Clinical trial NCT02527681
Conditions: Bacterial Infections
Sponsor: Basilea Pharmaceutica
Start date: 2016-11-22; Completion date: 2020-02-25
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study characterized the pharmacokinetics and safety of a single dose of ceftobiprole in neonates and infants aged ≤ 3 months.

Detailed description:

Arms: arm 1: Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, an advanced-generation cephalosporin developed for intravenous administration. Ceftobiprole is characterized by potent, broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative pathogens.
Interventions: intervention 1: Ceftobiprole medocaril
Intervention descriptions: intervention 1: Ceftobiprole medocaril was administered as a single intravenous infusion, with a bodyweight-adjusted volume, at a constant rate over 4 hours. The ceftobiprole dose was 7.5 mg/kg, which corresponds to 10.0 mg ceftobiprole medocaril.

Protocol documents:
Prot_001.pdf: 
NCT02527681 
 
 
CLINICAL STUDY PROTOCOL  
BPR-PIP-001 
Ceftobiprole medocaril 
Version 5.0 / 21 March 2019 
An open-label study to evaluate the single-dose pharmacokinetics and safety of 
ceftobiprole in neonate and infant subjects aged up to 3 months undergoing 
treatment with systemic antibiotics 
Protocol number/Version: 
BPR-PIP-001 / Version 5.0 
Compound: 
Ceftobiprole medocaril 
Phase of development: 
Phase 1 
EudraCT number: 
2013-004614-18 
Project Physician: 
Kamal Hamed, MD, MPH 
Project Pharmacologist 
Patrice Larger, MSc 
Project Statistician:  
Mikael Saulay, MSc 
Sponsor: 
Basilea Pharmaceutica International Ltd 
Grenzacherstrasse 487 
CH-4058 Basel/Switzerland 
Tel + 41 61 606 1111 
 
 
Confidentiality statement 
The information contained in this document is commercial confidential information which is the property 
of Basilea Pharmaceutica International Ltd, or is under its control. This information is provided to you in 
confidence as an investigator, potential investigator or consultant, for review by you, your staff and an 
applicable Independent Ethics Committee/Institutional Review Board, and may not be disclosed by the 
recipient to any other third party without prior written authorization from Basilea Pharmaceutica 
International Ltd, 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 potential participants 
or to another third party is required by applicable law or regulations or to obtain such informed consent 
from potential participants in such clinical study, the party 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 Pharmaceutica International Ltd. 
Note: This is an electronically controlled document. 
 
 


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SPONSOR SIGNATURES 
Protocol Number/Version: 
BPR-PIP-001 / Version 5.0 
Study title: 
An open-label study to evaluate the single-dose 
pharmacokinetics and safety of ceftobiprole in neonate 
and infant subjects aged up to 3 months undergoing 
treatment with systemic antibiotics  
Compound: 
Ceftobiprole medocaril 
Phase of development: 
Phase 1 
Project Physician: 
Kamal Hamed, MD, MPH 
Project Pharmacologist 
Patrice Larger, MSc 
Project Statistician:  
Mikael Saulay, MSc 
Sponsor: 
Basilea Pharmaceutica International Ltd 
Grenzacherstrasse 487 
CH-4058 Basel/Switzerland 
Tel + 41 61 606 1111 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE: An open-label study to evaluate the single-dose pharmacokinetics and safety of 
ceftobiprole in neonate and infant subjects aged up to 3 months undergoing treatment with 
systemic antibiotics  
Sponsor:  Basilea Pharmaceutica International Ltd 
Project Phase: 1 
Indication:  Clinical pharmacology 
Objectives 
Primary: to characterize the pharmacokinetics of single doses of ceftobiprole in neonates and 
infants aged ≤ 3 months.  
Secondary: to evaluate the safety and tolerability of ceftobiprole in neonates and infants aged 
≤ 3 months. 
Study design: Open-label, single-fixed dose, multicenter study 
Planned total sample size 
45 neonate or infant subjects, stratified for gestational age and post-natal age  
Number of centers and recruitment 
Up to 8 centers in Europe, and 10 centers in the USA, with additional centers and locations 
possible  
Subject inclusion criteria 
1. Neonates and infants ≤ 3 months, with gestational age ≥ 28 weeks 
2. Documented or presumed (or at risk of) bacterial infections, and currently receiving antibiotic 
treatment* 
3. Expected to survive beyond the first 7 days after enrolment 
4. Sufficient vascular access to receive study drug, and to allow blood sampling at a site 
separate from the study drug infusion site 
5. Parent’s / legally acceptable representative’s informed consent to participate in the study 
* Subjects must be scheduled to receive at least one infusion of systemic antibiotics before, and at 
least one infusion after, their ceftobiprole dose. 
Subject exclusion criteria 
1. Major birth defect or malformation syndrome+ 
2. Proven presence of an immunodeficiency 
3. HIV or other congenital viral or fungal infection 
4. Significant laboratory abnormalities including: 
− Haematocrit < 20% 
− Absolute neutrophil count (ANC) < 0.5 × 109/L 
− Platelet count < 50 × 109/L 
− Alanine aminotransferase (ALT), aspartate aminotransferase (AST) > 3 × the age-specific 
upper limit of normal (ULN) 


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5. Impaired renal function or known significant renal disease, as evidenced by an estimated 
glomerular filtration rate (using the Schwartz formula or other applicable formula) less than 
2/3 of normal for the applicable age group‡ 
6. Any condition which would make the subject or caregiver, in the opinion of the investigator, 
unsuitable for the study 
+ Subject eligibility will be decided based on an individualized assessment. Subjects with major 
birth defects or malformation syndromes should be excluded in view of the following 
• A low likelihood that the subject will complete the study 
• Increased risk of side effects with ceftobiprole (e.g. seizures in patients with CNS disorders) 
• An expected impact on pharmacokinetics (e.g., haemodynamically relevant shunts) 
‡ See Appendix 4 for supporting data and the table of GFR thresholds. 
Study drugs and formulations: 
Ceftobiprole medocaril powder for concentrate for solution for infusion (BAL5788) 
Concurrent control:  None 
Study drug dosage 
7.5 mg/kg body weight ceftobiprole (single-dose), administered as ceftobiprole medocaril 
Route of administration 
Intravenous 
Blinding 
Open-label 
Duration of subject participation 
Total duration 8 ± 3 days, comprising 24-hour screening, administration of a single dose of 
ceftobiprole, and 6 ± 3-day follow-up 
Main parameters 
Efficacy 
 
Not applicable 
Safety and tolerability 
Adverse events, laboratory tests (hematology, blood chemistry, urinalysis), vital signs, physical 
examination 
Pharmacokinetics 
Non-compartmental analysis : Cmax, t1/2 AUC0–t, AUC0–∞, CLS, VSS, T > MIC. 
The relationship between exposure (Cmax and AUC), derived pharmacokinetic (PK) parameters 
(CLS, VSS, t1/2) gestational age, post-natal age, body weight, body mass index, body surface area, 
and calculated creatinine clearance will also be assessed. 
Statistical analysis 
No hypothesis testing will be performed. PK data will be listed and analysed using descriptive 
statistics, including mean, median, SD, %CV, and range. Safety data will be listed and presented 
in frequency tables, summary tables, and shift tables. 


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Analysis populations 
Pharmacokinetics analysis population: all subjects who receive study drug and have adequate 
samples for determination of time-plasma concentration profiles of ceftobiprole. 
Safety analysis population: all subjects who receive any quantity of study drug. 
PROCEDURES 
A total of 45 male and female neonates and infants aged up to 3 months (inclusive) will be 
assigned to study treatment. Subjects must be undergoing treatment with systemic antibiotics for 
documented or presumed bacterial infections, or because they are at risk of infection. The study 
population will comprise 3 cohorts, each of 15 subjects, based on gestational age (28 to 32 weeks 
[completed]; 33 to 36 weeks [completed]; ≥ 37 weeks). In the two cohorts with subjects of 
gestational age ≤ 36 weeks, subjects will be further stratified by post-natal age (< 28 days; 
≥ 28 days) so that at least 5/15 subjects are assigned to study treatment in each post-natal age 
group. Cohorts will be sequentially dosed, with the first cohort comprising subjects of the highest 
gestational age. 
Parents or legally acceptable representatives will provide signed informed consent. Subjects in 
each cohort will be screened for eligibility within 24 hours before dosing. Enrolled subjects will 
be dosed in specialised neonatal care institutions/departments.  
Subjects will receive a single dose of ceftobiprole at 7.5 mg/kg body weight, given as a 4-hour 
constant-rate infusion of ceftobiprole medocaril. Blood samples (200–300 µL) for PK analysis 
will be obtained at baseline (pre-dose), and at 2, 4, 6, 8 and 12 hours after the start of dosing. Full 
portions of urine will be collected in subjects in whom a urinary catheter has been placed for their 
standard clinical care; urinary catheters will not be placed for the purpose of the study.  In 
subjects without a urinary catheter, one or more portions of urine may be obtained before, during, 
and after dosing.  
An aliquot of the infusion solution will be collected and frozen at below −65 °C immediately 
after sampling for analysis, to ensure that the correct dose was given. Subjects will be evaluated 
for safety on Day 7 ± 3  after dosing.  
Efficacy will not be evaluated. Safety assessments will include vital signs, physical examination, 
safety laboratory tests, and monitoring for adverse events. 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .........................................................................................................3 
ABBREVIATIONS ..................................................................................................................9 
1 INTRODUCTION AND BACKGROUND .......................................................................11 
1.1 Disease characteristics and treatment ...........................................................................11 
1.2 Ceftobiprole medocaril .................................................................................................11 
1.2.1 Nonclinical studies ..................................................................................................11 
1.2.2 Clinical studies ........................................................................................................13 
1.2.3 Rationale for dose selection and treatment period ..................................................14 
2 OBJECTIVES OF THE STUDY ........................................................................................15 
2.1 Primary objective ..........................................................................................................15 
2.2 Secondary objective ......................................................................................................15 
3 STUDY DESIGN ...............................................................................................................15 
3.1 Overview of study design and dosing regimen .............................................................15 
3.2 Discussion of study design ............................................................................................16 
3.3 Number of subjects/ assignment to treatment groups ...................................................16 
3.4 Centers ..........................................................................................................................17 
4 STUDY POPULATION .....................................................................................................17 
4.1 Target population ..........................................................................................................17 
4.2 Inclusion criteria ...........................................................................................................17 
4.3 Exclusion criteria ..........................................................................................................18 
4.4 Criteria for premature withdrawal and replacement of subjects ...................................18 
4.5 Concomitant and previous medication and treatment ...................................................18 
5 SCHEDULE OF ASSESMENTS AND PROCEDURES ..................................................19 
5.1 Summary schedule of assessments ...............................................................................19 
5.1.1 Screening (Days −1 to 1) .........................................................................................19 
5.1.2 Ceftobiprole dosing (Day 1) ....................................................................................21 
5.1.3 Follow-up assessment (Day 7±3) ............................................................................22 
5.2 Study procedures ...........................................................................................................22 
5.2.1 Efficacy ...................................................................................................................22 
5.2.2 Pharmacology ..........................................................................................................22 
5.2.3 Safety .......................................................................................................................24 
6 STUDY DRUGS ................................................................................................................26 
6.1 Dose and schedule .........................................................................................................26 
6.2 Administration ..............................................................................................................27 
6.3 Blinding and randomization ..........................................................................................29 
6.4 Packaging and labelling ................................................................................................29 


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6.5 Compliance check and accountability ...........................................................................29 
7 SUBJECT SAFETY ...........................................................................................................30 
7.1 Adverse events ..............................................................................................................30 
7.1.1 Definition of adverse events ....................................................................................30 
7.1.2 Evaluation of adverse events ...................................................................................30 
7.2 Serious adverse events ..................................................................................................31 
7.2.1 Definition of serious adverse events .......................................................................31 
7.2.2 Reporting of serious adverse events ........................................................................32 
7.3 Treatment and follow-up of adverse events ..................................................................33 
7.4 Laboratory test abnormalities ........................................................................................33 
7.5 Pregnancy ......................................................................................................................33 
7.6 Dose modifications for safety reasons ..........................................................................33 
7.7 Warnings and precautions .............................................................................................33 
8 STATISTICAL CONSIDERATIONS ...............................................................................34 
8.1 Primary and secondary study variables .........................................................................34 
8.2 Statistical and analytical methods .................................................................................34 
8.2.1 Statistical model ......................................................................................................34 
8.2.2 Sample size calculation ...........................................................................................34 
8.2.3 Hypothesis testing ...................................................................................................34 
8.2.4 Statistical analyses ...................................................................................................34 
8.2.5 Interim analysis .......................................................................................................35 
9 DATA QUALITY ASSURANCE AND VERIFICATION PROCEDURES ....................35 
9.1 Electronic case report forms .........................................................................................35 
10 PROTOCOL AMENDMENTS ..........................................................................................35 
11 PREMATURE TERMINATION OF THE STUDY ..........................................................35 
12 ETHICAL AND REGULATORY ASPECTS ...................................................................36 
12.1 Good Clinical Practice ..................................................................................................36 
12.2 Informed consent ...........................................................................................................36 
12.3 Subject confidentiality and data protection ...................................................................36 
12.4 Independent Ethics Committees / Institutional Review Boards ....................................36 
12.5 Study records .................................................................................................................37 
12.5.1 Investigator's Study File ..........................................................................................37 
12.5.2 Subject source documents .......................................................................................37 
12.5.3 Electronic case report forms ....................................................................................37 
12.5.4 Document retention and archiving ..........................................................................37 
13 MONITORING ...................................................................................................................38 
13.1 Monitoring ....................................................................................................................38 


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13.2 Source data verification ................................................................................................38 
14 AUDITS AND INSPECTIONS .........................................................................................38 
15 PUBLICATION POLICY ..................................................................................................38 
16 REFERENCES ...................................................................................................................39 
17 APPENDICES ....................................................................................................................40 
 
