after receiving the first 
dose of study drug are not to be replaced.
4.6
Study discontinuation
The Sponsor reserves the right to temporarily or permanently discontinue the study at any 
time. Reasons for study discontinuation may include, but are not limited to:

Safety concerns (an identified risk or potential risk that could have an impact on the
benefit-risk balance of the product or implications for public health).

Poor enrollment.

Non-compliance with the protocol, Good Clinical Practice (GCP) guidelines, or other
regulatory requirements by the Investigator(s).

Request to discontinue the study by a Health Authority.

Enrollment to either study group (term or pre-term) will be discontinued after the
minimum number of patients to the group is reached. Enrollment to the other group will
continue until the minimum required number of patients is also reached.
The Sponsor will ensure that all Investigators and the appropriate Health Authorities are 
promptly informed if the study is suspended or terminated prematurely for safety reasons. 
In the event of such a termination, the Investigator will also promptly notify the IEC/IRB.
5
SCHEDULE OF ASSESSMENTS AND PROCEDURES
5.1
Summary of schedule of assessments
Table 3 presents a summary of the schedule of assessments to be performed from screening 
through the LFU visit.
Adverse events will be monitored on an ongoing basis and at each study visit, beginning 
on study Day 1. Adverse event monitoring must be continued up to the LFU visit
(see Section 7.4).
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Table 3
Schedule of assessments
Visit name
Screening /
Baseline
Active treatment
(Days 1, 2, 3, 410, and, if applicable, 11–14)1
EOT2
TOC
LFU3
Assessment window
Day −2 to
Day 1
Day 1
Day 2
Day 3
Days 
410
Days 1114,
only if 
applicable
Within 24 h
after
last dose
7–14
days
after
last dose
28–35
days
after
last dose
Written informed consent4
X
Inclusion/exclusion criteria
X
Medical history and demographics (including 
antepartum/peripartum period)
X
Prior medications5
X
Physical examination6
X
X6
X
X
Length
X
Weight7
X
X7
X
X
X
X
X
X
Vital signs and pulse oximetry8
X
X8
X8
X8
X8
X8
X
X
Signs and symptoms of LOS
X
X
X
X
X
X
X
X
Hematology, blood chemistry, urinalysis9
X
X9
X
X9
Anion gap, C-reactive protein, procalcitonin, 
IL-6 (optional)10
X10
X10
Urine output11
X11
X11
Imaging tests (optional)12
X12
X12
Microbiological sampling13
X13
X13
Overall clinical outcome assessment14
X
X
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Microbiological outcome assessment15
X
X
Study drug administration1
X
X
X
X
X1
Concomitant medications16
X
X
X
X
X
X
X
X
Concomitant medical procedures
X
X
X
X
X
X
X
X
Adverse event assessment17
X
X
X
X
X
X
X
X
PK blood sampling18
X
Aminoglycoside monitoring, if applicable19
X19
Survival status20
X
Relapse assessment
X
EOT=end of treatment; LFU=last follow-up; LOS=late-onset sepsis; PK=pharmacokinetics; TOC=test of cure.
1 The duration of treatment with ceftobiprole (i.e., study drug) is 3–10 days, but this may be extended to 14 days if considered clinically necessary by the Investigator if in accordance 
with local standard of care (see Section 3.3.2). The duration of treatment with ampicillin and/or an aminoglycoside antibiotic, if given in combination with ceftobiprole, is at the 
Investigator’s judgment in accordance with local standard of care (i.e., may be terminated at any time if considered appropriate by the Investigator) and must be recorded.16
2 EOT assessment is to be performed on the day of last study drug administration, or as a separate visit within 24 hours of last study-drug administration. 
3 The LFU visit may be performed by telephone contact if the patient has been discharged from the hospital, unless an examination is needed to evaluate relapse or abnormalities 
recorded during the TOC visit (see Section 5.2.5).
4 Written informed consent (or, in the event of an emergency, verbal informed consent followed by written consent as soon as the situation allows) must be obtained before any 
study-specific procedures or assessments take place (see Section 10.2).
5 Prior medications taken within 7 days before the first dose of study drug is to be recorded. For patients who are being breastfed, all medications taken by the lactating mother within 
3 days before the first dose of study drug is to be recorded.
6 Complete physical examination is to be performed at Screening, the EOT visit, and the TOC visit. Complete or targeted physical examinations focusing on changes from baseline 
is to be performed during the active treatment period at the discretion of the Investigator as clinically indicated in accordance with local standard of care (see Section 5.5.2).
7 Body weight on Day 1, which is to be used for Day 1 dose calculation, should be obtained within 12 hours prior to the first dose of study drug. From Day 2 until the last day of 
study treatment, the dose should be calculated based on the patient’s first body weight of the day (see Section 5.5.2).
8 Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures) and pulse oximetry must be recorded within 30 minutes before the 
first study drug administration, and then three times daily during the active treatment period; if continuously monitored, the highest body temperature, respiratory rate, and pulse 
rate, and the lowest systolic and diastolic blood pressures and oxygen saturation obtained during an 8-hour period, are to be recorded. Vital signs and pulse oximetry must also be 
obtained at the EOT and the TOC visits (see Section 5.5.3).
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9 Hematology, blood chemistry, and urinalysis are to be performed at baseline and at the EOT visit. At all other visits, these laboratory evaluations are to be performed only if 
clinically indicated based on the Investigator’s judgment in accordance with local standard of care (for details, see Sections 5.2.2, 5.2.4, and 5.5.4).
10 Optional assessment of anion gap, C-reactive protein, procalcitonin, and IL-6 at any time from Screening until the end of active treatment, if considered clinically indicated by the 
Investigator in accordance with local standard of care.
11 If clinically indicated, measurement of urine output should be done over at least an 8-hour period. Use of a urinary catheter is based on the Investigator’s judgment in accordance 
with local standard of care. Urinary catheters are not required for the purposes of this study (see Sections 5.2.1, 5.2.2).
12 Results of imaging tests (e.g., chest X-ray, ultrasound, CT scan, MRI) performed as part of the patient’s standard clinical care within 72 hours before start of study treatment are to
be recorded in the eCRF. From Day 1 up to and including the TOC visit, imaging tests are to be performed if clinically indicated based on the Investigator’s judgment in accordance 
with local standard of care.
13 Screening/baseline and post-baseline blood specimens and any other specimens (e.g., urine, cerebrospinal fluid) for microbiological evaluation should be obtained as clinically 
indicated in accordance with local standard of care and as described in the Laboratory Manual.
14 At the EOT and TOC visits, the Investigator must rate the overall clinical outcome as ‘clinical cure’, ‘clinical failure’, or ‘unevaluable’.
15 Microbiological outcome is to be assessed only in patients with valid pathogens identified at the Screening/Baseline visit.  For details, see Section 5.6.3.
16 All medications taken after the recording of prior medications, and medications continued after enrollment in the study, should be recorded as concomitant therapy. For patients 
who are being breastfed, all concomitant medications taken by the lactating mother up to the LFU visit are to be recorded.
17 See Section 7.4.
18 PK blood sampling is to be done on treatment Day 3 as described in the Laboratory Manual: pre-dose before the first ceftobiprole infusion, at 2 hours (end of infusion), 4 hours, 
and 8 hours. PK samples should not be taken from the infusion lines. See Section 5.7.
19 In the event of combination treatment with an aminoglycoside, monitoring of aminoglycoside blood levels and monitoring for ototoxicity and/or nephrotoxicity should be performed 
according to recommendations in the local label and local standard of care.
20 Survival status is to be assessed.
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5.2
Study visits
Parent(s) or a LAR must provide written informed consent before any study-specific 
assessments or procedures are performed (see Section 10.2 for details).
5.2.1
Screening visit / Baseline (Day −2 to Day 1)
The following assessments and procedures will be performed at the screening visit (Day −2
to Day 1; see Table 3):

Medical history and demographics, including the antepartum/peripartum period
(see Section 5.3.1)

Review and recording of medications taken within 7 days before the first dose of study
drug. For patients who are being breastfed, medications taken by the lactating mother
within 3 days before the first dose of study drug will also be recorded.

Physical examination (see Section 5.5.2)

Length and body weight (see Section 5.5.2)

Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and
diastolic blood pressures) and pulse oximetry (see Section 5.5.3)

Signs and symptoms of LOS (see Section 5.6.4)

Local laboratory tests: results will be used for the assessment of inclusion/exclusion
criteria and throughout the study (for details, see Sections 4.2, 4.3, and 5.5.4).
Laboratory tests required as part of the screening process which have been performed
within 48 hours prior to the first dose of study drug do not need to be repeated,
regardless of whether they were performed before or after signing of the informed
consent form (ICF).

If clinically indicated, measurement of urine output (over at least an 8-hour period) in
patients hospitalised ≥8 hours before study drug dosing. Use of a urinary catheter is
based on the Investigator’s judgement in accordance with local standard of care.
Urinary catheters are not required for the purposes of this study.

Recording of results of imaging studies (e.g., chest X-ray, ultrasound, CT scan, MRI)
performed as part of the patient’s standard of care within 72 hours before the first dose
of study drug.

Collection of blood and other specimens for microbiological evaluation as clinically
indicated based on the Investigator’s judgement in accordance with local standard of
care (see Section 5.4)
The Investigator will review the results of the screening assessments and procedures, 
including results of laboratory tests, and all inclusion/exclusion criteria to ensure patient 
eligibility.
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5.2.2
Active treatment visits
The following assessments and procedures will be performed during study treatment visits
(Day 1 to Day 10 [or up to Day 14]; see Table 3):

Study drug administration should be initiated as soon as possible after enrollment. 
Ceftobiprole medocaril will be reconstituted and diluted for IV administration and 
administered as described in the Pharmacy Manual and in Section 6.6. If applicable, 
ampicillin and/or an aminoglycoside will be prepared and administered according to 
the manufacturer’s instructions and/or local standard of care. The dates and exact start 
and stop times of all ceftobiprole infusions, and if applicable, of all ampicillin and/or 
aminoglycoside infusions/injections must be recorded in the eCRF.

Physical examination: complete or brief physical examinations focusing on changes 
from baseline during the active treatment period will be performed at the discretion of 
the Investigator as clinically indicated in accordance with local standard of care
(see Section 5.5.2)

Body weight (see Section 5.5.2): body weight on Day 1, which will be used for Day 1 
dose calculation, should be obtained within 12 hours prior to the first dose of study 
drug. From Day 2 until the last day of study treatment, the dose should be calculated 
based on the patient’s first body weight of the day.

Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and 
diastolic blood pressures) and pulse oximetry must be recorded within 30 minutes 
before the first study drug administration, and then three times daily during the active
treatment period. If continuously monitored, the highest body temperature, respiratory 
rate, and pulse rate, and the lowest systolic and diastolic blood pressures and oxygen 
saturation obtained during an 8-hour period, will be recorded (see Section 5.5.3).

Signs and symptoms of LOS (see Section 5.6.4)

Local laboratory tests will be performed only if clinically indicated based on the 
Investigator’s judgement in accordance with local standard of care (see Section 5.5.4).

If clinically indicated, measurement of urine output (over at least an 8-hour period). 
Use of a urinary catheter is based on the Investigator’s judgement in accordance with 
local standard of care. Urinary catheters are not required for the purposes of this study.

Imaging studies (e.g., chest X-ray, ultrasound, CT scan, MRI) will be performed if 
clinically indicated based on the Investigator’s judgement in accordance with local 
standard of care.

Collection of blood and other specimens for microbiological evaluation as clinically 
indicated based on the Investigator’s judgement in accordance with local standard of 
care (see Section 5.4).

Review and recording of concomitant medications, including ongoing prior 
medications, and concomitant medical procedures, including ongoing prior procedures.

Adverse events must be monitored and recorded on an ongoing basis as outlined in 
Section 7.4.
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
PK blood sampling on Day 3: blood samples for measurement of ceftobiprole,
ceftobiprole medocaril, and open-ring metabolite concentrations will be collected
pre-dose and at 2 hours (end of infusion), 4 hours, and 8 hours, as described in detail in
the Laboratory Manual (see Section 5.4). PK samples should not be taken from the
infusion lines.

If applicable, determination of aminoglycoside blood levels and monitoring for
ototoxicity and nephrotoxicity should be performed according to the recommendations
provided in the local label and/or local standard of care.
5.2.3
End-of-treatment visit
The following assessments and procedures will be performed at the EOT visit (on the day 
of last study–drug administration or within 24 hours of the last dose of study drug; 
see Table 3):

Physical examination (see Section 5.5.2)

Body weight (see Section 5.5.2)

Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and
diastolic blood pressures) and pulse oximetry (see Section 5.5.3)

Signs and symptoms of LOS (see Section 5.6.4)

Local laboratory tests (see Section 5.5.4)

Collection of blood and other specimens for microbiological evaluation as clinically
indicated based on the Investigator’s judgement in accordance with local standard of
care (see Section 5.4)

Imaging tests (e.g., chest X-ray, ultrasound, CT scan, MRI) will be performed if
clinically indicated based on the Investigator’s judgement in accordance with local
standard of care.