LIST OF TABLES 
Table 1 
Summary of treatment and follow-up schedule ..................................................15 
Table 2 
Schedule of assessments .....................................................................................20 
Table 3 
Schedule of PK sampling and vital signs on Day 1 ............................................21 
Table 4 
Ceftobiprole administration and dose calculation by body weight ....................28 
Table 5  
Exposure to ceftobiprole at the NOAEL in juvenile rats ....................................41 
Table 6  
Observed pharmacokinetic and pharmacodynamics parameters corrected 
by the free fraction in the age group > 3 months to < 2 years (N=16) ...............42 
Table 7  
Predicted exposure to ceftobiprole in the age group ≥ 3 months to 
< 2 years ..............................................................................................................43 
Table 8 
Estimated normal and worst-case exposure and urinary concentrations 
following a single dose of 7.5 mg/kg ceftobiprole in neonates and infants 
up to a postnatal age of 3 months. ......................................................................43 
 
LIST OF APPENDICES 
Appendix 1 Rationale for dose selection (neonates / paediatric population ≤ 3 months 
of age) .................................................................................................................40 
Appendix 2 Collection, storage, and shipping of blood, plasma, infusion solution, and 
urine for pharmacokinetic analyses ....................................................................45 
Appendix 3 Criteria for evaluating relationship between adverse events and study 
treatment .............................................................................................................47 
Appendix 4 Laboratory reference values and formulas .........................................................49 
 
 


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ABBREVIATIONS 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANC  
Absolute neutrophil count 
AP  
Alkaline phosphatase 
AST  
Aspartate aminotransferase 
AUC  
Area under the curve 
BLQ  
Below the limit of quantitation 
BUN  
Blood urea nitrogen 
CHO  
Chinese hamster ovary 
CLCR  
Creatinine clearance 
Cmax  
Maximum observed plasma concentration 
CLs  
Systemic clearance 
CPK  
Creatinine phosphokinase 
CV  
Coefficient of variation (%CV) 
ECG  
Electrocardiogram 
eCRF  
Electronic case report form 
EDC  
Electronic data capture 
EEG  
Electroencephalogram 
GCP  
Good Clinical Practice 
GFR  
Glomerular filtration rate 
GGT  
Gamma-glutamyl transferase 
HGPRT  
Hypoxanthine-guanine phosphoribosyltransferase 
IB  
Investigator’s Brochure 
ICH  
International Conference on Harmonisation 
IEC/IRB  
Independent Ethics Committee / Institutional Review Board 
i.v.  
Intravenous 
LC  
Liquid chromatograph 
LDH  
Lactate dehydrogenase 
LOQ  
Limit of quantitation 


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MCH  
Mean corpuscular haemoglobin 
MCHC  
Mean corpuscular haemoglobin concentration 
MCV  
Mean corpuscular volume 
MIC  
Minimum inhibitory concentration 
MS  
Mass spectrometry 
NOAEL  
No-observed-adverse-effect level 
NOEL  
No-observed-effect level 
PMA  
Post-menstrual age 
PK  
Pharmacokinetic(s) 
QC  
Quality control 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SD  
Standard deviation 
T > MIC  
Time that concentration is above the MIC 
t1/2  
Half life 
t.i.d.  
Three times daily 
ULN  
Upper limit of normal 
Vss  
Volume of distribution at steady-state 
WBC  
White blood cell 
 
 
 


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1 
INTRODUCTION AND BACKGROUND 
1.1 
Disease characteristics and treatment 
Bacterial infection is a leading cause of morbidity and mortality in children. 
Bacterial infections in children may be caused by a wide range of Gram-positive or 
Gram-negative pathogens, including group B streptococci, coagulase-negative 
staphylococci, Methicillin-resistant Staphylococcus aureus and Gram-negative organisms 
[1–4]. Initial therapy in infants with severe infections is generally empiric because 
pathogen identification often requires impractical invasive sampling [3]. Accordingly, it 
is important to use antimicrobials that provide broad-spectrum antibacterial activity [5]. 
1.2 
Ceftobiprole medocaril 
1.2.1 
Nonclinical studies 
1.2.1.1 Pharmacology/microbiology/pharmacokinetics/pharmacodynamics.  
Ceftobiprole medocaril (BAL5788) is the water-soluble prodrug of ceftobiprole, a 
cephalosporin with bactericidal activity against a broad spectrum of Gram-positive 
bacteria, including methicillin-resistant Staphylococcus species, vancomycin-resistant 
S. aureus, and penicillin-resistant Streptococcus pneumoniae (PRSP). Ceftobiprole also 
demonstrates activity against Gram-negative bacteria, including Pseudomonas 
aeruginosa. Ceftobiprole is formulated for intravenous administration. Ceftobiprole is 
resistant to hydrolysis by the S. aureus PC1 Class A β-lactamase, and is relatively 
resistant to hydrolysis by many β-lactamases of Class C and Class A Gram-negative 
bacteria. Ceftobiprole is hydrolyzed by extended spectrum β-lactamases and metallo 
β-lactamases.  
The pharmacokinetic/ pharmacodynamic (PK/PD) parameter best correlating with 
efficacy was the time that the drug concentration exceeded the MIC (T > MIC), as for 
other β-lactam antibiotics.  
Protein binding of ceftobiprole in plasma in all animal species was low and concentration 
independent. Mean plasma protein binding in humans was 16%. In rats, excretion was 
almost complete (>94%) within 4 days after intravenous administration of ceftobiprole 
medocaril.  
Further details on the pharmacology, microbiology, PK and PD of ceftobiprole medocaril 
are provided in the Investigator’s Brochure (IB). 
1.2.1.2 Toxicology 
In animals, the primary targets of toxicity after intravenous administration were the 
kidneys and the infusion site.  
Renal toxicity was attributable to the high rate of glomerular filtration leading to high 
concentrations of ceftobiprole in urine, precipitation of ceftobiprole in distal parts of the 
nephron, and resulting renal tissue damage. This effect is not thought to apply to humans 
because glomerular filtration of ceftobiprole is much slower and urinary concentrations 
of ceftobiprole do not approach the limit of solubility.  


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• Local tolerance:  
− In small animals (4 or 13 week studies in rats or marmosets) concentration-
dependent slight to moderate local endothelial irritation was observed when 
ceftobiprole medocaril (prodrug) was administered over 4–8 hours into the Vena 
cava at concentrations up to 62 mg/mL.  
− In a local tolerability study in rabbits, repeated intravenous administration of 
ceftobiprole into the auricular vein (8 consecutive days with a 3-minute 
endothelial contact period per day) caused no irritation at concentrations of 2 and 
10 mg/mL (corresponding to ceftobiprole medocaril sodium nominal 
concentrations of 2.66 and 13.3 mg/mL).  
− Hemolysis, plasma turbidity and precipitation were observed in human, dog, rat 
and marmoset blood at concentrations ≥ 12.5 mg/mL. 
− In a previous clinical study including 64 children age 3 months to 17 years when 
ceftobiprole was administered intravenously at a concentration of 2 mg/mL as 
single dose over 2-hours (at dose levels of 7, 10, or 15 mg/kg) one moderate 
catheter-site related reaction was observed in a child in the age group ≥ 2 to 
< 6 years (ceftobiprole 15 mg/kg) and one mild phlebitis in a child in the age 
group ≥ 3 months to < 2 years (ceftobiprole 15 mg/kg). Overall, the available 
non-clinical and clinical data suggest that the expected risk of local irritation in 
the paediatric population with ceftobiprole is acceptable. 
• 
Ceftobiprole medocaril was neither teratogenic nor embryotoxic in rats and 
cynomolgus monkeys, and had no effects on fertility and early embryonic 
development in rats. No effects on behavioural or developmental parameters were 
noted in pups. No signs of skin sensitization, irritation, or phototoxicity were seen. 
The antigenic potential of ceftobiprole medocaril is low. No mutagenic potential was 
seen in the Ames test or in the Chinese hamster ovarian (CHO HGPRT) assay, and 
in vivo genotoxicity assays (micronucleus and unscheduled DNA synthesis assays).   
• 
The convulsive potential after intracerebroventricular administration to mice was 
comparable to that of imipenem. No cardiac or pulmonary toxicity was observed. 
• 
Neonatal and juvenile rats (one day old at start of dosing) given once daily 
subcutaneous doses of ceftobiprole medocaril for 50 days exhibited similar findings 
to those seen in adults. Besides minor signs of local irritation at the injection site, 
the primary target of toxicity were the kidneys, with microscopic changes 
(cytoplasmic globules in collecting ducts) only at the highest dose of 250 mg/kg/day 
(corresponding to 187.5 mg/kg/day of ceftobiprole) and partial recovery after a 
28-day recovery period. The no-observed-adverse-effect level (NOAEL) in juvenile 
animals was 100 mg/kg/day (corresponding to 75 mg/kg/day of ceftobiprole).  
 
 


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• 
Safety margins based on plasma exposures noted at the NOAEL in animals are 
approximately 1- to 5-fold and 1- to 3-fold for Cmax and 2- to 3-fold and 1- to 2-fold 
for AUC for administration of 500 and 1,000 mg ceftobiprole (BAL9141) infused to 
humans over 2 hours as ceftobiprole medocaril (BAL5788). The safety margin based 
on plasma concentrations of ceftobiprole seen at the no-observed-effect level 
(NOEL) for renal toxicity is 2- to 7-fold and 1- to 5-fold relative to clinical doses of 
500 and 1,000 mg, whereas relative to the clinical dose of 500 mg, the exposure ratio 
based on urine concentrations of ceftobiprole seen at the NOEL for renal toxicity is 
4- to 34-fold. These safety margins are applicable to single-dose or multiple-dose 
administration, since drug accumulation is negligible with multiple dosing in 
humans. 
Further details on the toxicology of ceftobiprole medocaril are provided in the IB. 
1.2.2 
Clinical studies 
1.2.2.1 Clinical pharmacology 
The PK of ceftobiprole in adult subjects are predictable, linear and time-independent 
across the dose range of 125 to 1,000 mg, and variability is low (< 30%). The volume of 
distribution at steady state (Vss) of ceftobiprole is 18 L, suggesting that distribution is 
restricted to the extracellular water compartment. The total body clearance of ceftobiprole 
is approximately 5 L/h, and the apparent half-life (t1/2) is 3 to 4 hours. 
Ceftobiprole is eliminated primarily unchanged by renal excretion, with minimal 
metabolism to an open-ring metabolite, which accounts for approximately 4% of total 
exposure. The predominant mechanism responsible for elimination is glomerular 
filtration. The systemic clearance of ceftobiprole correlates with the creatinine clearance. 
Therefore dose regimen adjustments are recommended in adult subjects with moderate 
and severe renal impairment, in end-stage renal disease subjects and in subjects with 
CLCR > 150 mL/min.  
In paediatric subjects given single doses of ceftobiprole at 15 mg/kg (age 3 months to 
< 6 years), or 10 mg/kg dose (age 6 years to < 12 years), the single-dose PK of 
ceftobiprole were generally within the range of what has previously been observed in 
healthy adult subjects after a single ceftobiprole 500 mg dose. However, in subjects given 
7 mg/kg (age 12 years to < 18 years), the systemic exposure was substantially lower than 
that achieved in adults after a single ceftobiprole 500 mg dose. The extent of conversion 
of the prodrug was demonstrated in vivo and in vitro as being age-independent from 
neonates to adults. 
Further details on the clinical pharmacology of ceftobiprole medocaril are provided in the 
IB. 
 
 


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1.2.2.2 Efficacy and safety 
In adults, ceftobiprole is approved in Europe for treatment of hospital-acquired 
pneumonia (excluding ventilator-associated pneumonia) and for community-acquired 
pneumonia. In the paediatric population, the safety and efficacy of ceftobiprole have not 
yet been established. 
In a previous clinical study in 64 paediatric subjects age 3 months to 17 years 
(study CSI1006), ceftobiprole  was administered intravenously at a concentration of 
2 mg/mL as a single dose over 2-hours (at dose levels of 7, 10, or 15 mg/kg). In this 
study, ceftobiprole was well tolerated with vomiting reported as the most frequent 
adverse event (AE) (6/64 subjects). The majority of AEs were mild in severity and 
considered not related to study drug. No deaths and no ceftobiprole-related serious 
adverse events (SAEs) were reported during the study, and no subjects discontinued due 
to a treatment-emergent AE.  
In  terms of local tolerability, one moderate catheter-site related reaction was observed in 
a child in the age group ≥ 2 to < 6 years (ceftobiprole 15 mg/kg) and one mild phlebitis in 
a child in the age group ≥ 3 months to < 2 years (ceftobiprole 15 mg/kg). Overall, the 
available pre-clinical and clinical data suggest that the expected risk of local irritation in 
the paediatric population with ceftobiprole is acceptable but should be carefully 
monitored. 
Further details on the clinical efficacy and safety of ceftobiprole are provided in the IB. 
1.2.3 
Rationale for dose selection and treatment period 
Neonate and infant subjects will receive a single infusion of 7.5 mg/kg ceftobiprole, 
administered as ceftobiprole medocaril, as a 4-hour continuous-rate infusion. The planned 
dose of ceftobiprole is justified by the results of study CSI1006, in which paediatric 
subjects aged 3 months to < 2 years received 15 mg/kg ceftobiprole [6], by PK modeling 
results and by the experience in the paediatric population with other beta-lactams.   
A detailed dosing rationale is provided in Appendix 1. A single-dose study is sufficient to 
determine the PK of ceftobiprole in subjects while minimizing risk. The results of a 
single-dose study may be predictive of multiple-dose PK if the clearance of ceftobiprole 
is high and the potential for drug accumulation is minimal.  
 