Overall clinical outcome assessment: clinical cure, clinical failure, or unevaluable (see
Section 5.6.1)

Microbiological outcome assessment: eradication, presumed eradication, persistence,
presumed persistence, or unevaluable (see Section 5.6.3)

Review and recording of changes in concomitant medications and concomitant
procedures

Adverse events must be monitored and recorded as outlined in Section 7.4.
5.2.4
Test-of-cure visit
The following assessments and procedures will be performed at the TOC visit (7−14 days 
after the last dose of study drug; see Table 3):

Physical examination (see Section 5.5.2)

Body weight (see Section 5.5.2)

Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and
diastolic blood pressures) and pulse oximetry (see Section 5.5.3)
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
Signs and symptoms of LOS (see Section 5.6.5)

Local laboratory tests will be performed only if clinically indicated based on the
Investigator’s judgement in accordance with local standard of care (see Section 5.5.4)

Imaging tests (e.g., chest X-ray, ultrasound, CT scan, MRI) will be performed if
clinically indicated based on the Investigator’s judgement in accordance with local
standard of care.

Collection of blood and other specimens for microbiological evaluation as clinically
indicated based on the Investigator’s judgement in accordance with local standard of
care (see Section 5.4).

Overall clinical outcome assessment: clinical cure, clinical failure, or unevaluable
(see Section 5.6.1)

Microbiological outcome assessment: eradication, presumed eradication, persistence,
presumed persistence, or unevaluable (see Section 5.6.3)

Review and recording of changes in concomitant medications and concomitant
procedures

Adverse events must be monitored and recorded as outlined in Section 7.4.
5.2.5
Last follow-up visit
The following assessments and procedures will be performed at the LFU visit (28−35 days 
after the last dose of study drug; see Table 3). This visit can be done by telephone contact 
unless an examination is needed to evaluate relapse or abnormalities recorded during the 
TOC visit.

Review and recording of changes in concomitant medications and concomitant
procedures

Adverse events must be monitored and recorded as outlined Section 7.4.

Survival status

Relapse assessment: Deterioration of the clinical condition compared to the TOC
visit, microbiological recurrence, or the requirement for additional antimicrobial
therapy for LOS
5.3
Medical history and concomitant medications
5.3.1
Medical history
A full medical history, including relevant abnormalities, surgeries, diseases, or disorders,
must be obtained at Screening.
Medical history also includes any relevant worsening of a patient’s condition which occurs 
after consent, but prior to the start of first study-drug administration (see Section 7.2.1).
5.3.2
Prohibited concomitant medications

Systemic antibacterial therapy other than ampicillin and aminoglycosides
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5.3.3
Permitted concomitant medications

Ampicillin and/or an aminoglycoside based on the Investigator’s judgement, local 
standard of care, and/or isolated or presumed pathogens

Topical antibacterial medications

Acetaminophen or paracetamol

Nonsteroidal anti-inflammatory drugs and systemic steroids

Non-antibacterial standard-of-care medications
5.4
Microbiology assessments
Microbiological evaluation and outcome assessment may be based on blood samples, urine, 
cerebrospinal fluid, or any other suitable specimen samples.
If clinically indicated and performed as part of the patient’s regular medical care, blood is 
to be obtained for microbiological evaluation at the Screening visit/Baseline (if possible
before any antibiotics are administered), or at any time through to LFU visit. Cultures 
should be repeated in accordance with standard of care if a positive result is obtained, until 
sterilization is confirmed. Gram stain, culture/PCR, and organism identification are to be 
performed at the local or regional laboratory, as applicable. All isolates, regardless of 
specimen source, are to be sent to the central microbiology laboratory for final organism 
identification and study-specific susceptibility testing.
See the Laboratory Manual for procedures regarding the collection, processing, storage, 
and shipment of pathogens. Rules for the assessment of the validity of pathogens are 
described in the Statistical Analysis Plan (SAP).
5.5
Safety assessments
The Investigator will evaluate safety by AE monitoring, clinical laboratory tests, vital 
signs, and physical examination (see schedule of assessments; Table 3).
Safety assessments must be performed at intervals indicated in the schedule of assessments 
(Table 3). More frequent assessments may be performed at the Investigator’s discretion, if 
medically indicated.
Safety data will be reviewed by the Sponsor and by the DSMB (see Section 3.4).
5.5.1
Adverse event monitoring
See Section 7.4 for details regarding AE collection and management.
5.5.2
Physical examination
A complete physical examination will be performed at Screening and at the EOT and TOC 
visits in accordance with Table 3, and will include examination of general appearance, skin, 
head, neck, eyes, ears, nose, throat, cardiovascular system, thorax/lungs, abdomen, lymph 
nodes, extremities, and nervous system.
Complete or targeted physical examinations focusing on changes from baseline will be 
performed during the active treatment period at the discretion of the Investigator as 
clinically indicated in accordance with local standard of care.
Any clinically-significant physical change from baseline that occurs after first study-drug 
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administration must be reported as an AE (see Section 7.4).
A patient’s length will be measured only during the Screening visit.
Body weight will be measured at Screening, daily during the active treatment period, and at 
the EOT and TOC visits. The weight obtained within 12 hours prior to the first dose 
of study drug will be used to calculate the dose on Day 1. From Day 2 until the last day of 
study treatment, the dose should be calculated based on the patient’s first body weight 
of the day.
5.5.3
Vital signs and pulse oximetry
Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and 
diastolic blood pressures) and pulse oximetry must be recorded during all visits from 
Screening up to and including the TOC visit (Table 3). During the active treatment period, 
vital signs must be recorded within 30 minutes before the first study drug administration, 
and then three times daily; if continuously monitored, the highest body temperature, 
respiratory rate, and pulse rate, and the lowest systolic and diastolic blood pressures and 
oxygen saturation obtained during an 8-hour period, will be recorded.
5.5.4
Laboratory parameters and PK sampling
The local laboratory tests include haematology, blood chemistry and urine analysis 
(dipstick) parameters as per the schedule of assessments (Table 3) and Table 4. Additional 
testing may be performed whenever clinically indicated at the discretion of the Investigator. 
All samples for a given study site must be analysed by the same local laboratory throughout 
the study, as designated by the Investigator. The results are to be printed, signed and dated 
by the Investigator or his/her designee.
In the event of unexplained abnormal laboratory test values, the tests must be repeated and 
followed up until return to the normal range, stabilisation, and/or until an adequate 
explanation of the abnormality has been determined. When a clear explanation is 
established this must be recorded in the eCRF.
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Table 4
Local laboratory parameters
Mandatory at Screening and the EOT visit; optional at active treatment visits and the TOC visit:
Haematology
Blood chemistry
Urine analysis (dipstick)
Haematocrit
Red blood cell count
White blood cell count
Absolute and immature neutrophils
Platelets
ALT
AST
Bilirubin (total)
Creatinine
Sodium
Potassium
Bicarbonate
Blood
Glucose
Ketones
Leukocytes
Nitrite
pH
Protein
Optional at Screening and active treatment visits:
Blood chemistry
Anion gap
C-reactive protein
Procalcitonin
IL-6
EOT=end-of-treatment; ALT=alanine aminotransferase; AST=aspartate aminotransferase; TOC= test-of-cure.
Note: Optional blood tests may be performed at the discretion of the Investigator in accordance with local standard of 
care, taking into consideration the maximum allowable blood draw volumes.
See the Laboratory Manual for blood volumes to be drawn from each patient for the local 
laboratory tests and for PK sampling. The combined volume of blood samples taken for 
study purposes or as part of standard of care must not exceed the limit specified in the 
Laboratory Manual. Any deviations from this must be clinically justified.
5.5.5
Pregnancy testing
Not applicable.
5.6
Efficacy assessments
5.6.1
Overall clinical outcome
At the EOT and TOC visits, the Investigator must assess the overall clinical outcome as:

Clinical cure

Signs and symptoms of LOS improved or normalised to an extent that no further
antibacterial therapy is required

Clinical failure

Discontinuation of study treatment and requirement for non-study antibacterial
therapy because of:
o
Insufficient therapeutic effect associated with study treatment, including
persistence or worsening of signs and symptoms of LOS
o
AE related to the study treatment

Death attributable to LOS
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
Unevaluable

Study data not available for evaluation of efficacy for any reason, including:
o
Lost to follow-up
o
Received < 48 hours of study treatment
o
Concomitant treatment with a systemic antibacterial administered for a reason 
other than LOS, which is active against the isolated LOS pathogen, or in the 
absence of microbiological evaluation, is active against common LOS 
pathogens
o
Diagnosis of any of the following conditions after enrollment in the study and 
discontinuation 
of 
study 
treatment: 
ventilator-associated 
pneumonia, 
meningitis, brain abscess, osteomyelitis, infective endocarditis, or necrotising 
enterocolitis
o
Death in which LOS is clearly non-contributory
o
Absence of clinical assessment for any reason
5.6.2
All-cause mortality
Vital status will be assessed at the LFU visit, whether performed in person or by telephone 
contact.
5.6.3
Microbiological outcome
The microbiological outcome categories at EOT and TOC are defined below. For a patient 
to have a favorable microbiological response, the outcome for each baseline pathogen must 
be eradicated or presumed eradicated. If the outcome for any pathogen is persistence or 
presumed persistence, the patient will be considered to have an unfavorable
microbiological response.
Microbiological outcome is to be assessed at the EOT and TOC visits by the Investigator
as follows

Eradication: Absence of baseline pathogen in follow-up cultures of source specimen

Presumed eradication: Absence of follow-up microbiological evaluation of source 
specimen, or unavailable microbiological results, for a patient with a valid baseline 
pathogen who was assessed as a clinical cure

Persistence: Continued presence of a baseline pathogen in follow-up cultures of any 
source specimen

Presumed persistence: Absence of follow-up microbiological evaluation of source 
specimen or unavailable microbiological results for a patient with a valid baseline 
pathogen and assessed as a clinical failure

Unevaluable: No valid pathogen identified at baseline, or no follow-up microbiological 
evaluation of source specimen obtained in a patient with clinical outcome assessed as 
unevaluable

Relapse: Baseline pathogen detected again in follow-up microbiological evaluation of 
any source specimen obtained between the TOC and LFU visits after documented 
eradication or presumed eradication at the TOC visit (note: this applies only to the 
microbiological outcome assessment at the LFU visit)
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5.6.4
Relapse at LFU
At the LFU visit, the Investigator must assess relapse as follows:

Deterioration of the patient’s clinical condition compared to the TOC visit,
microbiological recurrence, or the requirement for additional antimicrobial therapy for 
LOS
5.6.5
Signs and symptoms of LOS
The Investigator must rate the following signs and symptoms of LOS as:

‘absent’ or ‘present’ at baseline (pre-dose) 

‘absent’, ‘improved’, ‘unchanged’ or ‘worsened’ compared to baseline, on every day 
of active study treatment, and at the EOT, TOC, and LFU visits
1. Fever (> 38.0 °C / 100.4 °F rectal; > 37.5 °C / 99.5 °F axillary; > 37.5 °C / 99.5 °F 
oral; > 38.0 °C / 100.4 °F tympanic)
2. Hypothermia (< 36.6 °C / 97.9 °F rectal; < 36.5 °C / 97.7 °F axillary; 
< 35.5 °C / 95.9 °F oral; < 35.8 °C / 96.4 °F tympanic)
3. Abnormal heart rate
a. Bradycardia (< 100 beats/minute awake; < 80 beats/minute asleep)
b. Tachycardia (> 205 beats/minute awake; > 160 beats/minute asleep)
4. Signs of impaired circulation
a. Urine output 0.5–1 mL/kg/h (in patients with urinary catheters; note: urinary 
catheters are not required for the purposes of this study)
b. Hypotension
c. Signs of impaired peripheral perfusion, such as mottled skin, moist and cold skin, 
finger to forearm temperature gradient, or increased capillary refill time
5. Petechial rash OR sclerema neonatorum
6. Respiratory distress
a. New onset or worsening of apnea episodes
b. Tachypnea episodes
c. Increased oxygen requirements
d. Requirement for ventilatory support (note: proven ventilator-associated 
pneumonia is an exclusion criterion; see Section 4.3)
7. Gastrointestinal distress
a. Feeding intolerance
b. Poor sucking
c. Abdominal distension
8. Irritability
9. Lethargy
10. Muscular hypotonia
5.7
Pharmacokinetic assessments
PK will be assessed by means of sparse blood sampling on Day 3: pre-dose and at 2 hours 
(end of infusion), 4 hours, and 8 hours, as described in detail in the Laboratory Manual.
PK samples should not be taken from the infusion lines.
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6
STUDY TREATMENT
6.1
Blinding
This is an open-label study.
6.2
Randomization
This is a single-arm study. At least two term (gestational age ≥37 weeks) and six pre-term 
(gestational age ≥24 to 36 weeks) neonates and infants, with post-natal age ranging from 
≥3 days to ≤3 months will be enrolled, with no stratification.
6.3
Packaging and labelling
The study drug will be packed and labelled in accordance with local regulations and the 
Annex 13 Good Manufacturing Practice rules. Labels will include the identity of the 
Sponsor and Investigator, protocol number, drug identification, storage conditions, content 
of study drug, and expiry date. Information on drug shipment including temperature logger 
and acknowledgement of receipt form to be completed by the receiver will also be included.
6.4
Shipping and storage conditions
Vials of sterile lyophilised ceftobiprole medocaril containing the equivalent of 500 mg 
ceftobiprole will be shipped to the study sites, and the dry powder must be stored in a 
refrigerator (2−8 °C / 36−46 °F). All study drug must be kept under secure conditions, 
e.g., in the hospital pharmacy.
Further information on the shipping and storage conditions is provided in the 
Pharmacy Manual.
6.5
Preparation, presentation, and stability of study drug
Details on the presentation, preparation (including reconstitution and dilution steps), and 
stability of study drug are provided in the Pharmacy Manual.
6.6
Dosage and administration of study drug
Eligible patients will receive ceftobiprole as a 2-hour IV infusion according to the schedule 
in Table 5, with dose adjusted according to gestational and post-natal ages. Body weight 
on Day 1 should be obtained within 12 hours prior to the first dose of study drug. From 
Day 2 until the last day of study treatment, the dose should be calculated based on the 
patient’s first body weight of the day.
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Table 5
Ceftobiprole dosing regimen for the treatment of neonates and
infants with LOS
Gestational age 
group (weeks)
Post-natal age (days)
3 – 13
14 – 29
30 – 59
60 – 90
24 – 26
7.5 mg/kg q12h
7.5 mg/kg q12h
10 mg/kg q12h
10 mg/kg q12h
27 – 31
10 mg/kg q12h
10 mg/kg q12h
10 mg/kg q12h
15 mg/kg q12h*
32 – 36
10 mg/kg q12h
10 mg/kg q12h
15 mg/kg q12h*
15 mg/kg q12h*
≥37
15 mg/kg q12h*
15 mg/kg q12h*
15 mg/kg q12h*
15 mg/kg q8h*
Note: All doses will be infused over 2 hours. The maximum allowable dose in adult and pediatric patients is 500 mg 
regardless of body weight.
* Neonates and infants with a body weight < 4 kg should receive a maximum of 10 mg/kg/dose.
If ampicillin and/or an aminoglycoside are added, these IV solutions must not be mixed 
with ceftobiprole or administered through the same line as ceftobiprole. For further details, 
see the Pharmacy Manual.
6.7
Compliance and drug-supply accountability
The Investigator, and a pharmacist or a pharmacist delegate assigned by the Investigator, 
must maintain records of the delivery of study drug to the site, the inventory at the site, the 
use by each patient, and the return to the Sponsor or alternative disposal of unused product.
A Drug Dispensing Log must be kept current and must contain the following information:

Identification of the patient to whom the drug was dispensed

Principal Investigator name

Dates, quantity and batch number of the drug dispensed to the patient

Quantity of the drug remaining
The inventory must be available for inspection by the Sponsor’s monitor(s). All supplies, 
including partially used or empty vials, must be available for checking by the Sponsor’s 
monitor(s) during monitoring visits and at the end of the study.
6.7.1
Drug disposal
Any remaining drug, including empty vials, may be returned to the study supply packaging 
provider, or may be destroyed at the site on the request of the Sponsor provided the drug 
destruction is adequately documented. 
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7
SAFETY
The role of the DSMB in ensuring the protection of patients’ safety is described in 
Section 3.4. 
Stopping criteria for individual patients are described in Section 4.4.
7.1
Warnings and precautions
7.1.1
Ceftobiprole
Detailed warnings and precautions related to ceftobiprole are provided in the IB.
Serious and occasionally fatal adverse reactions have been reported in patients receiving 
beta-lactam 
antibiotics,
including 
hypersensitivity 
(anaphylaxis) 
and
Clostridioides difficile-associated colitis or pseudomembranous colitis. Seizures have been 
associated with the use of ceftobiprole, most commonly occurring in patients with 
pre-existing central nervous system/seizure disorders. Precipitation can occur when 
ceftobiprole medocaril is mixed with calcium-containing solutions in the same IV 
administration line. Therefore, ceftobiprole medocaril and calcium-containing solutions, 
except Lactated Ringer’s solution for injection, must not be mixed or administered 
simultaneously in the same intravenous line.
7.1.2
Ampicillin / aminoglycosides
The safety profiles of these standard-of-care antibiotics that may be combined with 
ceftobiprole at the discretion of the Investigator are well characterised due to their use over 
many years, and are described in their respective local labels.
Serious or significant adverse reactions that may occur in patients receiving ampicillin 
include hypersensitivity (anaphylaxis) and Clostridioides difficile-associated colitis or 
pseudomembranous colitis. Concurrent administration of ampicillin and allopurinol 
increases substantially the incidence of skin rashes.
Aminoglycosides generally have a narrow therapeutic window and therapeutic drug 
monitoring should be considered in patients treated with aminoglycosides to ensure 
adequate therapeutic exposure and to avoid toxicity due to overexposure. Relevant adverse 
reactions include among others hypersensitivity, ototoxicity, nephrotoxicity, impaired 
neuromuscular transmission, convulsions, and Clostridioides difficile-associated colitis or 
pseudomembranous colitis.
If ampicillin and/or an aminoglycoside are added, these IV solutions must not be mixed 
with ceftobiprole or administered through the same line as ceftobiprole.
7.1.3
Contraception and pregnancy
Not applicable.
7.2
Definitions
7.2.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical 
investigational patient administered a pharmaceutical product that does not necessarily 
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have a causal relationship with study-drug treatment. An AE can therefore be any 
unfavourable and unintended sign (for example, including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. Complications associated with scheduled 
procedures are considered AEs.
Events that occur following the full execution of the ICF but prior to dosing are discussed 
in Section 7.4.2.
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Activities (MedDRA), and grouped by System Organ Class and Preferred Term.
7.2.2
Serious adverse event
An SAE is any AE that meets 1 or more of the following criteria:

Results in death

Is life-threatening

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is classified as an important medical event or medically significant event
Medical and scientific judgement should be exercised in deciding whether an AE should 
be considered an important medical event (and consequently an SAE). Such events may 
not be immediately life-threatening or result in death or hospitalisation, but may jeopardise 
the patient, or may require intervention to prevent one of the outcomes listed in the 
definitions above. These situations should also usually be considered serious.
It should be noted that:

Death is considered an outcome of an AE. Whenever possible the underlying cause of 
death must be reported as the AE.

A life-threatening SAE is any adverse experience that places the patient at risk of death 
at the time of its occurrence, i.e., it does not include a reaction that, had it occurred in 
a more severe form, might have caused death.

Inpatient hospitalisation is defined as any inpatient admission, even if for less than 
24 hours. For chronic or long-term inpatients, inpatient admission also includes transfer 
within the hospital to an acute/intensive care inpatient unit.
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The following hospitalisations, whether planned before or during the study, should not be 
considered and reported as SAEs:

Routine treatment not associated with any deterioration in condition

Elective or planned treatment, including surgical interventions, both related and
unrelated to the patient’s LOS, if the plan for the respective intervention was
documented prior to the first dose of study drug

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the
patient’s LOS and has not worsened

Admission to a hospital or other institution for general care, not associated with any
deterioration in condition
7.2.3
Adverse drug reaction
In the context of this study protocol, an ADR or serious adverse reaction (SAR) is an AE or 
SAE respectively for which there is a reasonable possibility that the drug caused the 
event, i.e., it has been assessed by the Investigator and/or the Sponsor as either 
Possibly related or Probably related to the study drug or to ampicillin or an 
aminoglycoside (see Section 7.3.2).
7.2.4
Suspected unexpected serious adverse reaction
A suspected unexpected serious adverse reaction (SUSAR) is any SAE considered by the 
Investigator or by the Sponsor to be Possibly related or Probably related to the study drug
or to ampicillin or an aminoglycoside (see Section 7.3.2), which is not listed in the 
Reference Safety Information applicable at the time of occurrence of the event, or is not 
listed at the specificity (i.e., nature, outcome) or severity that has been observed.
7.2.5
Adverse events of special interest
An adverse event of special interest (AESI) is defined as a serious or non-serious AE that 
is of scientific and medical concern specific to the sponsor’s product for which ongoing 
monitoring and rapid communication by the investigator to the sponsor can be appropriate.
The following are considered AEs of special interest for the purposes of this study, based 
on nonclinical data and the known safety profile of ceftobiprole or the cephalosporin class 
of antibiotics. and are to be promptly reported in the eCRF, along with an assessment of 
relationship by the Investigator:

Hypersensitivity reactions

Convulsions

Clostridioides difficile-associated colitis or pseudomembranous colitis

Hepatic enzyme increased

Hyponatremia

Renal failure

Infusion site reactions

Thromboembolic events
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7.2.6
Further adverse event definitions
Wherever possible, a specific disease or syndrome rather than individual associated signs 
and symptoms should be identified. However, if an observed or reported sign or symptom 
is not considered by the Investigator to be a component of a specific disease or syndrome, 
it should be recorded as a separate AE.
Laboratory data are to be collected as stipulated in Section 5.5.4. Clinical syndromes 
associated with laboratory abnormalities are to be recorded as appropriate (e.g., diabetes 
mellitus instead of hyperglycemia).
7.2.7
Special Situations
Special Situations include overdose, misuse, and medication error. A Special Situation may 
occur with or without an associated AE.

Overdose: Administration of a quantity of a medicinal product once or cumulatively
which is above the maximum recommended dose indicated in the authorized product
information or administration specification set out in this protocol. Clinical judgement
should always be applied when applying this definition.

Misuse of a medicinal product: Intentional and inappropriate use of a medicinal
product not in accordance with the terms indicated in the authorized product
information or administration specification set out in this protocol.

Medication error: An unintended failure in the drug treatment process that leads to, or
has the potential to lead to, harm to the patient.
7.3
Evaluation of adverse events
7.3.1
Grading of severity
The severity of an AE will be graded on the following scale:

Mild: no change in baseline age appropriate behaviour*

Moderate: resulting in minor changes of baseline age-appropriate behaviour

Severe: resulting in major changes of baseline age-appropriate behaviour* and/or
non-life threatening changes in basal physiological processes**

Life-threatening

Fatal
* Age-appropriate behaviour refers to oral feeding behaviour, voluntary movements and activity, crying
pattern, social interactions and perception of pain
** Basal physiological processes refer to oxygenation, ventilation, tissue perfusion, metabolic stability and 
organ functioning
7.3.2
Assessment of causality
The relationship between an AE and the study drug will be determined by the Investigator 
on the basis of their clinical judgement and the following definitions.
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To align with the binary causality assessment required for clinical studies, based on the 
Investigator’s evaluations, the cases will be categorised as:

Unrelated: when evaluated as Unlikely related or Not related to the study drug or to 
ampicillin or an aminoglycoside

Related: when evaluated as Probably related or Possibly related to the study drug or to 
ampicillin or an aminoglycoside
UNRELATED
This category comprises events that are either

Not related to the study drug or to ampicillin or an aminoglycoside, i.e., clearly and 
incontrovertibly due only to extraneous causes such as the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient, 
or

Unlikely related to the study drug or to ampicillin or an aminoglycoside, i.e., the event 
may readily have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient
An AE is also categorised as Unlikely related / Not related if it does not follow a reasonable 
temporal sequence from administration of the study drug or ampicillin and/or an 
aminoglycoside, i.e., based on the time between the administration of study drug and 
occurrence of the event, a relationship is not plausible.
Examples for the absence of a reasonable temporal sequence from administration of the 
study drug are that the drug was:

Re-administered, and the event did not recur, or

Interrupted or stopped, and the event did not improve or disappear
Finally, an AE may be assessed to be Not related / Unlikely related if it does not follow a 
known pattern of the response to the study drug or drugs of the same substance class.
RELATED
Probably related
This category is applicable to an AE that is considered, with a high degree of certainty, to 
be related to the study drug or to ampicillin and/or an aminoglycoside (i.e., this category 
also comprises events that are definitely related to the study drug).
An AE event may be considered (at least) Probably related (or considered definitely 
related) to the study drug or ampicillin and/or an aminoglycoside if it meets one or more 
of the following criteria:

It follows a reasonable temporal sequence from administration of the study drug or 
ampicillin and/or an aminoglycoside, i.e., based on the time between the administration 
of study drug and the occurrence of the event, a relationship is plausible, e.g.,
–
The drug was interrupted or stopped, and the event improved or disappeared
–
The drug was re-administered, and the event recurred
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
It follows a known pattern of the response to the suspected drug or drugs of the same 
substance class

It cannot be reasonably explained by the known characteristics of the patient’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the 
patient
Possibly related
An AE may be considered to be (at least) Possibly related to the study drug or treatment 
with ampicillin and/or an aminoglycoside if:

It follows a reasonable temporal sequence from administration of the study drug or 
ampicillin and/or an aminoglycoside (see also additional explanations above), or it 
follows a known pattern of the response to the suspected drug or drugs of the same 
substance class; or

It may or may not have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient; or

It does not follow a plausible temporal relationship or a known pattern of response but 
there is no alternative explanation for the event.
7.4
Handling of safety information and collection periods
7.4.1
Responsibilities and procedures
The responsibility for the safety of an individual patient lies in all cases with the 
Investigator. This includes the timely review of all safety data obtained during the course 
of the study.
An Investigator must instruct the parent(s) or LAR to report any AEs the patient 
experiences.
7.4.2
Handling of safety data during the pre-treatment period
Any relevant change in, or worsening of, a patient’s condition occurring after execution of 
the study ICF but prior to dosing, is to be recorded in the medical history page of the eCRF 
(see Section 5.3.1), unless the occurrence is assessed as related to the study procedure, in 
which case it must be recorded in the AE page. If the event is assessed as both serious (see 
Section 7.2.2) and related to study-specific procedures, it must be reported to the Sponsor’s 
safety representative, using the same procedures as for an SAE (see Section 7.4.3.2).
7.4.3
Handling of safety data during the treatment period and up to the last 
scheduled follow-up
From the start of first dosing up to and including the LFU visit 28−35 days after the last 
study drug administration, any change in, or worsening of, a patient’s condition, all AEs, 
and Special Situations must be collected and reported in the eCRF (See Section 9.1.2).
SAEs must in addition be reported and recorded on the SAE form (see Section 7.4.3.2).
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7.4.3.1
Reporting procedures for adverse events that do not meet seriousness 
criteria
All AEs directly observed (physical examination, laboratory test, or other assessments), 
mentioned by the parent(s) or LAR, or reported by the parent(s) or LAR upon non-directive 
questioning, must be recorded on the AE pages of the eCRF in the English language, and 
should include the following information:

The term identifying the event. If possible, a diagnosis should be documented rather 
than signs and symptoms, using self-explanatory and concise medical terminology. If 
an observed or reported sign or symptom is not considered a component of a specific 
disease or syndrome by the Investigator, it should be recorded as a separate AE. 
Note that disease progression is considered an efficacy outcome parameter, and should 
not be recorded as an AE unless the outcome is death.

Duration (start and end dates)

Grading of severity (see Section 7.2.3)

Relationship to study drug (causality assessment) (see Section 7.3.2)

Action taken in regard to study drug or ampicillin and/or an aminoglycoside or any 
suspected concomitant medication

Additional treatments given for the event

Whether the event is an SAE (seriousness assessment) (see Section 7.2.2)

Outcome
Further details on completing the relevant pages in the eCRF are provided in the eCRF 
completion guidelines. In addition, concomitant medications (with start and stop dates) and 
medical history should be updated as needed.
Abnormal laboratory results should not be recorded as an AE unless the abnormal result
meets 1 or more of the following criteria:

Induces clinical signs or symptoms which require therapy or additional diagnostic 
evaluation

Requires study drug dose modification or discontinuation

Is considered clinically significant
If a laboratory abnormality meets 1 of the above criteria, the clinical syndrome associated 
with the laboratory abnormality is to be recorded (e.g., diabetes mellitus instead of 
hyperglycemia).
Adverse events must also be reported in the source document with at least the nature of the 
event, the start and end date, the relationship to study drug, treatment (if applicable), and 
outcome (in the initial or follow-up report).
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7.4.3.2
Reporting procedures for serious adverse events
7.4.3.2.1
Investigator’s responsibility
In addition to being reported and followed up as AEs (see Section 7.4), events which are 
classified as SAEs, must be reported to the Sponsor’s safety representative listed below, 
within 24 hours of awareness of the event.
In addition to completion of the SAE form, such reports may include detailed anonymised 
descriptions (e.g., discharge letter, autopsy report) and/or relevant data (e.g., ECG, 
laboratory tests, discharge summaries, post-mortem results). If any questions arise, the 
Sponsor’s medical monitor or designee should be consulted.
The information provided in an SAE form should be as complete as possible, but must at a 
minimum include the following:

The diagnosis / short description of the AE, and the reason for categorising the AE as
serious

Patient ID and treatment (if applicable)

Investigator’s name and phone number (if applicable)

Name of the suspect study drug or ampicillin or an aminoglycoside and dates of
administration

Assessment of causality
If all information about the event is not yet known, the Investigator will be required to 
report any additional information within 24 hours, and further information as it becomes 
available.
The Investigator or designee must notify the applicable IEC/IRB of the event in line with 
local requirements.
7.4.3.2.2
Sponsor’s responsibilities
The Sponsor must ensure the reporting of SUSARs and any expeditable SAEs to Health 
Authorities and IECs/IRBs in accordance with applicable laws and regulations.
In the event of a SUSAR, the Sponsor must ensure that Investigators active in any other 
interventional studies with the study drug for which it is the Sponsor are informed.
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Expectedness of SAEs for regulatory expedited reporting will be assessed by the Sponsor 
against the applicable Reference Safety Information of the study drug; for ceftobiprole, the 
Reference Safety Information is found in the IB in effect at the time of onset of the event.
7.4.4
Follow-up of adverse events
Once an AE is detected, it must be proactively followed at each visit (or more frequently 
if necessary) for any changes in severity, relationship to the study drug, interventions 
required for treatment, and the event’s outcome.
All AEs must be followed up until they have returned to baseline status or resolved to 
Grade 1, have stabilised, or until the scheduled LFU visit.
Unresolved ADRs, SARs, and unrelated SAEs at the time of the LFU visit must be 
followed up until they have, in the opinion of the Investigator, resolved to baseline, 
Grade 1, stabilised, or are deemed to be irreversible (including death), or until the parent(s) 
or LAR withdraw their consent.
7.4.5
Handling of post-study safety data
After the LFU visit, only SARs should be collected and reported; however, these events 
are not captured in the eCRF.
New SARs that occur after the LFU visit will be followed until they have, in the opinion 
of the Investigator, resolved to baseline, stabilised, or are deemed to be irreversible 
(including death), or until the parent(s) or LAR withdraw their consent for participation of 
the patient in the study.
7.4.6
Reporting and handling of pregnancies
Not applicable.
7.5
Adverse events associated with an overdose or any other Special 
Situation
Any overdose or any other Special Situation (with or without an AE) should be recorded 
in the eCRF.
All AEs associated with an overdose or medication error should be recorded on the eCRF 
(see Section 9.1.2). If the associated AE is assessed as an SAE, the event should be reported 
to the Sponsor immediately (see Section 7.4.3.2).
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BPR-PIP-003
Version 5.0
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8
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN
Details of the statistical analyses presented below will be provided in the SAP. A change 
to the data analysis methods described in the protocol will require a protocol amendment 
only if it alters a principal feature of the protocol. The SAP will be finalised prior to 
database lock. Any changes to the methods described in the plan will be described and 
justified in the final clinical study report.
8.1
Study endpoints
8.1.1
Primary endpoint
The primary endpoint is safety and tolerability in the Safety population, as assessed by 
AEs, SAEs, deaths, and discontinuations due to AEs during treatment with ceftobiprole 
and at the EOT, TOC, and LFU visits, as well as clinical laboratory tests, vital signs, and 
physical examination findings.
8.1.2
Secondary endpoints
Pharmacokinetics

Plasma levels of ceftobiprole, ceftobiprole medocaril, and open-ring metabolite in the 
PK population
Efficacy

Clinical cure rate at the EOT and TOC visits (ITT and CE populations)

All-cause mortality through Day 28 (ITT population)

Microbiological eradication or presumed eradication rate at the EOT and TOC visits
(mITT and ME populations)

Improved signs and symptoms of LOS at the Day 3, EOT, and TOC visits (ITT and CE 
populations)
8.2
Analysis populations
The following analysis populations are defined for this study:
8.2.1
Intent-to-treat (ITT) population / Safety population
All patients enrolled in the study who received at least one dose of ceftobiprole.
8.2.2
Clinically Evaluable (CE) population
Patients in the ITT population who received at least 48 hours of study treatment
(i.e., four or six infusions of ceftobiprole as applicable) and had a completed overall 
clinical outcome assessment at the TOC visit, no major protocol deviations, and no 
concomitant systemic non-study antibiotic therapy.
8.2.3
Microbiological Intent-to-treat (mITT) population
All patients in the ITT population with a valid pathogen identified at baseline.
8.2.4
Microbiologically Evaluable (ME) population
All patients in the CE analysis population with a valid pathogen identified at baseline and 
a microbiological outcome assessment at the TOC visit.
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8.2.5
Pharmacokinetics (PK) population
All patients who received ceftobiprole and had at least one sample of plasma concentration 
measurement obtained by the appropriate methodology.
8.3
Sample size considerations
The study is not powered for inferential statistical analysis. The sample size (eight patients; 
two term and six pre-term) is considered adequate to evaluate the safety of ceftobiprole in 
neonates and young infants with LOS.
8.4
Statistical and analytical methods
There will be no formal hypothesis testing in this study. Descriptive statistics will be 
applied to the primary and secondary endpoints as follows: number, mean, standard 
deviation, median, minimum, and maximum will be provided for continuous variables, and 
frequency distributions (counts and percentages) will be shown for categorical variables. 
All variables will be summarised overall and by gestational and post-natal ages as 
appropriate. Variables may be compared to baseline where applicable. Listings of 
individual patients’ data will also be produced.
A full Statistical Analysis Plan will be prepared before database lock.
8.4.1
Primary endpoint analysis
8.4.1.1
Safety/tolerability analysis
Safety will be assessed through summaries of AEs, clinical laboratory tests, vital signs, and 
physical examination findings. All safety analyses will be based on the Safety population.
The incidence of AEs and SAEs will be tabulated by System Organ Class (SOC) and 
Preferred Term (PT), and by severity, relationship to treatment, and outcome. Tables of 
AEs leading to study drug discontinuation and withdrawal from the study will also be 
provided.
Adverse occurrences (as defined in Section 7.2) will be provided in a listing.
Descriptive statistics summarising local laboratory data will be presented by study visit. 
The change from baseline to each post-baseline visit and to the overall worst post-baseline 
value will also be summarised.
Descriptive statistics of vital signs will be presented by study visit, as well as the change 
from baseline at each study visit. The percentage of abnormalities in the physical 
examination will be presented by study visit.
8.4.2
Secondary endpoint analyses
8.4.2.1
Pharmacokinetic analysis
Descriptive summary statistics of plasma concentrations of ceftobiprole, ceftobiprole 
medocaril, and open-ring metabolite in the PK population will be presented by timepoint 
and by gestational and post-natal ages. Population PK modelling, Monte Carlo simulations, 
and PK-PD analyses will be reported separately.
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8.4.2.2
Efficacy analyses
The following efficacy assessments will be analysed using descriptive statistics:

Clinical and microbiological outcome assessments at the EOT and TOC visits
(clinical outcomes in the ITT and CE populations; microbiological outcomes in the 
mITT and ME populations)

All-cause mortality through Day 28 (ITT population)