 


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2 
OBJECTIVES OF THE STUDY 
2.1 
Primary objective 
The primary objective is to characterize the pharmacokinetics of a single dose of 
ceftobiprole in neonates and infants aged ≤ 3 months.  
2.2 
Secondary objective 
The secondary objective is to evaluate the safety and tolerability of ceftobiprole in 
neonates and infants aged ≤ 3 months. 
3 
STUDY DESIGN 
3.1 
Overview of study design and dosing regimen 
This is an open-label, single-fixed-dose, multicenter study to be carried out in three 
sequential cohorts, each of 15 neonates or infants aged ≤ 3 months (45 subjects total). 
The study will be conducted mainly in European centers and centers in the USA, but 
additional centers or other countries may be considered.  
The study comprises (i) a pre-dosing screening phase of up to 24 hours, (ii) a 1-day 
dosing phase with single-dose intravenous administration of ceftobiprole at 7.5 mg/kg, 
and (iii) a post-dose follow up safety assessment on Day 7 ± 3 after ceftobiprole 
administration. 
Table 1 provides an overview of the study design. 
Table 1 Summary of treatment and follow-up schedule 
 
 
 
 
 
 
Screening 
Single intravenous infusion of ceftobiprole over 4 hours 
Follow-up 
 
 
Day –1 
Day 1 
Day 7±3 
 
 
 
 
 
 
 
 
Ceftobiprole medocaril equivalent to 7.5 mg/kg ceftobiprole  
 
 
 
This study will assign to treatment with ceftobiprole 45 male or female neonates and 
infants aged up to 3 months (inclusive) who are already undergoing treatment with 
systemic antibiotics for documented or presumed bacterial infections, or because they are 
at risk of infection.  
The study population will comprise 3 cohorts, each of 15 subjects, based on gestational 
age: 28 to 32 weeks [completed]; 33 to 36 weeks [completed]; ≥ 37 weeks.  
In the two cohorts with subjects of gestational age ≤ 36 weeks, subjects will be further 
stratified by post-natal age (< 28 days; ≥ 28 days) so that at least 5/15 subjects are 
assigned to study treatment in each post-natal age group.  


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Cohorts will be sequentially dosed, with Cohort 1 comprising subjects of the highest 
gestational age (see Sections 3.3 and 6.1). In Cohorts 2 and 3, dosing will not start until at 
least 5 subjects in the previous cohort have completed dosing as planned and the follow-
up safety evaluation (Day 7±3). 
Parents or legally acceptable representatives will provide signed informed consent. 
Informed consent must be obtained within 3 days prior to dosing on Day 1. Subjects in 
each cohort will be screened for eligibility within 24 hours before dosing. Enrolled 
subjects will be dosed in specialised neonatal care institutions/departments with support 
to allow parents/legally acceptable representatives or caregivers to stay close to their 
children, and staff trained in minimising stress and discomfort associated with blood 
sampling and urine sampling (if possible) for PK assessments.  
Dosing with ceftobiprole should be scheduled so that the 4-hour infusion and subsequent 
assessments do not conflict with the ongoing treatment with systemic antibiotic(s) or 
routine infant care. Blood samples (200–300 µL) for PK analysis will be obtained at 
baseline (pre-dose), and at 2, 4, 6, 8 and 12 hours after the start of dosing. Urine samples 
for sparse PK analysis will be collected (if possible) before, during, and after dosing. 
An aliquot of the infusion solution will be collected for analysis, to ensure that the correct 
dose was given. Subjects will be evaluated for safety on Day 7 ± 3 after dosing.  
Efficacy will not be evaluated. Safety assessments will include vital signs, physical 
examination, safety laboratory tests, and monitoring for AEs. 
3.2 
Discussion of study design 
The study design is conventional, and adequate for the determination of standard 
single-dose PK outcomes in neonates and infants. Blood sampling is minimal, but 
adequate to describe profiles of plasma drug concentration over time for each subject. 
Sparse urine PK sampling is intended to confirm successful administration of 
ceftobiprole, and to confirm renal elimination as unchanged drug plus ring-open 
metabolite, as observed in adults and children aged > 3 months.  
Safety measures include the selection of clinics specialized in neonatal care, the use of 
staff trained in minimizing infant stress and discomfort, and the sequential dosing and 
safety evaluation of full-term infants or neonates, followed by pre-term infants or 
neonates. Safety evaluations are practical, routine in neonate and infant care, and do not 
impose needless discomfort. Since eligible subjects will already be receiving an 
intravenous antibiotic, the administration of ceftobiprole does not impose substantial 
additional discomfort or risk.  
3.3 
Number of subjects/ assignment to treatment groups 
A total of 45 neonates and infants will be assigned to study treatment, comprising 
3 cohorts to be dosed sequentially in the following order: 
Cohort 1: 15 subjects with gestational age ≥ 37 weeks. 
Cohort 2: 15 subjects with gestational age 33 to [completed] 36 weeks. 
Cohort 3: 15 subjects with gestational age 28 to [completed] 32 weeks. 


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Cohorts 2 and 3 will be further stratified by post-natal age (≥ 28 days, or < 28 days) so 
that at least 5 subjects are assigned to study treatment in each group.  
The safety data and PK data of the first 3 subjects of Cohort 1 will be reviewed by the 
investigators and the sponsor’s clinical and drug safety representatives prior to dosing of 
subsequent subjects. 
In Cohorts 2 and 3, dosing may not start until at least 5 subjects in the prior cohort have 
completed dosing as planned, the follow-up safety assessments have been completed, and 
safety and PK data have been reviewed by the investigators and the sponsor. 
The investigators and the sponsor will have regular consultation meetings or 
tele-conferences to assess the safety and PK data during the course of the study. These 
meetings to review safety and PK data will be held whenever 5 new subjects (dosed in 
any cohort) have completed dosing and safety follow-up, and their PK data have been 
analysed. Consultation meetings may be conducted more frequently if required. 
Pharmacokinetic analyses will be provided in a timely fashion during the study. 
The discussion and consensus decision-making of the consultation meetings between the 
investigators and the sponsor’s clinical and drug safety representatives will be governed 
by a charter and documented in minutes.     
3.4 
Centers 
This study will be carried out in approximately 8 study centers in Europe, and in 
10 centers in the USA. In the event of slow recruitment, additional centers may be 
considered. 
4 
STUDY POPULATION 
4.1 
Target population 
The target population comprises male and female neonates and infants aged up to 
3 months (inclusive) who are undergoing treatment with systemic antibiotics for 
documented or presumed bacterial infections, or because they are at risk of infection. 
4.2 
Inclusion criteria 
Subjects must meet all of the following criteria to be assigned to study treatment: 
1. Neonates and infants ≤ 3 months, with gestational age ≥ 28 weeks 
2. Documented or presumed (or at risk of) bacterial infections, and currently receiving 
antibiotic treatment* 
3. Expected to survive beyond the first 7 days after enrolment 
4. Sufficient vascular access to receive study drug, and to allow blood sampling at a site 
separate from the study drug infusion site 
5. Parent’s / legally acceptable representative’s informed consent to participate in the 
study 
* Subjects must be scheduled to receive at least one infusion of systemic antibiotics before, and at least one infusion 
after, their ceftobiprole dose.  


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4.3 
Exclusion criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Major birth defect or malformation syndrome+ 
2. Proven presence of an immunodeficiency 
3. HIV or other congenital viral or fungal infection 
4. Significant laboratory abnormalities including: 
− Haematocrit < 20% 
− Absolute neutrophil count (ANC) < 0.5 × 109/L 
− Platelet count < 50 ×109/L 
− Alanine aminotransferase (ALT), aspartate aminotransferase (AST) > 3 × the age 
specific upper limit of normal (ULN) 
5. 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‡ 
6. Any condition which would make the subject or caregiver, in the opinion of the 
investigator, unsuitable for the study 
+ Subject eligibility will be decided based on an individualized assessment. Subjects with major birth defects or 
malformation syndromes should be excluded in view of the following 
• A low likelihood that the subject will complete the study 
• Increased risk of side effects with ceftobiprole (e.g. seizures in patients with CNS disorders) 
• An expected impact on pharmacokinetics (e.g., haemodynamically relevant shunts) 
‡ See Appendix 4 for supporting data and the table of GFR thresholds. 
4.4 
Criteria for premature withdrawal and replacement of subjects 
While premature withdrawal is generally not applicable to a single-dose study, the 4-h 
infusion may be stopped at the investigator’s discretion in the event of adverse reactions 
(including but not limited to allergic-type reactions, infusion site reactions, or clinically 
relevant changes in vital signs), or in the event of apparent infant distress, or at the 
request of the parent or the legally acceptable representative.  
If the infusion is stopped, the exact time of the termination will be entered into the 
electronic case report form (eCRF).  
Subjects who do not receive the complete infusion may be replaced by enrolment of a 
new subject meeting the same cohort definitions of gestational and post-natal age 
(see Section 3.3).  
4.5 
Concomitant and previous medication and treatment 
Each subject will receive treatment with systemic antibiotics (based on clinical grounds) 
as prescribed by the investigator. Subjects may also receive other medication and 
treatment, without restriction, at the investigator’s discretion.  
All medication given to the subject during the course of the study will be entered into the 
eCRF; information to be recorded will include the trade name of the medication, the 
indication, the dose and frequency of treatment, and the start and stop dates of treatment. 
Changes in the dose or schedule of a given medication will also be entered into the eCRF. 


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Medication given within 7 days before screening up to the start of ceftobiprole dosing 
will be recorded as prior medication; if given after the start of ceftobiprole dosing, up to 
the follow-up safety assessment on Day 7±3, it will be recorded as concomitant.  
5 
SCHEDULE OF ASSESMENTS AND PROCEDURES 
5.1 
Summary schedule of assessments 
Table 2 presents a summary of the assessments to be performed from screening to the 
final post-treatment visit.  
Table 3 presents a more detailed summary of the assessments and PK sampling times to 
be performed on Day 1.  
5.1.1 
Screening (Days −1 to 1) 
A parent or legally acceptable representative must provide written informed consent for a 
subject to participate in the study before any study-specific procedures are carried out.  
Informed consent must be obtained within 3 days prior to dosing on Day 1. Once written 
informed consent is obtained, subjects are considered enrolled in the study. 
Subjects in the appropriate Cohort (see Section 3.3) for whom consent has been provided 
will undergo screening evaluations within 24 hours prior to ceftobiprole dosing. 
Screening evaluations and dosing may be performed on the same day (Day 1). Laboratory 
analyses required as part of the screening process which have been performed within the 
48 hours prior to ceftobiprole dosing do not need to be repeated, regardless of whether 
they were performed before or after signing of the ICF. 
Screening evaluations (see Table 2) will comprise:  
• physical examination 
• medical history (within 30 days prior to enrolment)  
• review and recording of medication given within the previous 7 days, including 
systemic antibiotics to be given before and after ceftobiprole dosing  
• safety laboratory tests (haematology, clinical chemistry, and urinalysis; see 
Section 5.2.3.2)  
• review of enrolment criteria to ensure subject eligibility, including laboratory test 
results  
• vital signs, body weight and height 
Physical examination results and body weight obtained during the screening evaluation 
do not need to be repeated as Day 1 assessments if they were performed within 6 hours 
prior to dosing on Day 1.   
 
 


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Table 2 Schedule of assessments 
 
Screening 
Dosing 
Follow-up 
Day −1 to 1 
Day 1 
Day 7±3 
SCREENING AND ADMINISTRATIVE PROCEDURES 
   Written Informed consent1 
X 
 
 
   Inclusion/exclusion criteria 
X  
 
 
   Medical history 
X 
 
 
   Prior medications2 
X 
 
 
CEFTOBIPROLE ADMINISTRATION 
   Infusion of ceftobiprole3 
 
X 
 
   Collection of aliquot of infusion solution4 
 
X 
 
PHARMACOKINETIC PROCEDURES 
   Blood sample collection5 
 
X 
 
   Urine collection6 
 
X 
 
SAFETY PROCEDURES 
   Vital signs7 
X 
X 
X 
   Physical examination 
X 
X* 
X 
   Body weight and height8 
X 
X* 
X 
   Laboratory tests9 
X 
 
X 
   Concomitant medication 
 
X 
X 
   Adverse events 
 
<------------- X --------------> 
1 Informed consent must be obtained within 3 days prior to dosing on Day 1. 
2  Prior medications administered within the 7 days prior to dosing will be collected. 
3 Ceftobiprole must be administered via a separate infusion line. No other intravenous infusion may be given through 
the same line during the 4-hour ceftobiprole infusion, and – if feasible – attempts should be made to not simultaneously 
administer any other antibiotic treatment (i.e., through any infusion line) during the ceftobiprole infusion. If feasible, 
attempts should be made to allow for a minimum period of 30 minutes between the end of administration of any other 
antibiotic treatment and the start of ceftobiprole medocaril infusion. 
4 An aliquot of approximately 3 mL of infusion solution will be collected after completion of the ceftobiprole infusion 
and frozen at below −65 °C immediately after sampling. 
5 Blood samples of 200–300 µL will be obtained for PK analysis at the times described in Table 3. 
6 Attempts should be made to obtain urine at the times described in Table 3; NB: Full portions of urine will be collected 
from subjects in whom a urinary catheter has been placed for their standard clinical care. Urinary catheters will not be 
placed for the purpose of the study. For subjects without a urinary catheter, one or more portions of urine may be 
obtained before, during, and after dosing.  
7 Vital signs (body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures) will be measured 
at the times described in Table 3. 
8 Height must be recorded at screening only. The body weight determination on Day 1 will be used for dose calculation 
and should be obtained within 6-hours prior to dosing.   
9 Safety laboratory tests include haematology, biochemistry, and urinalysis (see Section 5.2.3.2). 
*Physical examination and body weight obtained during the screening evaluation do not need to be repeated as Day 1 
assessments if they were performed within 6 hours prior to dosing on Day 1.   
 