Signs and symptoms of LOS at the Day 3, EOT and TOC visits (ITT and CE 
populations)
8.4.3
Study drug exposure and compliance
The actual dose, duration in days, and compliance of the study drug will be listed by patient 
and summarised through descriptive statistics in the safety population.
8.4.4
Prior and concomitant treatments
Medications and significant non-drug therapies used prior to and after the start of the study 
drug will be listed by patient and summarised by Anatomical Therapeutic Chemical term 
and Preferred Term.
8.4.5
Handling of missing data and discontinuations
Missing data will not be imputed. Patients whose clinical response is unknown or not 
reported will be treated as non-responders.
Reasons for discontinuation and the date of discontinuation will be listed.
9
STUDY ADMINISTRATION AND REGULATORY ASPECTS
9.1
Study records
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.
9.1.1
Investigator Site File
The ISF must contain all essential documents as required by International Council for 
Harmonisation (ICH) E6 and applicable regulations, including the IB, this protocol and 
any subsequent amendments, eCRFs, Query Forms, documented IEC/IRB approvals, 
documented regulatory approvals, sample ICFs, drug records, staff curriculum vitae, and 
other appropriate documents/correspondence.
9.1.2
Case report forms
For each patient enrolled in the study, including patients who do not complete the study 
and patients for whom an eCRF is initiated during Screening but who are not dosed, an 
eCRF must be completed and signed by the Investigator or authorised site staff. If a patient 
discontinues from the study, the reason must be noted on the eCRF. If a patient is 
discontinued from the study because of an AE, thorough efforts should be made to clearly
document the outcome.
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the Sponsor in the eCRFs and in all required reports.
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If the eCRF is to be the source document for certain data, this must be discussed and agreed 
with the Sponsor in advance, and clearly documented.
9.1.3
Patient source documents
Patient source documents used to record key efficacy/safety parameters, independent of 
the eCRFs, may include, but are not limited to, patient hospital/clinic records, physicians’ 
and nurses’ notes, appointment books, original laboratory reports, X-ray, pathology and 
special assessment reports, signed ICFs, consultant letters, and patient screening and 
enrollment logs. Source documents are part of the study documents, and must be 
maintained and made available upon request for clinical monitoring visits, audits or 
inspections.
9.1.4
Document retention and archiving
The Investigator must keep all study documents on file for at least 25 years after completion 
or discontinuation of the study, unless otherwise required by applicable laws or regulations. 
Subsequently, the Sponsor will inform the Investigator when the study documents can be 
destroyed, subject to applicable regulations.
These files must be made available for audits and inspection, upon reasonable request, 
to the authorised representative of the Sponsor, or to Health Authorities.
Should the Investigator wish to assign the study records to another party, or move them to 
another location, the Sponsor must be notified in advance.
If the Investigator cannot guarantee the archiving requirement at the study site for any or 
all of the study documents, arrangements must be made between the Investigator and the 
Sponsor for appropriate storage.
9.2
Clinical monitoring
Before study initiation, at a site initiation visit, the Sponsor will review the protocol, eCRFs 
and other study documentation with the Investigators and the site staff.
The monitor must visit the Investigator and the study facilities on a regular basis throughout 
the study to verify adherence to GCP and this protocol, and the completeness, consistency 
and accuracy of the data being entered in the eCRFs. The monitor must also ensure that the 
study drug is being stored, dispensed, and accounted for in accordance with specifications.
The Investigator must ensure that the monitor has direct access to all required study data 
(source documents) during the regular monitoring visits. This includes all patient records 
needed to verify the entries in the eCRFs.
The Investigator must cooperate with the monitor to ensure that any protocol deviations or 
other issues detected in the course of monitoring visits are resolved.
Monitoring reports must be written after each monitoring visit, per site and per visit. These 
monitoring reports must be reviewed and approved by the respective supervisors of the 
Monitors.
Further monitoring instructions are provided in the Monitoring Plan.
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9.3
Audits and inspections
The study may be audited at any time, with appropriate notification, by qualified personnel 
from the Sponsor or its designees, to assess compliance with the protocol, GCP, and 
regulatory requirements. These audits may also be conducted for quality assurance 
purposes to ensure that complete and accurate data are submitted, and that all AEs are being 
identified and reported in compliance with the protocol and applicable regulations. The 
study may also be audited by Health Authority inspectors, after appropriate notification. 
In the event of an audit or an inspection, the Investigator must ensure that direct access to 
all study documentation, including source documents, is granted to the auditors or 
inspectors.
9.4
Protocol amendments
Protocol amendments must be prepared by a representative of the Sponsor, and be reviewed 
and approved in accordance with the Sponsor’s Standard Operating Procedures (SOPs).
All protocol amendments must be submitted to the appropriate IEC/IRB for information 
and approval, in accordance with applicable laws and regulations, and to Health Authorities 
if required.
Approval of a protocol amendment must be awaited before changes are implemented, 
with the exception of changes that are necessary to eliminate an immediate hazard to 
study participants, or changes involving only logistical or administrative aspects of the 
study (e.g., changes to monitors, changes to telephone numbers).
9.5
Premature termination of the study
The Sponsor reserves the right to terminate the study at any time (see Section 4.6). 
An Investigator has the right to terminate his or her participation in the study at any time. 
Should either of these events occur, both parties will arrange the necessary procedures after 
review and consultation.
If the study is to be terminated early, the Sponsor and the Investigator must ensure that 
adequate consideration is given to the protection of the interests of all patients enrolled in 
the study.
9.6
Publication policy
The Sponsor is committed to registering this study in a publicly accessible clinical trial 
registry (e.g., www.clinicaltrials.gov), and will ensure that the results of this study will be 
made available to the medical community consistent with the ICH GCP guidelines, the 
Sponsor’s SOPs, applicable laws and regulations, and the Good Publication Practice 
(GPP3) guidelines.
The Sponsor will prepare a clinical study report for submission to Health Authorities 
providing the results of all planned analyses within 6 months after the end of the study.
This study is intended for publication, even if terminated prematurely. Publication may 
include any or all of the following: posting of a synopsis online, submission of an abstract 
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and/or presentation at a scientific conference, or publication of a full manuscript. 
The Sponsor will work with the authors to submit a manuscript describing study results.
These timelines may be extended if additional time is needed for analysis, to protect 
intellectual property, or to comply with confidentiality agreements with other parties. 
Authors of the primary results manuscript will be provided the complete results from the 
clinical study report, subject to applicable confidentiality agreements.
When a manuscript is submitted to a biomedical journal, the Sponsor’s policy is to also 
include the protocol and SAP to facilitate peer and editorial review of the manuscript. If the 
manuscript is subsequently accepted for publication, the Sponsor will allow the journal to 
post on its website the key sections of the protocol that are relevant to evaluating the study, 
specifically including those sections describing the study objectives and hypotheses, the 
inclusion and exclusion criteria, the study design and procedures, the efficacy and safety 
measures, the SAP, and any relevant protocol amendments. The Sponsor reserves the right 
to redact proprietary information from these documents.
As this is a multicenter study, subsequent to the multicenter publication (or after public 
disclosure of the results online at www.clinicaltrials.gov if a multicenter manuscript is not 
planned), an Investigator and his or her colleagues may publish their data independently. 
The limitations of single study site observations in a multicenter study should always be 
described in such a manuscript.
Authorship credit and related decisions in regard to publication of the results of this study 
will comply with the GPP3 guidelines.
The Sponsor retains the right to review all proposed abstracts, manuscripts, or presentations 
regarding this study 45 days prior to submission for publication/presentation. Any 
information identified by the Sponsor as confidential must be deleted prior to submission; 
this confidentiality does not include efficacy and safety results. Sponsor review can be 
expedited to meet publication timelines.
10
ETHICS AND GOOD CLINICAL PRACTICE
10.1
Good clinical practice
The study must be conducted in compliance with this protocol, ICH Guideline E6, any 
relevant supplementary guidance on GCP, and applicable laws and regulations.
10.2
Informed consent
Eligible patients may only be enrolled in the study after their parent(s) or LAR provide
written IEC/IRB-approved informed consent. Written informed consent must be obtained 
by the Investigator or designee prior to initiation of any study procedures. In the event of 
an emergency, verbal consent is acceptable, followed by written informed consent as soon 
as the situation allows.
The procedure for obtaining informed consent for each individual participating in this 
study, must include adequate explanation of the aims, methods, objectives and potential 
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risks of the study. It must also be explained to parents or LARs that they are completely 
free to refuse to enter the study, or to withdraw from the study at any time for any reason.
Written consent must be witnessed and countersigned by the Investigator or a qualified 
designee, as appropriate. In obtaining and documenting informed consent, the Investigator 
must comply with applicable regulatory requirements and GCP as outlined in ICH 
Guideline E6 and other relevant guidelines, and the ethical principles having their origin 
in the Declaration of Helsinki.
Copies of signed ICFs must be given to the parent(s) or LAR, and the originals filed at the 
study site.
In the event that the parent(s) or LAR are temporarily unable or unavailable to sign the 
consent document, an impartial witness must be present during the entire informed consent 
discussion. After the parent(s) or LAR have verbally consented to participation in the study, 
the witness’s signature must be obtained on the form to attest that the information in the 
ICF was accurately explained, and was understood by the parent(s) or LAR.
The eCRFs for this study contain a section for documenting the parents’ or LAR’s informed 
consent, and this must be completed appropriately. If new safety information results in 
significant changes in the benefit-risk assessment for ceftobiprole, the ICF must be 
reviewed and updated. All parents or LARs of patients currently enrolled in the study who 
have not yet completed the treatment or post-treatment phases must be given the new 
information and a copy of the revised ICF, and asked to give their consent to the patient 
continuing in the study.
10.3
Patient confidentiality and data protection
The Investigator must ensure that patient anonymity is maintained, and that patients’ 
identities are protected from unauthorised parties. This includes any electronic data 
generated during the study. In the eCRF, or other documents submitted to the Sponsor, 
patients must be identified only by an identification code, and not by name. 
The Investigator must keep a confidential patient identification code list, as described in 
Section 8.3.21 of ICH Guideline E6. The Sponsor is responsible for ensuring compliance 
with all applicable data protection laws.
10.4
Independent Ethics Committees / Institutional Review Boards
This protocol and any accompanying material provided to the patient, including patient 
information sheets or descriptions of the study used to obtain informed consent, as well as 
any advertising material and information about any compensation provided to the parent(s) 
or LAR, must be submitted to an IEC/IRB operating in compliance with ICH Guideline E6 
and any relevant supplementary guidance on GCP, and with applicable laws and 
regulations. Approval from the IEC/IRB must be obtained and documented before starting 
the study.
Amendments made to the protocol after receipt of IEC/IRB approval must also be 
submitted to the IEC/IRB in accordance with local procedures and applicable laws and 
regulations.
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BPR-PIP-003
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11 PROTOCOL VERSION HISTORY
Date
Version
Summary of changes
16 May 2022
1.0
–
24 May 2022
2.0
• Addition of the definition of the end of the study
• Addition of adverse events of special interest
• Correction of the timeline for preparation of the clinical study report
11 July 2022
3.0
• Deletion of Section 9.2 Biological sample and bacterial isolate 
retention
20 July 2022
4.0
• Updated dose rationale in Section 1.4.3.
• Addition of the option in some circumstances that treatment with 
ceftobiprole may be stopped after 5 days at the discretion of the 
Investigator.
• Clarification that in Inclusion criterion 3, clinical criterion (i), 
references to hypotonia are to muscular or arterial hypotonia.
• Addition to Inclusion criterion 3 laboratory criterion (d), Interleukin-6 
elevated according to local laboratory thresholds.
• Clarification that for the purposes of Exclusion criterion 4, the patient 
must have proven ventilator-associated pneumonia.
• Change of the duration of systemic antibacterial therapy within 7 days 
before start of study medication from 48 to 72 hours for the purposes of 
Exclusion criterion 12.
• Clarification that during the active treatment period, vital signs must be 
recorded within 30 minutes before the first study drug administration, 
and then three times daily.
• Section 7.2.7 has been amended to ensure that Special Situations are 
applicable to a patient population aged from ≥3 days to ≤3 months.
• Addition of two categories to the grading of the severity of adverse 
events.
• Section 7.4.2 has been amended to clarify the recording and reporting 
requirements for events occurring after execution of the study ICF but 
prior to dosing.
9 July 2024
5.0
• Amendment of the planned study population to require at least eight 
patients, comprising at least two term neonates and six pre-term 
neonates.
• Reduction of the expected minimum treatment duration from 7 days to 
3 days.
• Clarification of inclusion criterion ‘hypotonia’ by removing ‘arterial’
from inclusion criterion 3(i)
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12 REFERENCES
(Abitbol 2014) Abitbol CL, Seeherunvong W, Galarza MG, et al. Neonatal kidney size and 
function in preterm Infants: What is a true estimate of glomerular filtration rate? 
J Pediatr 2014; 164:1026–31.
(Awad 2014) Awad SS, Rodriguez AH, Chuang YC, et al. A Phase 3 randomized double-
blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the 
treatment of hospital-acquired pneumonia. Clin Infect Dis 2014; 59:51–61.
(Bosheva 2021) Bosheva M, Gujabidze R, Károly É, et al. A Phase 3, randomized, 
investigator-blinded trial comparing ceftobiprole with a standard-of-care 
cephalosporin, with or without vancomycin, for the treatment of pneumonia in 
pediatric patients. Pediatr Infect Dis J 2021; 40:e222–9.
(CHMP-PDCO 2009) CHMP and PDCO. Guideline on the investigation of medicinal 
products in the term and preterm neonate. 25 June 2009. EMEA/536810/2008.
(Craig 2008) Craig WA, Andes DR. In vivo pharmacodynamics of ceftobiprole against 
multiple bacterial pathogens in murine thigh and lung infection models. Antimicrob 
Agents Chemother 2008; 52:3492–6.
(Dong 2015) Dong Y, Speer CP. Late-onset neonatal sepsis: recent developments. Arch 
Dis Child Fetal Neonatal Ed 2015; 100:F257–63.
(Fleischmann 2021) Fleischmann C, Reichert F, Cassini A, et al. Global incidence and 
mortality of neonatal sepsis: a systematic review and meta-analysis. Arch Dis Child 
2021; 0:1–8.
(Hamed 2020) Hamed K, Engelhardt M, Jones ME, et al. Ceftobiprole versus daptomycin 
in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III 
trial. Future Microbiol 2020; 15:35–48.
(Lodise 2007) Lodise TP, Pypstra R, Kahn JB, et al. Probability of target attainment for 
ceftobiprole as derived from a population pharmacokinetic analysis of 150 subjects. 
Antimicrob Agents Chemother 2007; 51:2378–87.
(Nicholson 2012) Nicholson SC, Welte T, File TM Jr, et al. A randomised, double-blind 
trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for 
the treatment of patients with community-acquired pneumonia requiring 
hospitalisation. Int J Antimicrob Agents 2012; 39:240–6.
(Overcash 2021) Overcash JS, Kim C, Keech R, et al. Ceftobiprole compared with 
vancomycin plus aztreonam in the treatment of acute bacterial skin and skin structure 
infections: results of a phase 3, randomized, double-blind trial (TARGET). Clin 
Infect Dis 2021; 73:e1507–17.
(Rhodin 2009) Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function 
maturation: a quantitative description using weight and postmenstrual age. Pediatr 
Nephrol 2009; 24:67–76.
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Ceftobiprole medocaril
Clinical Study Protocol
BPR-PIP-003
Version 5.0
9 July 2024
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd, Allschwil
Page 66 of 69
(Rubino 2021a) Rubino CM, Cammarata AP, Smits A, et al. Model-based approach for 
optimizing ceftobiprole dosage in pediatric patients. Antimicrob Agents Chemother 
2021 Nov; 65(11):e01206-21.
(Rubino 2021b) Rubino CM, Polak M, Schröpf S, et al. Pharmacokinetics and safety of 
ceftobiprole in pediatric patients. Pediatr Infect Dis J 2021; 40:997–1003.
(Shane 2017) Shane AL, Sánchez PJ, Stoll BJ. Neonatal sepsis. Lancet 2017; 390:
1770–80.
(Schwartz 2009) Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate 
GFR in children with CKD. J Am Soc Nephrol 2009; 20:629–37.
(Troutman 2018) Troutman JA, Sullivan MC, Carr GJ, Fisher J. Development of growth 
equations from longitudinal studies of body weight and height in the full term and 
preterm neonate: from birth to four years postnatal age. Birth Defects Res 2018; 
110:916–32.
(Van den Anker 2006) Van den Anker J (Chair). Workshop on regulatory and scientific 
issues related to the investigation of medicinal products intended for neonatal use. 
2006; EMEA/484678/2006.
NCT05856227