 


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Table 3 Schedule of PK sampling and vital signs on Day 1 
Time 
Vital signs 
Blood samples 
Urine collection* Infusion solution aliquot 
collection 
−2 to 0 h 
 
 
X 
 
−15 min 
X 
 
 
 
Pre-dose 
 
X 
 
 
0 to 2 h 
 
 
X 
 
1 h 
X 
 
 
 
2 h 
 
X 
 
 
2 h 15 min 
X 
 
 
 
2 to 4 h 
 
 
X 
 
4 h (end of 
infusion) 
 
X 
 
X 
4 to 8 h 
 
 
X 
 
6 h 
X 
X 
 
 
8 h 
 
X 
 
 
8 to 12 h 
 
 
X 
 
12 h 
 
X 
 
 
* NB: Full portions of urine will be collected from subjects in whom a urinary catheter has been placed for their 
standard clinical care. Urinary catheters will not be placed for the purpose of the study. For subjects without a urinary 
catheter, one or more portions of urine may be obtained before, during, and after dosing. 
 
5.1.2 
 Ceftobiprole dosing (Day 1) 
The ceftobiprole dose should be scheduled so that the infusion and subsequent 
assessments (see Table 3) do not conflict with the ongoing therapy with systemic 
antibiotics, or routine care.  
Ceftobiprole medocaril must be reconstituted and diluted for intravenous (i.v.) 
administration as described in Section 6.2. Briefly, a single infusion of ceftobiprole 
medocaril will be given at 7.5 mg/kg (calculated as ceftobiprole mg equivalents; see 
Section 6.1), in a weight-adjusted volume of infusion solution given as a constant rate 
over 4 hours. The date and exact start and stop times of the infusion will be entered into 
the eCRF.  
Ceftobiprole must be administered via a separate infusion line. No other intravenous 
infusion may be given through the same line during the 4-hour ceftobiprole infusion, and 
– if feasible – attempts should be made to not simultaneously administer any other 
antibiotic treatment (i.e., through any infusion line) during the ceftobiprole infusion. If 
feasible, attempts should be made to allow for a minimum period of 30 minutes between 
the end of administration of any other antibiotic treatment and the start of ceftobiprole 
medocaril infusion. Body weight measured on Day 1 will be used for dose calculation 
and should be obtained within 6 hours prior to dosing.   


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Blood samples (200–300 µL) and urine (if possible) for PK analysis will be collected and 
prepared (see Sections 5.2.2.1 and 5.2.2.2, respectively), at times described in Table 3.  
A physical examination will be performed on Day 1 and body weight will be obtained, 
unless physical examination and body weight were obtained during the screening 
evaluation within 6 hours prior doing on Day 1. 
Vital signs will be recorded at times described in Table 3.  
After completion of the ceftobiprole infusion, an aliquot of approximately 3 mL of 
infusion solution will be collected and sent for analysis as described in Appendix 2.  
Changes in medication will be recorded. Adverse events will be monitored and recorded 
continuously throughout the study (see Table 2 and Section 5.2.3.1). 
5.1.3 
Follow-up assessment (Day 7±3) 
Each subject will be evaluated for safety on Day 7 ± 3 after ceftobiprole dosing. Safety 
assessments will comprise physical examination, vital signs, safety laboratory tests 
(haematology, clinical chemistry, and urinalysis; see Section 5.2.3.2), and AEs.  
5.2 
Study procedures 
5.2.1 
Efficacy  
The efficacy of ceftobiprole will not be assessed in this study. 
5.2.2 
Pharmacology 
5.2.2.1 Collection and preparation of blood samples 
Blood samples of 200–300 µL will be obtained for PK analysis at the times described in 
Table 3.  
The date and exact times of blood sampling will be entered into the eCRF. 
Blood for PK analysis should preferably be collected from a vein in the contralateral arm 
to that used for the i.v. administration of ceftobiprole; however collection may be at any 
site other than the infusion site, including heel prick sampling or collection through a 
central line, if available. 
Blood samples will be immediately transferred into pre-chilled tubes containing citric 
acid and EDTA as a coagulant. Samples will be centrifuged, and the supernatant will be 
frozen and kept at below −65 °C until shipment. Frozen samples will be shipped to the 
sponsor as described in Appendix 2.  
Details on handling of PK samples are provided in the Pharmacokinetics Manual for this 
study (provided separately). 
5.2.2.2 Collection and preparation of urine samples 
Attempts should be made to obtain urine at the times described in Table 3.  
Full portions of urine will be collected in subjects in whom a urinary catheter has been 
placed for their standard clinical care. For more details see the Pharmacokinetics Manual 


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for this study (provided separately). Urinary catheters will not be placed for the purpose 
of the study.  
In subjects without a urinary catheter one or more portions of urine may be obtained at 
any time during the periods indicated in Table 3, and the date and exact time of sample 
collection will be entered into the eCRF. The total amount of collected urine should be 
stabilized with citric acid, frozen and kept at below −65 °C until shipment. Frozen urine 
should be shipped to the sponsor as described in Appendix 2. For details see the 
Pharmacokinetics Manual for this study (provided separately). 
5.2.2.3 Analysis of ceftobiprole concentrations 
Plasma and urine concentrations of ceftobiprole medocaril, ceftobiprole, and of the open-
ring metabolite (BAL1029), will be quantified by means of a validated liquid-
chromatography/ tandem mass spectrometry (LC-MS/MS) method. 
5.2.2.4 Pharmacokinetic parameters 
Plasma and urine samples will be analysed for concentrations of ceftobiprole, and if 
applicable for concentrations of ceftobiprole medocaril and the open-ring metabolite 
(BAL1029). The analysis will be performed using validated gradient reversed-phase 
liquid chromatography coupled with a tandem mass spectrometer (LC/LC-MS/MS); 
analysis will be carried out under the supervision of the sponsor. 
Calibration and quality control (QC) samples will be prepared in blank and pre-tested 
human plasma or urine, and will be subject to the same assay procedure as experimental 
samples. The limit of quantification (LOQ) will be defined as the lowest concentration of 
analyte in a human plasma or urine sample, which can be quantitatively determined with 
inter-assay precision and accuracy of 100 ± 20%. Lower concentrations will be denoted as 
‘BLQ’ (below limit of quantitation). Assay performance will be controlled by the 
analysis of QC samples. When calculating mean drug levels for a subject cohort, if < 50% 
of samples are BLQ, drug levels in these samples will be set to zero. If ≥ 50% of samples 
are BLQ, no mean value will be calculated. 
Time-concentration profiles of ceftobiprole in plasma will be analysed by use of 
non-compartmental models. Actual sampling times will be used in all calculations. 
The following PK parameters will be determined for each individual, cohort, and by 
post-natal age:  
Cmax 
The observed maximum plasma concentration. 
t1/2 
The apparent terminal elimination half-life, calculated by t1/2 = ln2/β, where β is the elimination 
rate constant, estimated by linear least squares regression of the plasma concentration versus time 
data in the terminal elimination phase. 
AUC0–t The area under the plasma concentration-time curve from time zero to the last sampling time with 
a concentration above the LOQ. AUC0–t will be calculated according to the linear trapezoidal rule. 
AUC0–∞ The area under the plasma concentration-time curve from time zero to infinity, estimated from 
AUC0–t + Ct/β, where t is the last sampling time with a concentration above the LOQ. 
CLS 
The total systemic clearance, estimated by CLS = dose/AUC0–∞. 
VSS 
The apparent volume of distribution at steady state, estimated by VSS = (dose × AUMC/AUC2) –
 (dose × T/2AUC), where AUMC is the area under the first moment curve and T is the infusion 


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time. 
T > MIC The length of time plasma concentrations of ceftobiprole exceed the MIC (4 µg/mL). 
Concentrations of ceftobiprole, ceftobiprole medocaril, and open-ring metabolite 
(BAL1029) in urine will be determined; these results will be analysed by use of 
descriptive statistics. If a sufficient number of samples are available, parameters of 
urinary excretion may be determined. 
The relationship between exposure (Cmax and AUC), derived PK parameters (CLS, VSS, 
t1/2) gestational age, post-natal age, body weight, body mass-index, body surface area, 
and calculated creatinine clearance will also be assessed. 
5.2.3 
Safety  
The investigator will evaluate subject safety by AE monitoring, physical examination, 
vital signs and safety laboratory tests (see Table 2). 
5.2.3.1 Adverse event monitoring 
All AEs occurring from the start of first study medication (Day 1) must be documented as 
an AE, regardless of whether the event is considered to be related to the study drug or not 
(see Section 7.1.1). 
If possible, a diagnosis should be documented rather than signs and symptoms. All AEs 
should be recorded in the English language. The investigator should consider whether 
reports from the parents, legally acceptable representatives or caregivers should be 
recorded as AEs.  
Subjects who withdraw because of a drug-related AE should be followed up until 
recovery. Adverse events will be recorded throughout the study, from the start of first 
study medication (Day 1) to the final assessment at follow-up. Reporting of SAEs is 
described in Section 7.2.2. 
5.2.3.2 Laboratory tests 
Blood and urine samples obtained at screening and at the follow-up evaluation on 
Day 7±3 will be analysed for the following safety laboratory parameters: 
Haematology:  
Haematocrit, red blood cell (RBC) count, total and differential white blood cell 
(WBC) count, platelet count, and reticulocyte count. 
Blood chemistry:  
Aspartate aminotransferase (AST) alanine aminotransferase (ALT), total bilirubin, 
creatinine, sodium, chloride and potassium.  
Urinalysis:  
Dipstick for pH, glucose*, blood*, and protein.* 
(*Microscopic examination of sediment if positive) 
 
The choice of site and procedure for blood draws (e.g., venous site or heel-prick, or 
through an existing arterial line) will be made by the investigator depending on the 
availability of access, the volume of blood required, and the type of laboratory test to be 
done. Blood draws should be performed according to standard procedures of the 
institution.  


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The anticipated volume of blood required for PK assessment will be approximately 
1.2 mL to 1.8 mL (6 sampling time points, see Table 3, with a blood volume of  
200–300 µL per sample).  
 


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5.2.3.3 Physical examination 
Each subject will undergo a physical examination at screening, on Day 1 and at the 
follow-up assessment on Day 7±3. Abnormalities will be described in the eCRF. 
Physical examination and body weight obtained during the screening evaluation do not 
need to be repeated as Day 1 assessments if they were performed within 6 hours prior to 
dosing on Day 1.   
5.2.3.4 Vital signs 
Vital signs will include body temperature, respiratory rate, pulse rate, and systolic 
and diastolic blood pressures. Vital signs will be measured at the times described in 
Table 2 and Table 3, and results will be entered into the eCRF. 
Note: Body temperature may be measured either axillary, orally, rectally, tympanic or 
skin temperature (e.g. by a patch); however, for each subject only one method should be 
used consistently throughout the entire study. 
6 
STUDY DRUGS 
6.1 
Dose and schedule 
Subjects will receive a single infusion of ceftobiprole medocaril, given in a 
weight-adjusted volume at a constant rate over 4 hours. The dose will be 7.5 mg/kg, 
calculated as ceftobiprole equivalents (7.5 mg ceftobiprole corresponds to 10.0 mg 
ceftobiprole medocaril sodium).  
Ceftobiprole must be administered via a separate infusion line. No other intravenous 
infusion may be given through the same line during the 4-hour ceftobiprole infusion, and 
– if feasible – attempts should be made to not simultaneously administer any other 
antibiotic treatment (i.e., through any infusion line) during the ceftobiprole infusion. If 
feasible, attempts should be made to allow for a minimum period of 30 minutes between 
the end of administration of any other antibiotic treatment and the start of ceftobiprole 
medocaril infusion. 
As described in Section 3.3, subjects will be assigned to 3 cohorts on the basis of 
gestational age, and further stratified by post-natal age. The 3 cohorts will be dosed 
sequentially. Subjects in Cohorts 2 and 3 may not be dosed until at least 5 subjects from 
the previous cohort have received their full planned dose and undergone the follow-up 
safety evaluation (Day 7±3).  
Before initiation of dosing in Cohort 2 and Cohort 3, available safety data from subjects 
in the previous cohort will be made available to all investigators, and the decision to 
initiate dosing in a new cohort will be made jointly by the sponsor and the investigators.  
 
 


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6.2 
Administration 
Details on study drug preparation and administration are described in the Study Drug 
Administration Manual (provided separately). Sterile technique will be used in all stages 
of preparation. Procedures can be briefly summarized as follows: 
a) Ceftobiprole medocaril will be supplied in vials containing 500 mg ceftobiprole 
(corresponding to 667 mg of ceftobiprole medocaril) as lyophilized powder. 
b) The vial will be reconstituted with 10 mL dextrose 5% to obtain a reconstituted 
solution of a concentration of 50 mg/mL ceftobiprole. 
c) 4 mL (equivalent to 200 mg ceftobiprole) of this reconstituted solution will be further 
diluted with 46 mL of dextrose 5% in a 50 mL syringe. The final volume in the 
syringe will be 50 mL, and the concentration of ceftobiprole in that 50 mL syringe will 
be 4 mg/mL. 
d) Depending on the body weight of the subject, the required volume corresponding to a 
dose of 7.5 mg/kg ceftobiprole will be infused using a calibrated infusion pump device 
as shown in Table 4. For example, for a child of 1 kg body weight, 7.5 mg ceftobiprole 
will be administered, corresponding to 1.88 mL of the 4 mg/mL ceftobiprole solution. 
The infusion rate for a 4-hour infusion is therefore 0.47 mL/h.  
 