 
Ceftobiprole medocaril
Clinical Study Protocol
BPR-PIP-003
Version 5.0
9 July 2024
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd, Allschwil
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13 APPENDICES
Appendix 1
Renal function
For assessment of renal function, serum creatinine is typically used after the first week of 
life in term neonates and after 4 weeks in pre-term neonates. Before then, intra-individual 
changes (related to post-menstrual age) in serum creatinine are used as a guide to renal 
function.
In addition, the following references should be considered:

Schwartz and colleagues (Schwartz 2009) published the following modified formula 
(based on serum creatinine levels determined with the enzymatic method):
Estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) = 0.413 • length (cm) / 
creatinine (mg/dL).

Abitbol
and colleagues (Abitbol
2014) reported serum creatinine levels of 
0.68 ± 0.14 mg/dL during post-natal days 3–7 in 60 pre-term neonates (34 ± 3 weeks). 
The same report presented a graph of eGFRs calculated with the modified Schwartz 
formula, in which the values of all age groups were > 20 mL/min/1.73 m2. Of note, the 
creatinine-based equation underestimated the GFR compared to the CysC-based 
equations, especially in pre-term neonates.

Two graphs presented at an EMA Workshop on regulatory and scientific issues related 
to the investigation of medicinal products intended for neonate use (Van den Anker 
2006) indicated that serum creatinine levels in neonates with a body weight > 1000 g, 
or a gestational age > 27 weeks, fell from a maximum of about 110 µmol/L on day 1 to 
about 50 µmol/L within 3 to 4 weeks.
Conclusion
Serum creatinine levels are generally used to monitor renal function (CHMP-PDCO 2009).
Glomerular filtration rate (GFR) is indirectly proportional to serum creatinine, i.e., a GFR 
of two-thirds of normal corresponds to a 1.5-fold greater than normal serum creatinine 
level. Since post-menstrual age is the best parameter of kidney maturation, the following 
creatinine thresholds (determined with the enzymatic method) may be used to support the 
evaluation of Exclusion criterion 7:
Post-menstrual age
(weeks)
Creatinine 
(mg/dL)
Rationale
28 – 34 completed
1.32
150% of the upper limit of the laboratory normal ranges
35 – 42 completed
1.10
Arithmetic mean of 1.32 and 0.88
> 42
0.88
Upper limit of the laboratory normal ranges of the lower age 
groups and slightly more than 150% of 0.5 mg/dL, the stable 
creatinine level during the first 2 years of life
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Clinical Study Protocol
BPR-PIP-003
Version 5.0
9 July 2024
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd, Allschwil
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Considering these serum creatinine thresholds, a GFR estimated with the modified 
Schwartz formula of less than the values given below might provide evidence of impaired 
renal function or known significant renal disease:
Length (cm)
eGFR threshold (mL/min/1.73 m2)
Post-menstrual age (weeks)
28 – 34 completed
35 – 42 completed
> 42
33
10.3
12.4
15.5
34
10.6
12.8
16.0
35
11.0
13.1
16.4
36
11.3
13.5
16.9
37
11.6
13.9
17.4
38
11.9
14.3
17.8
39
12.2
14.6
18.3
40
12.5
15.0
18.8
41
12.8
15.4
19.2
42
13.1
15.8
19.7
43
13.5
16.1
20.2
44
13.8
16.5
20.7
45
14.1
16.9
21.1
46
14.4
17.3
21.6
47
14.7
17.6
22.1
48
15.0
18.0
22.5
49
15.3
18.4
23.0
50
15.6
18.8
23.5
51
16.0
19.1
23.9
52
16.3
19.5
24.4
53
16.6
19.9
24.9
54
16.9
20.3
25.3
55
17.2
20.7
25.8
56
17.5
21.0
26.3
57
17.8
21.4
26.8
58
18.1
21.8
27.2
59
18.5
22.2
27.7
60
18.8
22.5
28.2
Investigators will exercise their clinical knowledge in conjunction with these thresholds 
when determining the applicability of Exclusion criterion 7 to potential participants in the 
study.
NCT05856227


 
Ceftobiprole medocaril
Clinical Study Protocol
BPR-PIP-003
Version 5.0
9 July 2024
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Appendix 2
Investigator’s protocol signature page
BASILEA
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE
Protocol
BPR-PIP-003
Basilea product:
Ceftobiprole medocaril
Protocol title:
A multicenter open-label, single-arm, multiple-dose study to evaluate 
the safety, pharmacokinetics, and efficacy of ceftobiprole medocaril in 
term and pre-term neonates and infants up to 3 months of age with 
late-onset sepsis
Sponsor:
Basilea Pharmaceutica International Ltd, Allschwil
Date / Version:
9 July 2024 / Version 5.0
Name of Principal Investigator: 
Study site: 
I agree to the conditions relating to this study as set out in the above named Protocol and Study 
Procedures. I fully understand that any changes instituted by the Investigator(s) without previous 
discussion with the Sponsor’s Project Clinician, Clinical Pharmacologist and Biostatistician 
(only if required) would constitute a violation of the protocol, including any ancillary studies or 
procedures performed on study patients (other than those procedures necessary for the wellbeing 
of the patients).
I agree to follow International Council for Harmonisation (ICH) guidelines for good clinical 
practice (GCP), and specifically, to obtain approval from the applicable Independent Ethics 
Committee / Institutional Review Board prior to study start, allow direct access to source 
documents, and agree to inspection by auditors from the Sponsor and regulatory authorities. I 
will ensure that the investigational product(s) supplied by the Sponsor will be used only as 
described in the protocol for this study, and I acknowledge that if any other use is desired, written 
permission must be obtained from the Sponsor.
I acknowledge that I have read the protocol for this study, and I agree to carry out all of 
its terms in accordance with applicable laws and regulations.
Please print name and date next to the signature
Signature
Name
Date
Principal Investigator
NCT05856227

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Protocol BPR-PIP-003
A multicenter, open-label, single-arm, multiple-dose study to evaluate the safety, 
pharmacokinetics, and efficacy of ceftobiprole medocaril in term and pre-term 
neonates and infants up to 3 months of age with late-onset sepsis
Date:
26 February 2025
Version:
1.0
Number of pages:
17
Confidentiality statement
All information contained in this document is confidential and proprietary information of Basilea 
Pharmaceutica International Ltd, Allschwil (‘Basilea’). This information is provided only for the purposes 
identified within the document, and may not be disclosed by you to any third party without prior written 
authorization from Basilea. If it is determined that disclosure to a third party is required by applicable law 
or regulations, the person to whom the information is disclosed must be informed that the information is 
confidential, and that it may not be further disclosed without prior written authorization from Basilea.
NCT05856227


BPR-PIP-003 
Statistical Analysis Plan
Version 1.0
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Confidential – Proprietary information of Basilea Pharmaceutica International Ltd, Allschwil
Page 2 of 17
TABLE OF CONTENTS
TABLE OF CONTENTS ....................................................................................................2
LIST OF TABLES ..............................................................................................................3
LIST OF APPENDICES .....................................................................................................3
LIST OF ABBREVIATIONS .............................................................................................4
1
INTRODUCTION ........................................................................................................5
2
OBJECTIVES...............................................................................................................5
2.1
Primary objective .................................................................................................5
2.2
Secondary objectives............................................................................................5
3
INVESTIGATIONAL PLAN.......................................................................................5
3.1
Overall study design.............................................................................................5
3.1.1
Brief summary .................................................................................................5
3.1.2
Number of patients...........................................................................................6
3.1.3
Treatments .......................................................................................................6
3.2
Study endpoints....................................................................................................7
3.2.1
Primary endpoints............................................................................................7
3.2.2
Secondary endpoints........................................................................................7
4
GENERAL STATISTICAL CONSIDERATIONS......................................................7
4.1
Sample size justification.......................................................................................8
4.2
Analysis populations ............................................................................................8
4.2.1
Intent-to-treat population / Safety population..................................................8
4.2.2
Clinically Evaluable population.......................................................................8
4.2.3
Microbiological Intent-to-treat population ......................................................8
4.2.4
Microbiologically Evaluable population .........................................................8
4.2.5
Pharmacokinetic population ............................................................................8
4.3
Other important considerations............................................................................8
4.3.1
Definition of baseline.......................................................................................8
4.3.2
Definition of infecting organism (i.e., pathogen) ............................................8
4.3.3
Study day calculation and visit windows.........................................................9
4.3.4
Missing and partial data...................................................................................9
4.3.5
Duration (e.g., for adverse events).................................................................10
4.3.6
Coding dictionaries........................................................................................10
5
PATIENT DISPOSITION..........................................................................................10
5.1
Disposition .........................................................................................................10
5.2
Protocol deviations.............................................................................................10


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5.3
Inclusion and exclusion criteria..........................................................................10
6
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................11
6.1
Demographics and general baseline characteristics...........................................11
6.2
Medical history...................................................................................................11
7
TREATMENTS AND MEDICATIONS....................................................................11
7.1
Prior and concomitant medications....................................................................11
7.2
Concomitant procedures.....................................................................................11
7.3
Study treatments.................................................................................................11
7.3.1
Study drug exposure ......................................................................................11
7.3.2
Study drug administration..............................................................................12
8
EFFICACY ANALYSIS ............................................................................................12
8.1
Overall clinical outcome ....................................................................................12
8.2
All-cause mortality through Day 28...................................................................12
8.3
Microbiological response ...................................................................................12
8.4
Signs and symptoms of late-onset sepsis ...........................................................12
9
SAFETY ANALYSIS.................................................................................................13
9.1
Adverse events ...................................................................................................13
9.1.1
Incidence of adverse events ...........................................................................14
9.1.2
Relationship of adverse events to study drug ................................................14
9.1.3
Severity of adverse event...............................................................................14
9.1.4
Adverse events of special interest..................................................................15
9.2
Physical examination..........................................................................................15
9.3
Clinical laboratory evaluations...........................................................................15
9.4
Vital signs...........................................................................................................16
10 PHARMACOKINETICS............................................................................................16
11 INTERIM ANALYSES..............................................................................................16
12 CHANGES IN THE PLANNED ANALYSIS...........................................................16
13 APPENDICES ............................................................................................................17
LIST OF TABLES
Table 1
Ceftobiprole dosing regimen for the treatment of neonates and infants with 
late-onset sepsis ............................................................................................6
LIST OF APPENDICES
Appendix 1
Adverse event and prior/concomitant medication date imputations...........17


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LIST OF ABBREVIATIONS
ACM
All-cause mortality
AE
Adverse event
AESI
Adverse Event of Special Interest
ATC
Anatomical Therapeutic Chemical
CE
Clinically Evaluable
DSMB
Data and Safety Monitoring Board
eCRF
Electronic CRF
EOT
End-of-treatment
ITT
Intent-to-treat
IV
Intravenous
LFU
Last follow-up
LOS
Late-onset sepsis
ME
Microbiologically Evaluable
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Microbiological Intent-to-treat
PK
Pharmacokinetic(s)
PT
Preferred Term
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
TOC
Test-of-cure
WHO DDE
World Health Organization Drug Dictionary 
Enhanced


BPR-PIP-003 
Statistical Analysis Plan
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1
INTRODUCTION
This document outlines the statistical methods to be implemented in the analysis of data 
collected within the scope of Basilea Pharmaceutica International Ltd., Allschwil, Protocol 
BPR-PIP-003 (A multicenter, open-label, single-arm, multiple-dose study to evaluate the 
safety, pharmacokinetics, and efficacy of ceftobiprole medocaril in term and pre-term 
neonates and infants up to 3 months of age with late-onset sepsis).
The purpose of this Statistical Analysis Plan (SAP) is to define the planned statistical 
methods in line with the study objectives. This plan should be read in conjunction with the 
study protocol (Version 5.0, dated 9 July 2024 at the time of finalization). All analyses will 
be conducted using SAS® Version 9.4 or higher.
2
OBJECTIVES
2.1
Primary objective
The primary objective of study BPR-PIP-003 is to characterize the safety profile of 
ceftobiprole medocaril in term and pre-term neonates and infants up to 3 months of age 
with late-onset sepsis (LOS).
2.2
Secondary objectives
The secondary objectives are to assess in term and pre-term neonates and infants up to 
3 months of age with LOS treated with ceftobiprole medocaril:

Pharmacokinetics (PK) of ceftobiprole

Clinical response

All-cause mortality (ACM)

Microbiological response.
3
INVESTIGATIONAL PLAN
3.1
Overall study design
3.1.1
Brief summary
This is a multicenter, open-label, single-arm, multiple-dose study of intravenous (IV)
ceftobiprole in term and pre-term neonates and infants up to 3 months of age with LOS.
Study therapy consists of IV ceftobiprole medocaril for 3–10 days, which may be extended 
to 14 days if considered clinically necessary by the Investigator. Ceftobiprole may be 
combined with ampicillin and/or an aminoglycoside based on the Investigator’s judgment, 
local standard of care, and/or isolated or presumed pathogens. If added, the treatment 
duration of ampicillin and/or an aminoglycoside is at the discretion of the Investigator.
Each patient is expected to complete the study in approximately 5–7 weeks, including 
screening, an estimated treatment duration of 3–10 days with possible extension up to 
14 days, end-of-treatment (EOT) visit, test-of-cure (TOC) visit 7–14 days after last 
ceftobiprole dose, and a last follow-up (LFU) visit 28–35 days after last ceftobiprole dose. 


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Safety assessments will be done throughout the study. Specimens for microbiological 
assessment will be obtained as clinically indicated in accordance with local standard of 
care. Blood samples for PK analysis will be collected on Day 3. Efficacy outcomes will be 
assessed at the EOT, TOC, and LFU visits.
An overview of the study design is provided in protocol Section 3. The schedule of 
assessments and procedures for the different periods are provided in protocol Section 5.1.
An independent Data and Safety Monitoring Board (DSMB) will review patient data on an 
ongoing basis to determine whether any safety concerns are observed, and whether the 
study should be allowed to continue, as specified in the DSMB Charter.
3.1.2
Number of patients
At least eight patients will be enrolled in the study, comprising at least two term patients 
(gestational age ≥ 37 weeks) and at least six pre-term patients (gestational age ≥ 24 to 36 
weeks), with post-natal age ranging from ≥ 3 days to ≤ 3 months.
3.1.3
Treatments
Eligible patients will receive ceftobiprole as a 2-hour IV infusion according to the schedule 
in Table 1, with dose adjusted according to gestational and post-natal ages. Body weight 
on Day 1 should be obtained within 12 hours prior to the first dose of study drug. From 
Day 2 until the last day of study treatment, the dose should be calculated based on the 
patient’s first body weight of the day.
Table 1
Ceftobiprole dosing regimen for the treatment of neonates and infants 
with late-onset sepsis
Gestational age 
group (weeks)
Post-natal age (days)
3 – 13
14 – 29
30 – 59
60 – 90
24 – 26
7.5 mg/kg q12h
7.5 mg/kg q12h
10 mg/kg q12h
10 mg/kg q12h
27 – 31
10 mg/kg q12h
10 mg/kg q12h
10 mg/kg q12h
15 mg/kg q12h*
32 – 36
10 mg/kg q12h
10 mg/kg q12h
15 mg/kg q12h*
15 mg/kg q12h*
≥37
15 mg/kg q12h*
15 mg/kg q12h*
15 mg/kg q12h*
15 mg/kg q8h*
Note: All doses will be infused over 2 hours. The maximum allowable dose in adult and pediatric patients is 500 mg 
regardless of body weight.
* Neonates and infants with a body weight < 4 kg should receive a maximum of 10 mg/kg/dose.


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3.2
Study endpoints
3.2.1
Primary endpoints
The primary endpoint is safety and tolerability in the Safety population, as assessed by 
adverse events (AEs), serious adverse events (SAEs), deaths, and discontinuations due to 
AEs during treatment with ceftobiprole and at the EOT, TOC, and LFU visits, as well as 
clinical laboratory tests, vital signs, and physical examination findings.
3.2.2
Secondary endpoints
The pharmacokinetics secondary endpoints are:

Plasma levels of ceftobiprole, ceftobiprole medocaril, and open-ring metabolite (PK 
population).
The efficacy secondary endpoints are:

Clinical cure rate at the EOT and TOC visits [Intent-to-treat (ITT) and Clinically 
Evaluable (CE) populations]

ACM through Day 28 (ITT population)

Microbiological eradication or presumed eradication rate at the EOT and TOC visits 
(Microbiological Intent-to-treat (mITT) and Microbiologically Evaluable (ME)
populations)

Improved signs and symptoms of LOS at the Day 3, EOT, and TOC visits (ITT and CE 
populations).
4
GENERAL STATISTICAL CONSIDERATIONS
Summary outputs, where possible, will be presented by neonate groups (term and pre-term) 
and overall. No formal hypothesis testing will be performed. Continuous data will be 
described using descriptive statistics (n, mean, standard deviation [SD], median, minimum, 
and maximum). Categorical data will be described using the patient count and percentage 
in each category. Non-zero percentages will be rounded to one decimal place, except 100%, 
which will be displayed without any decimal places. For the summary statistics of all 
numerical variables unless otherwise specified, minimum and maximum will be displayed 
to the same level of precision as reported, up to a maximum of three decimal places. Mean 
and median will be displayed to one level of precision greater than the data collected, up 
to a maximum of three decimal places. Standard deviation will be displayed to two levels 
of precision greater than the data collected, up to a maximum of three decimal places.
When count data are presented, the percentage will be suppressed when the count is zero,
to draw attention to the non-zero counts. A row denoted ‘Missing’ will be included in count 
tabulations where specified in the table shells, to account for dropouts and missing values. 
The denominator for all percentages will be the number of patients in the population of 
interest, unless otherwise specified.
All data will be displayed in listings sorted by neonate groups (term and pre-term) and 
subject ID.


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4.1
Sample size justification
This study is not powered for inferential statistical analysis. The sample size (eight patients; 
two term and six pre-term) is considered adequate to evaluate the safety of ceftobiprole in 
neonates and infants aged ≤3 months with LOS.
4.2
Analysis populations
4.2.1
Intent-to-treat population / Safety population
The Intent-to-treat (ITT) / Safety population consists of all enrolled patients who received 
at least one dose of ceftobiprole.
4.2.2
Clinically Evaluable population
The Clinically Evaluable (CE) population consists of patients in the ITT population who 
received at least 48 hours of study drug and had a completed overall clinical outcome 
assessment at the TOC visit, no major protocol deviations, and no concomitant systemic 
non-study antibiotic therapy.
4.2.3
Microbiological Intent-to-treat population
The mITT population consists of all patients in the ITT population with a causative
pathogen identified at baseline.
4.2.4
Microbiologically Evaluable population
The ME population consists of all patients in the CE population with a causative pathogen 
identified at baseline and a microbiological outcome assessment at the TOC visit.
4.2.5
Pharmacokinetic population
The PK population consists of all patients who received at least one dose of ceftobiprole 
and had at least one sample of plasma concentration measurement obtained by the 
appropriate methodology.
4.3
Other important considerations
4.3.1
Definition of baseline
Unless otherwise specified, baseline is defined as the last non-missing assessment prior to 
the first study drug administration. Both scheduled and unscheduled visits and assessments 
will be used in determining baseline.
4.3.2
Definition of infecting organism (i.e., pathogen)
The identification of organisms as infecting (i.e., pathogen) or non-infecting is based on 
Investigator assessment as reported in the eCRF. The assessment may be based on blood 
samples, urine, cerebrospinal fluid, or any other suitable specimen samples.
When multiple samples from the same specimen are taken on a specific study day and 
isolates are not all sent for central microbiology testing, or when local and central 
identification differ, only the results from the central microbiology laboratory on that study 
day will be considered for the identification of organisms.


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A causative pathogen is an infecting organism confirmed by central identification.
4.3.3
Study day calculation and visit windows
Visit windowing approaches will not be used for this study, and visit-based summaries will 
include scheduled assessments only. If more than the specified number of measurements 
has been taken in a scheduled visit, the latest recorded values will be used in visit 
summaries, unless otherwise stated. All scheduled and unscheduled post-baseline 
assessments will be used for derivation of minimum and maximum post-baseline values. 
If more than one assessment has the same minimum or maximum value, then the record 
with earliest occurrence will be selected respectively as the minimum or maximum 
assessment.
The following conventions will be used to calculate analysis study day:

Day 1 is the day of first study drug administration. Day −1 is the day before Day 1. 
No Day 0 is defined for this study.

Prior to Day 1, the algorithm is:
Study Day = visit/examination date −date of first study drug administration

For Day 1 and subsequent days, the algorithm is:
Study Day = visit/examination date −date of first study drug administration + 1.
Summary data such as AEs and concomitant medications will not be reported by visit. 
Tables that report abnormalities (e.g., clinically-notable abnormalities, laboratory shift 
tables) will include all assessments.
4.3.4
Missing and partial data
The following rules for missing data will be followed:

Adverse event and prior/concomitant medication date imputations will follow the rules 
described in Appendix 1.

The causality assessment for AEs should not be missing and will be queried for a value. 
Adverse events with missing causality will be considered related to study drug.

For ACM through Day 28, patients with unknown survival status will be considered 
deceased for the efficacy outcome. If it is known that the patient died but death date is 
unknown, then the death date will be imputed to last date known to be alive +1 day.

Unless otherwise specified, missing values for other individual data points will remain 
as missing. Missing values will not be imputed, and only observed values will be used 
in data analyses and presentation.