 


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Table 4 
Ceftobiprole administration and dose calculation by body weight 
Body 
weight 
(kg) 
Ceftobiprole 
single  dose  
(mg) 
Required volume  
 in mL of  the 
reconstituted 
ceftobiprole solution  
(50 mg/mL) 
Required 
volume of 
dextrose 5 % 
Total 
syringe 
volume 
Volume of the 
final solution for 
infusion  
administered 
from the  
50 mL syringe 
Infusion 
rate 
(mL/h) 
0.7 
5.25 
4 mL 
46 mL 
50 mL 
1.31 mL 
0.33 
0.8 
6 
4 mL 
46 mL 
50 mL 
1.50 mL 
0.38 
0.9 
6.75 
4 mL 
46 mL 
50 mL 
1.69 mL 
0.42 
1 
7.5 
4 mL 
46 mL 
50 mL 
1.88 mL 
0.47 
1.2 
9 
4 mL 
46 mL 
50 mL 
2.25 mL 
0.56 
1.5 
11.25 
4 mL 
46 mL 
50 mL 
2.81 mL 
0.70 
1.8 
13.5 
4 mL 
46 mL 
50 mL 
3.38 mL 
0.84 
2 
15 
4 mL 
46 mL 
50 mL 
3.75 mL 
0.94 
2.5 
18.75 
4 mL 
46 mL 
50 mL 
4.69 mL 
1.17 
3 
22.5 
4 mL 
46 mL 
50 mL 
5.63 mL 
1.41 
3.5 
26.25 
4 mL 
46 mL 
50 mL 
6.56 mL 
1.64 
4 
30 
4 mL 
46 mL 
50 mL 
7.50 mL 
1.88 
4.5 
33.75 
4 mL 
46 mL 
50 mL 
8.44 mL 
2.11 
5 
37.5 
4 mL 
46 mL 
50 mL 
9.38 mL 
2.34 
5.5 
41.25 
4 mL 
46 mL 
50 mL 
10.31 mL 
2.58 
6 
45 
4 mL 
46 mL 
50 mL 
11.25 mL 
2.81 
6.5 
48.75 
4 mL 
46 mL 
50 mL 
12.19 mL 
3.05 
7 
52.5 
4 mL 
46 mL 
50 mL 
13.13 mL 
3.28 
7.5 
56.25 
4 mL 
46 mL 
50 mL 
14.06 mL 
3.52 
8 
60 
4 mL 
46 mL 
50 mL 
15.00 mL 
3.75 
 
Body weight used for dose calculation will be obtained on Day 1 within 6 hours prior to 
dosing. 
The reconstituted and infusion solutions must not be frozen, and must not be exposed to 
direct sunlight before infusion. 
Only dextrose 5% is permitted for reconstitution and dilution. Once ceftobiprole in the 
vial has been reconstituted with 10 mL of dextrose, further dilution of the 4 mL from the 
reconstituted solution with 46 mL of dextrose 5% (to obtain a 50 mL syringe with a 
concentration of 4 mg/mL) must be completed within 1 hour.  
The final solution for infusion in the 50 mL syringe is chemically and physically stable 
under the following conditions: 
• 
24 hours in a refrigerator (2–8 °C) followed by 12 hours at room temperature 
• 
12 hours at room temperature 


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The infusion therefore must be completed within these time limits. Reconstituted and 
infusion solutions must be prepared under sterile conditions. Unless the method of 
reconstitution/dilution precludes the risk of microbiological contamination, the solutions 
should be used immediately, rather than within the times based on chemical and physical 
stability.  
Further details of ceftobiprole administration are described in the Study Drug 
Administration Manual (provided separately). 
After the end of the ceftobiprole infusion, a 3-mL aliquot of the drug infusion solution 
will be collected for analysis of ceftobiprole concentration (see Appendix 2). The 3-mL 
aliquot must be frozen at below −65 °C. 
6.3 
Blinding and randomization 
This is an open-label study. Subjects will not be randomized, but will be enrolled and 
assigned to 3 cohorts on the basis of gestational age, and further stratified by post-natal 
age (see Section 3.3). Cohorts will be dosed sequentially, starting with higher gestational 
age (see Section 3.3). As described in Section 6.1, the decision to start dosing in 
Cohorts 2 and 3 will be made jointly by the sponsor and the investigators after review of 
safety data and PK data from at least 5 subjects in the previous cohort. 
6.4 
Packaging and labelling 
Study drug vials will be supplied by the sponsor to the investigator. The sponsor will 
ensure that the study medication and certificates of analysis are available before the start 
of the study.  
Study drug for i.v. administration will be presented as vials of sterile lyophilized 
ceftobiprole medocaril (BAL5788) containing the equivalent of 500 mg ceftobiprole. The 
lyophilisate will be stored in a refrigerator (2 °C – 8 °C).  
The study drug vial labels will identify the sponsor, study number, vial contents, batch 
number, and expiry date.  
Study drug will be kept in a secure location under adequate storage conditions. Further 
details on handling, preparation, and administration of i.v. ceftobiprole are provided the 
Study Drug Administration Manual (provided separately). 
6.5 
Compliance check and accountability 
Compliance will be assessed by direct observation of each subject during infusion of the 
study medication, and by measurement of ceftobiprole concentrations in plasma and 
urine. 
A Drug Dispensing Log must be kept current, and should contain the following 
information: 
• 
the identification of the subject to whom the drug was dispensed (subject number) 
• 
the date(s) and quantity of the drug dispensed to the subject 
• 
the initials of the person who dispensed the drug (pharmacist) 
• 
the initials of the person who administered the drug (nurse) 


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The inventory must be available for inspection by the Clinical Study Monitor. Drug 
supplies, including partially used or empty containers and the dispensing logs, must be 
returned to the Clinical Study Monitor at the end of the study. 
When requested in writing by the sponsor, unused drug supplies may be destroyed by the 
investigator. Records must be maintained by the investigator which show the 
identification and quantity of each unit disposed of, the method of destruction (taking into 
account applicable legal requirements), and the person who destroyed the test substance. 
These records must be submitted to the sponsor. 
7 
SUBJECT SAFETY 
7.1 
Adverse events 
7.1.1 
Definition of adverse events 
An AE is any adverse change from the subject’s baseline (pre-therapy) medical condition 
which occurs during the course of a clinical study after test medication has been given, 
whether considered related to treatment or not. Treatment includes all study drugs 
administered during the course of the study. Events involving exacerbations or worsening 
of pre-existing illnesses should be recorded as AEs.  
A treatment-emergent AE in this study is defined as any AE occurring between first 
administration of study drug and the follow-up visit at study Day 7±3. If the last 
scheduled study visit occurs later than 10 days after stopping the treatment, any AE 
occurring after Day 10 will be considered non-treatment-emergent unless reassigned 
based on a medical review conducted by the sponsor prior to database lock. 
Adverse medical occurrences that appear between the provision of informed consent and 
first drug administration will be entered into the Medical History section of the eCRF.  
If possible, a diagnosis should be documented rather than signs and symptoms. All AEs 
should be recorded in the English language. 
Abnormal laboratory values or test results constitute AEs only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy. These events 
are to be entered into the Adverse Events section of the eCRF under the signs, symptoms 
or diagnoses associated with them.  
7.1.2 
Evaluation of adverse events 
The intensity of AEs will be graded on the following three-point scale: 
Mild: 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Moderate: Moderate symptoms; minimal, local or noninvasive intervention indicated 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; or disabling 
 
 


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The relationship of AEs to the study treatment will be assessed as: 
• 
unrelated 
• 
remotely related 
• 
possibly related; or 
• 
probably related 
Appendix 3 provides criteria for relationship assessments. 
A causal relationship is suspected for all AEs reported with a relationship of ‘possible’ or 
‘probable’.  
7.2 
Serious adverse events  
Any SAE occurring during the course of the study, irrespective of the treatment received 
by the subject, must be reported to the sponsor or designated safety representative within 
24 hours of awareness of the event. 
7.2.1 
Definition of serious adverse events  
An SAE is any AE that at any dose: 
• 
results in death 
• 
is life-threatening 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require intervention to prevent one of the 
outcomes listed in the definitions above. These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. An unexpected AE is 
an AE the nature or severity of which is not consistent with the applicable product 
information. 
Note: Death is considered an outcome of an AE. Whenever possible the underlying cause 
of death should be reported as the AE. 
A life-threatening AE is any adverse experience that places the subject at risk of death at 
the time it occurred, i.e., it does not include an event that, had it occurred in a more 
severe form, might have caused death. 
 
 


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In-patient hospitalization is defined as any in-patient admission (even if less than 
24 hours). For chronic or long-term in-patients, in-patient admission also includes 
transfer within the hospital to an acute/intensive care unit (e.g., from a medical floor to 
the coronary care unit, from the neurological floor to the tuberculosis unit). 
Preplanned hospitalizations and elective surgery which are not due to a worsening or 
exacerbation of an underlying disease do not constitute an SAE. 
7.2.2 
Reporting of serious adverse events  
Any SAE occurring during the active treatment period or during the protocol-defined 
follow-up period until the last study visit, whether considered treatment-related or not, 
must be reported immediately to the sponsor’s safety representative listed below. The last 
study visit in this study will be scheduled on Day 7 ± 3 after stopping the treatment. If the 
last scheduled study visit occurs later than on Day 7 ± 3 after stopping the treatment, 
SAEs must be reported until the actual (late) visit date. 
Adverse event reporting will not be solicited after the last study visit: 
• A serious adverse event (including those resulting in death) that occurs after this time 
and which is considered related to study drug, should be reported. 
• For deaths which occur after the last study visit (until database lock) that are reported 
unsolicited (related or unrelated to study drug), the date of death will be captured in 
the eCRF.    
• Serious events that are reported unsolicited after the last study visit that are unrelated 
to study drug will not be collected and will not be reported as serious adverse events.  
Safety contact 
PrimeVigilance Limited, 
The Surrey Research Park, 
26–28 Frederick Sanger Road, 
Guildford, Surrey GU2 7YD, UK. 
Email: Basilea@primevigilance.com 
eFax (UK): 
+44 (0)800 0669192 
eFax (US): 
+1 866 902 7489 
The Sponsor’s safety representative will submit reports for expeditable SAEs to health 
care authorities and Independent Ethics Committees / Institutional Review Boards 
(IECs/IRBs) as required by applicable laws and regulations. 
The investigator must notify the local IEC/IRB of an SAE in writing in accordance with 
applicable laws and regulations. 
 
 


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The description of the SAE should be as complete as possible and allow for a medical 
assessment of the case. At a minimum, the SAE report must contain: 
• a subject identifier 
• an adverse event description 
• action taken with regards to study drug 
• outcome information 
• the investigator’s causality assessment 
Such preliminary reports must be followed by detailed descriptions, which may include 
copies of hospital case reports, autopsy reports, and other documents if requested and 
applicable.  
Causality should be rated by the investigator according to Appendix 3 of the protocol.  
A causal relationship is suspected for all AEs reported with a relationship of ‘possible’ or 
‘probable’. 
7.3 
Treatment and follow-up of adverse events 
The investigator or other physician in attendance will administer therapy as clinically 
indicated. All SAEs and those AEs for which the relationship to study drug is plausibly 
related, should be followed up until they have returned to baseline status or stabilized. 
If a clear explanation is established, it should be entered into the eCRF. 
7.4 
Laboratory test abnormalities 
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until they have returned to the normal range and/or an 
adequate explanation of the abnormality is found. If a clear explanation is established, it 
should be entered into the eCRF. Abnormal laboratory results should be recorded as an 
AE if they induce clinical signs or symptoms, are considered clinically significant, or 
require therapy. 
7.5 
Pregnancy 
Not applicable.  
7.6 
Dose modifications for safety reasons 
The intended dose may not be modified; however the 4-h infusion may be stopped at the 
investigator’s discretion (see Section 4.4). 
7.7 
Warnings and precautions 
Detailed warnings and precautions are provided in the IB. Serious or significant adverse 
reactions that may occur in subjects receiving β-lactam antibiotics include 
hypersensitivity (anaphylaxis), Clostridium difficile associated diarrhea/ pseudo-
membranous colitis, superinfections of non-susceptible organisms, precipitation when 
co-administered through the same infusion line with calcium-containing solutions, and 
seizures.  
 


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8 
STATISTICAL CONSIDERATIONS 
8.1 
Primary and secondary study variables 
The primary study variables are PK parameters Cmax, AUC0-∞ and T > MIC (presuming an 
MIC of 4 µg/mL).  
Secondary variables comprise other PK parameters (see Section 5.2.2.4), and safety 
variables as described in Section 5.2.3.  
8.2 
Statistical and analytical methods 
8.2.1 
Statistical model 
Plasma concentrations at each time point of measurement will be evaluated by descriptive 
statistics, including arithmetic mean, standard deviation (SD), minimum, maximum, and 
median. Actual sampling times will be used to calculate PK parameters. If ≤ 50% of the 
values at a given time point are BLQ, these values will be set to zero for mean value 
calculation. If more than 50% of the values at a given time point are BLQ, no mean value 
will be calculated. Mean plasma concentration profiles of each cohort will be generated 
according to these criteria. 
For PK evaluation, BLQ-values at infusion start will be set to zero, BLQ-values at the 
end of the sampling period will be disregarded for PK assessment. Single BLQ values 
during blood sampling will be taken as ‘missing values’, if the following sample(s) show 
a concentration above the BLQ value. 
8.2.2 
Sample size calculation 
No sample size calculation has been performed for this study. Study drug treatment of 
15 subjects per dosing cohort (total N = 45), is based on experience and is considered 
sufficient to fulfil the objectives of this study. 
8.2.3 
Hypothesis testing 
No formal hypothesis testing will be performed.  
8.2.4 
Statistical analyses 
A full Statistical Analysis Plan (SAP) will be prepared before database locking. 
Pharmacokinetic parameters will be presented by individual listings and descriptive 
summary statistics including arithmetic and geometric means, arithmetic and geometric 
coefficients of variation, standard deviation, minimum, median, and maximum. 
Adverse events will be listed by individual subject and by frequency tables broken by 
body system. Vital signs will be listed and summarized by means and standard 
deviations. Laboratory test values will be presented in individual subject listings with 
flagging of values outside the normal ranges and marked normal ranges, by frequency 
tables for each parameter showing the numbers of subjects with values outside normal 
ranges and marked normal ranges, and by shift tables for each parameter showing the 
numbers of subjects with adverse changes from baseline. 


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Subjects may be excluded from the PK analysis if they significantly violate the inclusion 
or exclusion criteria, deviate significantly from the protocol or if data are unavailable 
which may influence the PK analysis. All subjects who receive any amount of study 
medication will be included in the analysis of safety. Subjects excluded from any analysis 
will be listed along with the reasons for exclusion. 
8.2.5 
Interim analysis 
No hypothesis-testing interim analysis is planned. PK data from early dosing cohorts may 
be analysed before dosing in later cohorts is started or completed. Safety data will be 
reviewed on an ongoing basis. 
9 
DATA QUALITY ASSURANCE AND VERIFICATION 
PROCEDURES 
9.1 
Electronic case report forms 
An electronic data capture (EDC) system is used to collect the data in this study. The 
EDC system provides functionality for the clinical sites to enter the data directly into the 
eCRFs and respond to data discrepancies. Once the data are entered, the information is 
encrypted and transmitted over the Internet to a clinical trial server, where it is 
electronically reviewed. Any resulting data queries are immediately sent back to the site 
for resolution.  
The system automatically keeps a full audit trail of all data changes that occur. The 
clinical team will undertake additional manual review of the data, but all resulting data 
queries or clarifications will be entered into the EDC system for resolution. All eCRFs 
will be completed according to instructions provided in the eCRF Completion Guidelines 
and ICH GCP guidelines. 
10 
PROTOCOL AMENDMENTS 
Substantial protocol amendments must be prepared by the Sponsor and be reviewed and 
approved by the Project Physician. 
Protocol amendments must be submitted to the appropriate IEC or IRB for information 
and approval in accordance with applicable requirements, and to regulatory authorities if 
required. Approval must be awaited before any changes are implemented, except for 
changes necessary to eliminate an immediate hazard to study subjects, or changes 
involving only logistical or administrative aspects of the study (e.g., changes to monitors, 
telephone numbers etc. 
11 
PREMATURE TERMINATION OF THE STUDY 
The sponsor reserves the right to terminate the study at any time, and an investigator has 
the right to terminate his or her participation to the study at any time. Should this be 
necessary, both parties will arrange the procedures on an individual study basis after 
review and consultation. In terminating the study, the sponsor and the investigator must 
ensure that adequate consideration is given to the protection of the subject’s interests. 
 
 


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12 
ETHICAL AND REGULATORY ASPECTS 
12.1 
Good Clinical Practice 
The study will be conducted in accordance with the ICH Tripartite Guideline E6 
Guideline for Good Clinical Practice [7] and applicable regulatory requirements. 
12.2 
Informed consent 
It is the responsibility of the investigator, or a person designated by the investigator 
(if acceptable under local regulations), to obtain prior written informed consent from the 
subject’s parent(s) or legally acceptable representative for each individual participating in 
this study, after adequate explanation of the aims, methods, objectives and potential 
hazards of the study. It must also be explained to the subject’s parent(s) or legally 
acceptable representative that they are completely free to refuse consent for the infant to 
enter the study, and to withdraw the infant from the study at any time for any reason. 
Appropriate forms for obtaining written informed consent will be provided by the 
sponsor/designee, and reviewed by the IEC/IRB responsible for oversight of the study 
site. 
If the parent(s) or legally acceptable representative are unable to read the informed 
consent form, an impartial witness should be present during the entire informed consent 
discussion. After the parent(s) or legally acceptable representative have orally consented 
to the subject’s participation in the study, the witness’s signature on the form will attest 
that the information in the consent form was accurately explained to, and understood by, 
the parent(s) or legally acceptable representative.  
The eCRFs for this study contain a section for documenting informed consent, which 
must be completed appropriately. If new safety information results in significant changes 
in the risk/benefit assessment, the consent form will be reviewed and updated if 
necessary. Parent(s) or legally acceptable representatives of all subjects who have not 
completed the last study follow-up visit must be informed of the new information, given 
a copy of the revised form, and asked to give their consent to the subject continuing in the 
study. 
12.3 
Subject confidentiality and data protection 
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. This includes any electronic data 
generated during the study. In the eCRFs or on other documents submitted to the sponsor, 
subjects must not be identified by their names, but by an identification code. The 
investigator must keep a confidential subject identification code list as described in 
ICH GCP §8.3.21, and must ensure that all local data protection laws are respected. 
12.4 
Independent Ethics Committees / Institutional Review Boards 
This protocol and any accompanying material provided to the subject (such as subject 
information sheets or descriptions of the study used to obtain informed consent), as well 
as any advertising or compensation given to the subject, will be submitted to an IEC/IRB. 


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Approval from the IEC/IRB must be obtained before starting the study, and should be 
documented specifying the date on which the committee met and granted approval. 
Amendments made to the protocol after receipt of the IEC/IRB approval must also be 
submitted to the IEC/IRB in accordance with local procedures and regulatory 
requirements. 
12.5 
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. 
12.5.1 Investigator's Study File 
The Investigator's Study File will contain all essential documents as required by ICH E6, 
e.g., the protocol/amendments, pdf of eCRF with audit trail, IEC/IRB and governmental 
approval with correspondence, sample informed consent forms, drug records, staff 
curriculum 
vitae 
and 
authorization 
forms 
and 
other 
appropriate 
documents/correspondence etc. 
12.5.2 Subject source documents 
Subject source documents used to record key efficacy/safety parameters independent of 
the eCRFs may include for example subject hospital/clinic records, physician's and 
nurse's notes, appointment book, original laboratory reports, ECG, EEG, X-ray, 
pathology and special assessment reports, signed informed consent forms, consultant 
letters, and subject screening and enrolment logs. 
12.5.3 Electronic case report forms 
For each subject enrolled, an eCRF must be completed and signed off electronically by 
the investigator or authorized sub-investigator. This also applies to records for those 
subjects who fail to complete the study (even during a screening period if an eCRF was 
initiated). If a subject is withdrawn from the study, the reason must be entered into the 
eCRF. If a subject is withdrawn from the study because of a treatment-limiting 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. 
If the eCRF is to be the source document for certain data, this must be discussed and 
agreed with the sponsor in advance, and be clearly documented. 
12.5.4 Document retention and archiving 
The investigator must keep all study documents on file for at least 15 years after 
completion or discontinuation of the study. Subsequently the sponsor will inform the 
investigator when the study documents can be destroyed, subject to local regulations.  
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. 


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If the investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, arrangements must be made between the investigator and 
the sponsor for appropriate storage. 
13 
MONITORING 
13.1 
Monitoring 
The study monitor will visit the investigator and the study facilities on a regular basis 
throughout the study to verify the adherence to GCP, the protocol and the completeness, 
consistency and accuracy of the data being entered into the eCRFs.  
13.2 
Source data verification 
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 subject records 
needed to verify the entries in the eCRFs.  
14 
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. The study may also be inspected 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, will be granted to the auditors or inspectors. 
15 
PUBLICATION POLICY 
The results of this study will be made available, e.g. submitted for publication and/or 
presentation at scientific meetings in a timely manner. All manuscripts or abstracts have 
to be submitted to the sponsor prior to publication or presentation, allowing the sponsor 
to protect proprietary information and to provide comments based on information from 
other studies that may not yet be available to the investigator. In accordance with 
standard editorial and ethical practice, the sponsor will support publication of multicenter 
studies only in their entirety and not as individual center data. Authorship will be 
determined by mutual agreement. 
 
 


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16 
REFERENCES 
1. Curtis C, Shetty N. 2008. Recent trends and prevention of infection in the neonatal 
intensive care unit. Curr Opin Infect Dis 21: 350–356. 
2. Strunk T et al. 2013. Genetic and epigenetic susceptibility to early life infection. Curr 
Opin Infect Dis doi: 10.1097/QCO.0b013e32835fb8d9. 
3. Blumer JL et al. 1995. Sequential, single-dose pharmacokinetic evaluation of 
meropenem in hospitalized infants and children Antimicrob Agents Chemother 39 : 
1721–1725. 
4. Zingg W et al. 2008. Healthcare-associated infections in neonates. Curr Opin Infect 
Dis 21: 228–234. 
5. Parker EM et al. 1995. The pharmacokinetics of meropenem in infants and children: a 
population analysis. Antimicrob Agents Chemother 36 (Suppl A) : 63–71. 
6. Clinical Study Report 30982081-CSI-1006 (1 October 2010). 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. Protocol 30982081-CSI-1006. 
7. ICH Tripartite Guideline E6, “Guideline for Good Clinical Practice” (July 1996). 
8. Clinical Study Report 30982081-CSI-1004 (31 January 2006). An open-label, 
pharmacokinetic study of single and multiple intravenous infusions of ceftobiprole 
500 mg administered to healthy, adult subjects (Protocol 30982081-CSI-1004).  
9. Nonclinical Research Report for Study 901275 (12 November 2008). Ceftobiprole 
medocaril (BAL5788): A subcutaneous toxicity study in neonatal and juvenile albino 
rats (TOX8611).  
 


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17 
APPENDICES 
Appendix 1 
Rationale for dose selection (neonates / paediatric population 
≤ 3 months of age)  
Overview of dosing rationale 
The dose selected for this study is 7.5 mg/kg as a single-dose 4-hour infusion. 
The selection of this dosing regimen was based on the following considerations: 
1. The level of drug exposure that have been demonstrated to be effective in treating 
nosocomial pneumonia and community-acquired pneumonia in adults 
2. The PK and safety results of a previous single-dose study in paediatric subjects aged 
≥ 3 months to < 18 years (study CSI-1006) 
3. The AE profile of ceftobiprole in adults  
4. The results of a toxicity study in juvenile animals  
5. Pharmacokinetic modeling results 
6. The experience in the paediatric population with other beta-lactams 
Target drug exposure and efficacy considerations 
Ceftobiprole is a cephalosporin and belongs to the β-lactam class of antibiotics. 
For β-lactam antibiotics, it is well established that the time (T) that plasma concentrations 
of drug are above the minimum inhibitory concentration (MIC) for a given pathogen 
(T>MIC) correlates well with therapeutic efficacy1. For ceftobiprole an unbound  T>MIC 
corresponding to ≥ 50% of the drug dosing interval (e.g. 4 hours for a drug given every 
8 hours) for broad spectrum coverage was demonstrated in preclinical studies2 and in the 
Phase 3 studies in nosocomial pneumonia (BAP248/307)3 and in community-acquired 
pneumonia (CAP-3001)4.  
Accordingly, considering that ceftobiprole will be used as a broad-spectrum antibiotic, a 
dosing regimen resulting in unbound (f) plasma drug levels above a non-species related 
breakpoint MIC of 4 µg/mL for at least 50% of the dosing interval is the target. The 
efficacy of ceftobiprole in paediatric subjects is expected to be similar to that in adults if 
the %fT>MIC with regard to ceftobiprole plasma levels is comparable. 
 
 
                                                 
1 Craig. Does the dose matter? Clin Infect Dis 2001;33:233–237 
2 Craig. In vivo pharmacodynamics of ceftobiprole against multiple bacterial pathogens in murine thigh and lung infection models. 
Antimicrob Agents Chemother 2008; 52:3492–3496 
3 Muller. %ft.>MIC predicts probability of clinical outcome in the treatment of nosocomial pneumonia by ceftobiprole. ECCMID 
2013 Poster P904 
4 Muller. %ft.>MIC predicts the microbiological eradication at end of treatment with ceftriaxone or ceftobiprole in patients with 
community acquired pneumonia. ICAAC 2013 Poster A-472 
 


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Previous pharmacokinetic and safety results 
Experience in adults 
The disposition of ceftobiprole is linear in the dose range investigated (from 250 mg to 
1000 mg). The half-life is approximately 3 h with limited accumulation after repeated 
every 8-hour (q8h) administration. The PK are highly reproducible, with a low inter-and 
intra-subject variability. Ceftobiprole is distributed in the extracellular compartment 
(18 L), and is weakly bound to plasma proteins (16%). Its elimination is predominantly 
renal by passive glomerular filtration (> 80% of the dose recovered as unchanged drug in 
urine); creatinine clearance is therefore the main driver of exposure to ceftobiprole.  
Ceftobiprole was well tolerated in adult healthy subjects and patients in clinical studies, 
with the main reported treatment-emergent AEs being dysgeusia, nausea and vomiting. 
In pooled safety data from two Phase 3 studies in subjects with complicated skin and soft 
tissue infections (dosing regimens of 500 mg q12h 1-h infusion and 500 mg q8h 2-h 
infusion), the incidence of these AEs was not related to the dose but was rather related to 
the infusion duration, suggesting a Cmax related effect. The dose regimen that was 
primarily investigated in phase 3 studies in adult subjects with complicated skin and soft 
tissue infections, community-acquired pneumonia and nosocomial pneumonia was 
500 mg q8h as a 2-h infusion. Multiple doses up to 1000 mg q8h as a 1.5-h infusion were 
also investigated in adult healthy subjects, and were well tolerated. 
Experience in juvenile animals  
A study was conducted in neonatal and juvenile male and female rats (commencing on 
post-partum Day 1 up to 50 days, followed by a 28-day recovery period).  Exposure to 
ceftobiprole was determined in each dose group investigated throughout the study. The 
NOAEL in this study was determined to be 100 mg ceftobiprole medocaril/kg/day [9].  
The corresponding exposures are summarized in Table 5.  
Table 5  
Exposure to ceftobiprole at the NOAEL in juvenile rats  
100 mg/kg/day s.c.  
Female rats 
Male rats  
Study day  
post-partum 
Approximate human 
equivalent age  
Cmax  
(µg/mL) 
AUC0-8h  
(µg.h/mL) 
Cmax  
(µg/mL) 
AUC0-8h  
(µg.h/mL) 
Day 1  
neonate  
65.9 
261 
55.7 
265 
Day 18  
~ 6 years  
101 
133 
92.6 
148 
Day 49  
~ 14 years  
84.0 
119 
76.1 
139 
Human experience in the paediatric population  
Study CSI-1006 evaluated the PK of ceftobiprole when administered as a single dose in 
paediatric subjects 3 months to < 18 years of age who required therapeutic or 
prophylactic therapy with systemic antibiotics. Subjects were enrolled and dosed 
according to four age groups: 3 months to < 2 years (15 mg/kg dose), 2 years to < 6 years 
(15 mg/kg), 6 years to < 12 years (10 mg/kg), and 12 years to < 18 years (7 mg/kg). 
In the PK evaluable subset, ceftobiprole volume of distribution and systemic clearance 
increased with age and reached almost healthy-adult historical values in the 12 to 
< 18 years age group [6].  