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4.3.5
Duration (e.g., for adverse events)
If date and time are collected, then duration is calculated as event end date and time minus 
event onset date and time. Duration will be displayed as days and fractions of days, or as 
hours and fractions of hours, as appropriate.
If only the date is collected, then the duration in days is calculated as event end date minus 
event onset date + 1.
4.3.6
Coding dictionaries
Adverse events and medical history are to be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 25.1 or later. Previous and concomitant 
treatments are to be coded using the World Health Organization Drug Dictionary Enhanced 
(WHO DDE) dated 01MAR2024 or later (format B3).
5
PATIENT DISPOSITION
5.1
Disposition
The following analysis sets will be summarized: patients in the ITT/Safety population, 
patients enrolled but never dosed, patients in the CE population, patients in the mITT 
population, patients in the ME population, and patients in the PK population. All 
percentages will be based on the number of patients in the ITT population. Patients who 
failed screening, and the reasons for screen failure, will be listed only.
Patient disposition (treatment, EOT, TOC, and LFU) will be summarized for the ITT 
population.
5.2
Protocol deviations
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. Protocol deviations will be documented by the clinical 
monitor throughout the course of monitoring visits. The protocol deviations will be 
categorized as important and non-important deviations, with important deviations further 
classified as major or minor (see the definition of the CE population in Section 4.2.2).
All protocol deviations will be listed, with patients with major protocol deviations leading 
to exclusion from CE population identified prior to database lock.
5.3
Inclusion and exclusion criteria
Full inclusion and exclusion criteria are listed in protocol Section 4.2 and 4.3, respectively. 
Data for inclusion/exclusion criteria for each patient will be listed.


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6
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
6.1
Demographics and general baseline characteristics
The following demographics and baseline characteristics data will be presented in tables 
using descriptive statistics for the ITT, CE, mITT, and PK populations:

Post-natal age, gestational age, breastfed by lactating mother status, sex, race, ethnicity

Height, weight.
6.2
Medical history
Medical history will be summarized overall and for each System Organ Class (SOC) and 
Preferred Term (PT), for the ITT population.
7
TREATMENTS AND MEDICATIONS
7.1
Prior and concomitant medications
All medications, other than the study drug, used during the study (from 7 days prior to the 
first dose of study drug, or from 3 days prior to the first dose of study drug for medications 
taken by the lactating mother), must be documented on the appropriate section of the eCRF.
Prior medications are defined as medications with a stop date prior to the first dose of study 
drug. Concomitant medications are defined as medications that are either ongoing at the 
time of the first dose of study drug, or start after the first dose of study drug.
The number and percentage of patients who receive prior and/or concomitant medication 
will be summarized separately by ATC level 2, ATC level 4, and PT.
At each level of summarization, a patient is counted once if he/she reports one or more 
medications at that level. All prior medications and concomitant medications will be 
summarized for the ITT population.
The imputation algorithm for partial concomitant medication dates is provided in Appendix 
1.
7.2
Concomitant procedures
Concomitant procedures are defined as procedures that are either ongoing on the time of
the first dose of study drug, or with a start date missing, or start after the first dose of study 
drug. All concomitant procedures will be listed.
7.3
Study treatments
7.3.1
Study drug exposure
Duration of study drug therapy and compliance will be summarized for the Safety 
population.

Study drug duration is defined as:
Days of (Date and time of the last dose – Date and time of first dose), rounded to one 
decimal.


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
Compliance is defined as:
Actual total dose (mg) / Planned total dose (mg)
Compliance will be classified into one of the categories < 80%, 80–120%, or > 120%, and 
will be presented as the number and percentage of patients in each category for the Safety 
population.
7.3.2
Study drug administration
All study drug administration data will be listed.
8
EFFICACY ANALYSIS
8.1
Overall clinical outcome
Overall clinical outcome is to be assessed at the EOT and TOC visits by the Investigator 
as ‘Clinical cure’, ‘Clinical failure’, or ‘Unevaluable’ (see protocol Section 5.6.1 for 
details). Clinical cure rate and reasons for failure or unavailability of data will be 
summarized in a table for the ITT and CE populations.
8.2
All-cause mortality through Day 28
Vital status is to be assessed at the LFU visit, in person or by telephone contact. Patients 
will be considered to have died at Day 28 if they meet all the following criteria:

A death is reported on the eCRF

The study day for death is ≤28.
The ACM at Day 28 will be summarized in a table for the ITT population.
8.3
Microbiological response
Microbiological outcome is to be assessed at the EOT and TOC visits by the Investigator 
as ‘Eradication’, ‘Presumed eradication’, ‘Persistence’, ‘Presumed persistence’, 
‘Unevaluable’, or ‘Relapse’ (see protocol Section 5.6.3 for details). If applicable, the 
relapse status of the patient is to be assessed at the LFU visit, by the Investigator.
Patients will be considered to have experienced microbiological eradication if they are 
classified as ‘Eradication’ or ‘Presumed eradication’. Microbiological eradication at EOT 
and TOC, and relapse status at the LFU visit, will be summarized in a table for the mITT 
and ME populations.
All microbiological data will be listed.
8.4
Signs and symptoms of late-onset sepsis
Signs and symptoms of LOS are to be assessed by the Investigator as ‘Present’, ‘Absent’, 
‘Improved’, ‘Unchanged’, or ‘Worsened’.


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Overall signs and symptoms assessment will be derived and summarized at Day 3, EOT,
and TOC, for the ITT and CE populations. The following rules will be applied for 
categorization:
1. Each post-baseline sign or symptom evaluation is re-classified as stated in the 
following table:
Post-baseline
Baseline
Present
Absent
Improved
Unchanged
Worsened
Present
Unchanged
Resolved
Improved
Unchanged
Worsened
Absent
Worsened
Absent
NA
Absent
Worsened
2. Overall assessment for each visit is derived as follows:

Resolved: all signs and symptoms are classified as ‘Resolved’ or ‘Absent’ (see table 
above).

Improved: all signs and symptoms are classified as ‘Resolved’ or ‘Improved’ or 
‘Absent’ (see table above), with at least one ‘Improved’.

Unchanged: all signs and symptoms are classified as ‘Resolved’, ‘Improved’ or 
'Unchanged’ or ‘Absent’ (see table above), with at least one ‘Unchanged’.

Worsened: there is at least one sign or symptom classified as ‘Worsened’.
All signs and symptoms data will be listed.
9
SAFETY ANALYSIS
All Safety analyses will be conducted using the Safety population.
9.1
Adverse events
Adverse events are defined in protocol Section 7.2. As the definition includes only events 
which occur after first study-drug administration, all AEs are considered to be ‘treatment
emergent’. Pre-treatment events are reported as medical history. Relationship and action 
taken referring to ampicillin and aminoglycoside are listed only.
An overview summary of number and percentage of patients will be provided for any AE, 
study-drug-related AEs, SAEs, study-drug-related SAEs, AEs leading to treatment 
discontinuation, study-drug-related AEs leading to treatment discontinuation, AEs leading 
to treatment interruption / dose reduction, study-drug-related AEs leading to treatment 
interruption / dose reduction, AEs leading to death, study-drug-related AEs leading to 
death, AEs of special interest (see Section 9.1.4), and study-drug-related AEs of special 
interest will be provided.
All AEs, SAEs, and AEs leading to death will be presented in separate listings.


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9.1.1
Incidence of adverse events
The number and percentage of patients reporting AEs will be tabulated by SOC and PT for 
all AEs, and separately for study-drug-related AEs. Patients with multiple events will be 
counted only once within each category. SOC and PT will be sorted in descending order of 
frequency in the total of all treatment groups.
In addition, the following categories will be summarized similarly:

AEs up to EOT visit

AEs up to TOC visit

SAEs

AEs leading to treatment discontinuation

AEs leading to treatment interruption / dose reduction.
9.1.2
Relationship of adverse events to study drug
The relationship to ceftobiprole is collected based on the possibility that the study drug 
caused the event. The possible relationships are ‘Not Related’, ‘Unlikely’, ‘Possible’, 
‘Probable’, and ‘Not Applicable’, with AEs assessed as ‘Possible’ or ‘Probable’ classified 
as study-drug-related.
A summary of AEs will also be presented by relationship to study drug, SOC and PT. If a 
patient reports multiple occurrences of the same AE, only the worst relationship category
will be counted.
Adverse events that are missing an assessment of relationship to study drug will be counted 
in the study-drug-related AEs summary table, but will be presented in the summary table 
by relationship and in listing with a ‘Missing’ relationship.
9.1.3
Severity of adverse event
Severity of AEs is collected in the eCRF as ‘Mild’, ‘Moderate’, or ‘Severe’, and a summary 
of AEs by severity will be presented in a table. If a patient reports multiple occurrences of 
the same AE, only the most severe will be counted. AEs that are missing severity will be 
presented in tables as severity ‘Unknown’.


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9.1.4
Adverse events of special interest
Adverse events of special interest (AESI) are defined in protocol Section 7.2.5 as
hypersensitivity reactions, convulsions, clostridioides difficile-associated colitis or 
pseudomembranous colitis, hepatic enzyme increased, hyponatremia, renal failure, 
infusion site reactions, and thromboembolic events. These AESIs will be identified using 
the following narrow Standardized MedDRA Query (SMQ) or MedDRA PTs:

Hypersensitivity reactions (Narrow SMQ code 20000214)

Convulsions (Narrow SMQ code 20000079)

Clostridioides (Clostridium) difficile-related AEs (Narrow SMQ code 20000080)

Hepatic enzyme increased (PTs: Hepatic function abnormal, Alanine aminotransferase, 
Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate 
aminotransferase abnormal, Aspartate aminotransferase increased, Hepatic enzyme 
abnormal, Hepatic enzyme increased, Liver function test abnormal, Liver function test 
increased, Transaminases increased)

Hyponatremia (PTs: Blood sodium decreased or Hyponatraemia)

Acute renal failure (Narrow SMQ code 20000003)

Extravasation events (injections, infusions and implants) (Broad SMQ code 20000136)

Embolic and thrombotic events (Narrow SMQ code 20000081).
Adverse events of special interest will be summarized by SOC and PT.
9.2
Physical examination
Physical examination results for all patients will be presented in a listing.
9.3
Clinical laboratory evaluations
Local laboratory tests include hematology, blood chemistry, and urine analysis (dipstick) 
parameters in accordance with the protocol Schedule of Assessments and protocol Table 
4.
Summary tables for laboratory parameters including actual values and change from 
baseline values will be presented for mandatory laboratory parameters with numeric values 
by visit.
Laboratory data will also be summarized using shift tables where appropriate. Each 
patient’s continuous laboratory safety parameter values will be flagged as ‘low’, ‘normal’, 
or ‘high’ relative to the normal ranges of the laboratory. Each patient’s categorical 
laboratory safety parameter values will be flagged as ‘abnormal’ or ‘normal’. These 
categorical data will be summarized in shift tables comparing the minimum post-baseline 
value, maximum post-baseline value, and all other relevant post-baseline visits, with those 
at the baseline visit.
Laboratory data collected at unscheduled visits will be included in listings, and will 
contribute to tables of shifts from baseline and tables showing changes from baseline to 


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highest value and lowest value. Unscheduled laboratory results will not be windowed for 
the purposes of assigning a nominal visit.
All clinical laboratory parameters will be presented in a listing including normal ranges,
and indicating if the value is out of range.
9.4
Vital signs
Summary tables of observed values and changes from baseline, as well as minimum and 
maximum post-baseline values, will be presented for vital-sign data, including weight (g), 
body temperature (°C), respiration rate (breaths/minute), pulse rate (bpm), systolic blood 
pressure (mmHg), diastolic blood pressure (mmHg), and pulse oximetry (%), at each visit 
on a given timepoint, in the Safety population.
10
PHARMACOKINETICS
Plasma concentrations of ceftobiprole, ceftobiprole medocaril, and the open-ring 
metabolite will be reported at each time point specified in the protocol Schedule of 
Assessments.
Non-compartmental PK analysis and a population PK model will be developed and 
reported separately.
11
INTERIM ANALYSES
No interim analyses will be performed.
12
CHANGES IN THE PLANNED ANALYSIS
There are no changes between the protocol-defined statistical analyses and those presented
in this SAP.
The definition of the CE population has been clarified in this SAP. Patients should have 
received at least 48 hours of study drug to be included in the CE.


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13
APPENDICES
Appendix 1 Adverse event and prior/concomitant medication date imputations
Imputation rules for partial dates
Adverse event start date imputation
Parameter
Missing
Additional conditions
Imputation
Start date for 
AEs
D
M and Y same as M and Y of first dose of 
study drug
Date of first dose of study 
drug
M and/or Y not same as date of first dose of 
study drug
First day of month
D and M
Y same as Y of first dose of study drug
Date of first dose of study 
drug
Y is after Y of first dose
1 January
D, M, Y
None – date completely missing
Date of first dose of study 
drug
D = day; M = month; Y = year; AE = adverse event.
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Prior and concomitant medication start date imputation
Parameter
Missing
Imputation
Start date for 
medication
D
First day of the month under consideration
D and M
1 January
D, M, Y
1 January of the year of informed consent 
Stop date for 
medication
D
Last day of the month under consideration
D and M
31 December
D, M, Y
31 December of the year of follow-up visit 
D = day; M = month; Y = year.
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month.