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At the doses administered in study CSI-1006 to subjects < 12 years of age (15 mg/kg for 
subjects < 6 years and 10 mg/kg for subjects 6 years to < 12 years), the single-dose PK of 
ceftobiprole were generally within the range of what has previously been observed 
in healthy adult subjects after a single ceftobiprole 500 mg dose (q8h 2-h infusion), 
i.e., PD target of 62.3%–90.1% was achieved [8].  
However, at the doses investigated, in each age group there were children underexposed 
in terms of PD target and notably in the age group of > 3 months – < 2 years [IB, 6]. 
Observed PK and PD parameters corrected by the free fraction in the age group > 3 
months - < 2 years are presented in Table 6. 
Table 6  
Observed 
pharmacokinetic 
and 
pharmacodynamics 
parameters 
corrected by the free fraction in the age group > 3 months to < 2 years 
(N=16) 
Ceftobiprole dose administered: 15 mg/kg 2-h infusion (single dose) 
T1/2 (h) 
2.1 (1.1–4.1) 
fCmax (µg/mL) 
18.9 (8.22–41.2) 
fAUC0-8h (µg.h/mL) 
60.4 (25.2–124) 
fT>MIC = 4 µg/mL (h) 
5.3 (2.8–7.5) 
Number of subjects below the target of 50% of dosing interval 
2 out of 16 
The safety profile observed in study CSI-1006 after single-dose administration of 
ceftobiprole (7 mg/kg to 15 mg/kg) was generally similar to that observed in adults. 
No new or unexpected safety signals associated with study drug were observed. 
31 subjects (48%) reported at least one treatment-emergent AE. The majority of 
treatment-emergent AEs were mild in severity and considered not related to study drug. 
The most common AEs were vomiting (reported in 6 subjects [9%]) and pruritus 
(reported in 3 subjects [5%]). No deaths or drug-related SAEs were reported during the 
study. No subjects discontinued due to a treatment-emergent AE.  
Pharmacokinetic modeling 
The modeling strategy was to optimize the dosing regimen (dose, dosing interval and 
infusion duration) for paediatric subjects > 3 months to < 2 years in order to maximize 
fT>MIC=4 µg/mL and maintain exposure in the range well tolerated by adults, and below 
the exposure at the NOAEL in the juvenile rat study [9] for the corresponding age groups. 
Several variables were explored: incremental higher doses (up to 25 mg/kg), infusion 
times (2 or 4 hours), dosing regimen (q6h or q8h), and combinations of these variables. 
Total and unbound parameters were generated using a free fraction of 0.84 as reported in 
adults. The optimized dosing regimen for the age group of ≥ 3 month to < 2 years was 20 
mg/kg as a 4-h infusion q8h from an exposure/PD and safety point of view as 
summarized in Table 7. Exposure in this age group at the recommended dose of 20 mg 4-
h infusion q8h is 2 to 3-fold lower than the exposure obtained at the NOAEL in the 
juvenile toxicity study for Day 1 post-partum pups. 
 


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Table 7  
Predicted exposure to ceftobiprole in the age group ≥ 3 months to 
< 2 years 
Number of subjects (N=16) 
Ceftobiprole dose of 20 mg/kg 4-h infusion q8h 
 fT>MIC=4 µg/mL below 50% of dosing interval 
0 
Above highest adult Cmax 
0 
Above highest adult AUC 
1 
Above exposure (Cmax and AUC) at NOAEL 
0 
 
A PK model developed for neonates and infants was based on the fact that ceftobiprole is 
eliminated by the kidneys, and approximately 90% of the dose is recovered unchanged in 
urine, distribution is restricted to the extracellular compartment, and the systemic 
clearance of ceftobiprole correlated (coefficient of correlation of 0.9858) with the 
creatinine clearance in a dedicated clinical pharmacology study in renally impaired 
subjects. The model provided estimates for exposure and urinary concentration presented 
in Table 8. 
Table 8 
Estimated normal and worst-case exposure and urinary concentrations 
following a single dose of 7.5 mg/kg ceftobiprole in neonates and infants 
up to a postnatal age of 3 months. 
PNA 
Dose 
(mg) 
Normal condition 
Worst-case 
Dose 
(mg /h) 
Urine 
output 
(mL/h) 
Urine 
conc. 
(mg/ 
mL) 
Scr  
(mg/dL) 
T1/2 
(h) 
AUC 
(µg.h/ 
mL) 
Scr  
(mg/dL) 
T1/2 
(h) 
AUC 
(µg.h/ 
mL) 
8 d 
25.7 
0.38 
2.3 
63.2 
1.10 
10 
189.3 
6.4 
7 
0.94 
15 d 
27.4 
0.35 
2.2 
60.5 
1.10 
11 
189.8 
6.9 
7 
0.94 
1 mo 
30.5 
0.28 
1.9 
50.5 
0.88 
9 
157.1 
7.6 
8 
0.94 
2 mo 
37.7 
0.25 
1.9 
51.6 
0.88 
10 
182.5 
9.4 
10 
0.94 
3 mo 
44.0 
0.23 
1.6 
42.8 
0.88 
9 
166.5 
11.0 
12 
0.94 
PNA = postnatal age; Scr = serum creatinine; T1/2 = half-life; AUC = area under the curve 
 
Experience in paediatric subjects with other β-lactams 
Numerous PK studies and population PK/PD analysis in paediatric subjects and neonates 
were conducted with meropenem. Depending on the infusion duration (0.5 h to 4 h) doses 
of 20 mg/kg to 40 mg/kg were predicted to be efficacious in full-term and pre-term 
neonates5,6,7. These doses are similar to those investigated in infants with age > 2 months.  
                                                 
5 Padari. Short versus long infusion of meropenem in very-low-birth-weight neonates. Antimicrob Agents Chemother. 
2012;56:4760-4 


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The present study will include full-term neonates and pre-term neonates. The creatinine 
clearance is reduced in pre-term neonates8. Therefore, a conservative approach is taken 
and a dose of 7.5 mg/kg 4-h infusion will be investigated in neonates and children age 
3 months or below.  This dose level of 7.5 mg/kg is considered to provide an adequate 
safety margin for subjects whose renal excretion capacity may be limited, and will allow 
for appropriate dose modeling to determine whether further dose stratification is required 
within the various groups of neonates, e.g. based on gestational or post-natal age, body 
weight, body surface area, creatinine clearance or other covariates.  
 
 
                                                                                                                                                 
6 Bradley. Meropenem pharmacokinetics, pharmacodynamics, and Monte Carlo simulation in the neonate. Pediatr 
Infect Dis J. 2008;27:794-9 
7 Ohata. Optimal dosage regimen of meropenem for pediatric patients based on pharmacokinetic/ pharmacodynamic 
considerations. Drug Metab Pharmacokinet. 2011;26(5):523-31 
8 van den Anker. Meropenem pharmacokinetics in the newborn. Antimicrob Agents Chemother. 2009;53(9):3871–9 
 


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Appendix 2 
Collection, storage, and shipping of blood, plasma, infusion 
solution, and urine for pharmacokinetic analyses 
Details on handling of PK samples are provided in the Pharmacokinetics Manual for this 
study (provided separately). The Pharmacokinetics Manual also contains instructions on 
shipping samples, including transport logistics. Materials needed for sampling will be 
provided by the sponsor. 
Preprinted labels for blood, plasma, urine, and infusion solution collection tubes will be 
supplied by the sponsor. They will include the protocol number, matrix (coded by label 
color), subject number, planned time of collection. Labels should be fixed lengthwise to 
room-temperature tubes, with the colored portion at the bottom of the tube. DO NOT 
place any tape around the label; the labels are designed to stick without the use of tape. 
The actual date and clock sampling times should be entered into the eCRFs. All tube 
labels should be in indelible ink (ball-point pen). 
Blood collection  
Blood samples will be collected and transferred immediately into pre-chilled tubes  
containing 2M citric acid. Exposure to direct sunlight should be avoided. 
Plasma preparation  
As soon as possible, but not later than 30 minutes after blood collection, plasma should 
be separated from blood cells by centrifugation in a refrigerated centrifuge 
(approximately +4 °C). The plasma supernatant should be transferred immediately into a 
labeled tube and stored below −65 °C until shipment. 
Urine collection  
The total amount of urine produced by the subject at the time of collection (if possible) 
should be transferred into polypropylene collection bottles made of light-protecting 
material; exposure of urine samples to sunlight should be avoided. The urine collection 
bottles will be adjusted after collection with 2M citric acid. The pH should be between 
4.0 and 5.5. Samples will be stored below −65 °C until shipment. 
Infusion solution collection  
An aliquot of infusion solution will be collected after completion of the infusion, 
transferred to a tube, and stored below  −65 °C until shipment. 
 
 


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Shipping 
Plasma, urine, and infusion solution samples should be shipped in an upright position on 
dry ice. 
Frozen samples will be shipped to: 
Swiss BioQuant AG 
c/o Dr. Christoph Siethoff 
Kägenstrasse 18 
CH-4153 Reinach, Switzerland 
Tel: +41 61 716 9812  
Fax +41 61 716 9815 
 
E-mail: christoph.siethoff@swissbioquant.com 
 
 
 


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Appendix 3 
Criteria for evaluating relationship between adverse events and 
study treatment 
UNRELATED 
This category is applicable to an AE that meets the following 3 criteria: 
1. It does not follow a reasonable temporal sequence from administration of the study 
drug, i.e. the time between the administration of study drug and occurrence of the event is 
not plausible. If the study drug was interrupted or stopped the event did not improve or 
disappear.  (There are important exceptions when an AE does not disappear upon 
discontinuation of the study drug, yet study drug-relatedness clearly exists; e.g., (1) bone 
marrow depression, (2) tardive dyskinesias.). If the study drug was re-administered it did 
not reappear. 
2. It does not follow a known pattern of the response to the suspected study drug or drugs 
of the same substance class. 
3. It is judged to be clearly and incontrovertibly due only to extraneous causes such as the 
subject’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject.  
REMOTE  
This category is applicable to an AE that meets the following three criteria: 
1. It does not follow a reasonable temporal sequence from administration of the study 
drug, i.e. the time between the administration of study drug and occurrence of the event is 
not plausible. If the study drug was interrupted or stopped the event did not improve or 
disappear. If the study drug was re-administered it did not re-appear. 
2. It does not follow a known pattern of the response to the suspected study drug or drugs 
of the same substance class. 
3. It may readily have been produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the subject. 
POSSIBLE  
This category is applicable to an AE that does not meet the criteria for “unrelated” or 
“remote”, nor the criteria for “probable”. An AE would be considered possible if, or 
when, for example: 
1. It follows a reasonable temporal sequence from administration of the study drug 
(see also additional explanations above) or it follows a known pattern of the response to 
the suspected study drug or drugs of the same substance class.  
2. It may or may not have been produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the subject. 
Note: If an event neither follows a plausible temporal relationship nor a known pattern of 
response but there is no alternative explanation for the event, this will usually be judged a 
possibly related event.  


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PROBABLE  
This category is applicable to an AE that is considered, with a high degree of certainty, to 
be related to the study drug. An AE may be considered probable, if it meets the following 
3 criteria: 
1. It follows a reasonable temporal sequence from administration of the study drug, 
i.e. the time between the administration of study drug and occurrence of the event is 
plausible. If the study drug was interrupted or stopped the event did improve or 
disappear. (There are important exceptions when an AE does not disappear upon 
discontinuation of the study drug, yet drug-relatedness clearly exists; e.g., (1) bone 
marrow depression, (2) tardive dyskinesias.) If the study drug was re-administered it did 
re-appear. 
2. It follows a known pattern of the response to the suspected study drug or drugs of the 
same substance class. 
3. It cannot be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the 
subject. 
Regardless of the criteria mentioned above, reappearance of an event upon re-challenge 
will be regarded as strong evidence of probable relationship to study drug. 
 
 


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Appendix 4 
Laboratory reference values and formulas 
 
Impaired renal function or known significant renal disease, as evidenced by an 
estimated glomerular filtration rate 
Kidney maturation in the neonate has been described in two European guidance 
documents. 9,10 The key points are: 
• Glomerular filtration matures faster than the tubular function. Both depend not only 
on age and maturational status but also on adverse factors occurring in the pre- and 
post-natal period, including for example intrauterine growth retardation or 
administration of nephrotoxic drugs to the mother and the neonate. 
• Post-menstrual age (PMA) (gestational age [GA] + postnatal age) of the neonate is 
likely to be the best parameter of the ongoing neonatal maturation 
– There may be two-fold to four-fold difference in GFR values between premature 
and full-term newborns. 
– From 26 weeks of GA at birth to 34 weeks of PMA, the increase in GFR is 
limited because of incomplete nephrogenesis. 
– Birth triggers a dramatic increase in GFR. The GFR increases from 
10 mL/min/1.73 m2 at birth to 20 to 30 mL/min/1.73 m2 after 2 weeks. 
– After the first month, serum creatinine remains stable during the first 2 years of 
life (under 44 μMol/L = 0.5 mg/dL in the full-term neonate). 
• Serum creatinine is elevated in the first days of life reflecting maternal creatinine and 
a low intrinsic GFR. 
• In premature neonates, the persistence of an elevated serum creatinine during the first 
weeks of life is the result of a transitory process of tubular creatinine reabsorption. 
• To monitor renal function serum creatinine is used after the first week of life in 
full-term neonates and after 4 weeks in premature neonates. Before these times, 
intra-individual changes (related to post-menstrual age) in serum creatinine are used 
as a guide to renal function. 
In addition, the following references must be considered: 
• Schwartz11 published the following modified formula (based on creatinine levels 
determined with the enzymatic method): 
eGFR (mL/min/1.73m2) = 0.413 • length (cm) / creatinine (mg/dL) 
 
                                                 
9  EMA (2004) Discussion paper on the impact of renal immaturity when investigating medicinal products intended 
for paediatric use 
10  CHMP, PDCO (2009) Guideline on the investigation of medicinal products in the term and preterm neonate 
11  Schwartz GJ, et al (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–37 


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• Laboratory normal ranges (enzymatic method): 
 
Creatinine (mg/dL) 
UZ Leuven 
0.31 – 0.88 (< 1 month) 0.16 – 0.39 (1–12 months) 
AZ Sint-Jan 
0.24 – 0.85 (< 2 month) 0.17 – 0.42 (2–12 months) 
 
Abitbol12 reported creatinine levels of 0.68 ± 0.14 mg/dL during postnatal day 3–7 in 
60 preterm infants (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 greater than 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.  
• In the meropenem PK study published by Van den Anker13, a creatinine level of 
greater than 140 µmol/L (= 1.58 mg/dL) led to the exclusion of the subject from the 
study. 
• Two graphs presented at an EMA Workshop on regulatory and scientific issues 
related to the investigation of medicinal products intended for neonate use14 indicated 
that creatinine levels in neonates of more than 1000 g body weight, or a GA of more 
than 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.10 GFR is indirectly 
proportional to creatinine, i.e. a GFR of 2/3 of normal corresponds to a 1.5-fold higher 
than normal creatinine level. Since PMA 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 5: 
PMA (weeks) 
Creatinine 
(mg/dL) 
Rationale 
28–34 completed 
1.32 
150% of the upper limit of the laboratory normal ranges  
35–42 completed 
1.1 
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 
                                                 
12  Abitbol CL et al (2014) Neonatal kidney size and function in preterm Infants: What is a true estimate of glomerular 
filtration rate? J Pediatr 164:1026-31). 
13  Van den Anker JN, et al (2009) Meropenem pharmacokinetics in the newborn. AAC 53(9):3871 
14  Van den Anker (2006) Workshop on Regulatory and Scientific Issues related to the Investigation of Medicinal 
Products intended for Neonatal Use 


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Considering these 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/1.73m2) 
 
Post-menstrual age (weeks) 
38–34 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 5 to individual patients. 
 

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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
 
Sponsor: 
Basilea Pharmaceutica International Ltd. 
 
Study title: 
An open-label study to evaluate the single-dose 
pharmacokinetics and safety of ceftobiprole in 
neonate and infant subjects aged up to 3 months 
undergoing treatment with systemic antibiotics 
 
Study number: 
BPR-PIP-001 
 
Development Phase: 
Phase 1 
 
SAP version: 
Final v2.0 – 17 Aug 2020 
 
Trial Biostatistician: 
Signature 
Date 
Name: Mariya Antonova 
 
Sponsor's representative: 
Signature 
Date 
Name:  Kamal Hamed 
Function: Head of Clinical Development - Infectious 
Diseases / Project Physician 
Company:  Basilea Pharmaceutica International Ltd 
City:  Basel 
Country:  Switzerland 
Signature 
Date 
Name:  Mikael Saulay 
Function: Data Management & Biostatistics Lead 
Company:  Basilea Pharmaceutica International Ltd 
City:  Basel 
Country:  Switzerland 
Confidentiality statement: 
▪ 
The information provided in this document is strictly confidential. 
▪ 
The Recipients of the SAP must not disclose the confidential document and any related 
information to other persons. 
▪ 
In addition, they must keep this confidential document in a controlled environment which 
prevents unauthorized access to the document. 
 
 
 
NCT02527681 


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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................................................... 3 
1 Introduction ....................................................................................................................................................... 4 
2 Study Objectives, main Parameters and Design .............................................................................................. 4 
2.1 
Study Objectives ..................................................................................................................................... 4 
2.1.1 
Primary objective ........................................................................................................................ 4 
2.1.2 
Secondary objective................................................................................................................... 4 
2.2 
Main Study Parameters .......................................................................................................................... 4 
2.2.1 
Efficacy ...................................................................................................................................... 4 
2.2.2 
Safety and Tolerability ............................................................................................................... 4 
2.2.3 
Pharmacokinetics ...................................................................................................................... 4 
2.3 
Study Design ........................................................................................................................................... 4 
2.3.1 
Study design and sample size ................................................................................................... 4 
2.4 
Assessments........................................................................................................................................... 5 
2.4.1 
Interim analyses ......................................................................................................................... 6 
3 Analysis populations ......................................................................................................................................... 7 
3.1 
Pharmacokinetics Population ................................................................................................................. 7 
3.2 
Safety Population .................................................................................................................................... 7 
4 Statistical Considerations and analysis ............................................................................................................ 7 
4.1 
General Considerations .......................................................................................................................... 7 
4.2 
Derived Variables.................................................................................................................................... 7 
4.3 
Handling of Missing Data and/or Invalid Data and Outliers .................................................................... 8 
5 Statistical plan and methods ............................................................................................................................. 8 
5.1 
Background Characteristics .................................................................................................................... 9 
5.1.1 
Patient disposition ...................................................................................................................... 9 
5.1.2 
Protocol deviations ..................................................................................................................... 9 
5.2 
Demographics and Other Baseline Characteristics ................................................................................ 9 
5.2.1 
Demographics ............................................................................................................................ 9 
5.2.2 
Medical history ......................................................................................................................... 10 
5.3 
Prior and Concomitant Medications ...................................................................................................... 10 
5.4 
Treatment Compliance and Exposure .................................................................................................. 10 
5.5 
Safety Analysis...................................................................................................................................... 10 
5.6 
Clinical Laboratory Evaluations ............................................................................................................ 11 
5.7 
Vital Signs ............................................................................................................................................. 11 
6 References ..................................................................................................................................................... 12 


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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
Protocol Version 5.0 
21 March 2019 
LIST OF ABBREVIATIONS 
 
AUC 
Area under the curve 
AE 
Adverse event 
BLQ 
Below the limit of quantitation 
BMI 
Body mass index 
BSA 
Body surface area 
CI 
Confidence interval 
CLS 
Systemic clearance 
Cmax 
Maximum observed plasma concentration 
ITT 
Intent-to-treat 
IV 
Intravenous 
MIC 
Minimum inhibitory concentration 
PK 
Pharmacokinetic(s) 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
t1/2 
Half-life 
T > MIC 
Time that concentration is above the MIC 
VSS 
Volume of distribution at steady-state 
WBC 
White blood cell 
RBC 
Red blood cell 


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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
1 
INTRODUCTION 
This statistical analysis plan covers the detailed procedures for performing the statistical analyses and 
producing tables, listings and figures in the study described in Basilea Pharmaceutica International Ltd. 
(Basilea) Protocol BPR-PIP-001, version 5 dated 21st of March 2019.. 
 
2 
STUDY OBJECTIVES, MAIN PARAMETERS AND DESIGN 
 
2.1 
Study Objectives 
2.1.1 Primary objective 
The primary objective of this study is to characterize the pharmacokinetics (PK) of a single dose of 
ceftobiprole in neonates and infants aged ≤ 3 months. 
2.1.2 Secondary objective 
The secondary objective of this study is to evaluate the safety and tolerability of ceftobiprole in neonates 
and infants aged ≤ 3 months. 
 
2.2 
Main Study Parameters 
2.2.1 Efficacy 
Not applicable for this study. 
2.2.2 Safety and Tolerability 
Adverse events, laboratory tests (hematology, biochemistry, urinalysis), vital signs, physical 
examination. 
2.2.3 Pharmacokinetics 
Non-compartmental analysis: Cmax, t1/2, AUC0–t, AUC0–∞, CLS, VSS, T > MIC. 
The relationship between exposure (Cmax and AUC), derived PK parameters (CLS, VSS, t1/2), 
gestational age, post-natal age, body weight, body mass index, body surface area, and calculated 
creatinine clearance will also be assessed. 
 
2.3 
Study Design 
2.3.1 Study design and sample size 
This is an open-label, single-fixed-dose, multicenter study carried out in three sequential cohorts. 
Each cohort consists of 15 neonates or infants aged ≤ 3 months (45 subjects total). 
The study will be conducted in European and United States centers. 
 
No sample size calculation has been performed for this study. Study drug treatment of 15 subjects 
per dosing cohort (total N = 45) is based on experience and is considered sufficient to fulfil the 
objectives of this study. 
 
The study comprises: 
I. 
A pre-dosing screening phase of up to 24 hours, 
II. 
A 1-day dosing phase with a single-dose intravenous administration of ceftobiprole at 
7.5 mg/kg, and 
III. 
A post-dose follow-up safety assessment on Day 7 ± 3 after ceftobiprole administration. 


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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
2.3.1.1   Cohorts 
The study population was initially planned to comprise of 3 cohorts, with 15 subjects in each cohort, 
based on gestational age (28 to 32 weeks [Cohort 3]; 33 to 36 weeks [Cohort 2]; ≥ 37 weeks [Cohort 
1]). 
Due to the very low rate of patient recruitment, only cohort 1 was successfully completed. There is no 
cohort 2 and cohort 3 population at the end of the study. 
 
2.4 
Assessments 
The study assessments from screening to follow-up are summarized in Table 1 below: 
 
Table 1: Schedule of assessments 
Screening 
Day −1 to 1 
Dosing 
Day 1 
Follow-up 
Day 7±3 
SCREENING AND ADMINISTRATIVE PROCEDURES 
Written Informed consent1 
X 
Inclusion/exclusion criteria 
X 
Medical history 
X 
Prior medications2 
X 
CEFTOBIPROLE   ADMINISTRATION 
Infusion of ceftobiprole3 
X 
Collection of aliquot of infusion solution4 
X 
PHARMACOKINETIC   PROCEDURES 
Blood sample collection5 
X 
Urine collection6 
X 
SAFETY PROCEDURES 
Vital signs7 
X 
X 
X 
Physical examination 
X 
X* 
X 
Body weight and height8 
X 
X* 
X 
Laboratory tests9 
X 
X 
Concomitant medication 
X 
X 
Adverse events 
< ------------- X -------- ------> 
1 Informed consent must be obtained within 3 days prior to dosing on Day 1. 
2 Prior medications administered within the 7 days prior to dosing will be collected. 
3 Ceftobiprole must be administered via a separate infusion line. No other intravenous infusion may be given through the same line 
during the 4-hour ceftobiprole infusion, and – if feasible – attempts should be made to not simultaneously administer any other antibiotic 
treatment (i.e., through any infusion line) during the ceftobiprole infusion. If feasible, attempts should be made to allow for a minimum 
period of 30 minutes between the end of administration of any other antibiotic treatment and the start of ceftobiprole medocaril infusion. 
4 An aliquot of approximately 3 mL of infusion solution will be collected after completion of the ceftobiprole infusion and frozen at 
below −65 °C immediately after sampling. 
5 Blood samples of 200–300 µL will be obtained for PK analysis at the times described in Table 2. 


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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
6 Attempts should be made to obtain urine at the times described in Table 2; NB: Full portions of urine will be collected from subjects 
in whom a urinary catheter has been placed for their standard clinical care. Urinary catheters will not be placed for the purpose of the 
study. For subjects without a urinary catheter, one or more portions of urine may be obtained before, during, and after dosing. 
7 Vital signs (body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures) will be measured at the times 
described in Table 2. 
8 Height must be recorded at screening only. The body weight determination on Day 1 will be used for dose calculation and should be 
obtained within 6-hours prior to dosing. 
9 Safety laboratory tests include hematology, biochemistry, and urinalysis (see protocol Section 5.2.3.2). 
*Physical examination and body weight obtained during the screening evaluation do not need to be repeated as Day 1 assessments if 
they were performed within 6 hours prior to dosing on Day 1. 
 
 
The schedule of PK sampling and vital signs on Day 1 are summarized in Table 2 below: 
 
Table 2: Schedule of PK sampling and vital signs on Day 1 
Time 
Vital signs 
Blood samples 
Urine collection* 
Infusion solution aliquot 
collection 
−2 to 0 h 
X 
−15 min 
X 
Pre-dose 
X 
0 to 2 h 
X 
1 h 
X 
2 h 
X 
2 h 15 min 
X 
2 to 4 h 
X 
4 h (end of 
infusion) 
X 
X 
4 to 8 h 
X 
6 h 
X 
X 
8 h 
X 
8 to 12 h 
X 
12 h 
X 
* NB: Full portions of urine will be collected from subjects in whom a urinary catheter has been placed for their standard 
clinical care. Urinary catheters will not be placed for the purpose of the study. For subjects without a urinary catheter, one 
or more portions of urine may be obtained before, during, and after dosing. 
 
 
2.4.1 Interim analyses 
No hypothesis-testing interim analysis is planned. PK data from early dosing cohorts may be analyzed 
before dosing in later cohorts is started or completed. Safety data will be reviewed on an ongoing basis. 


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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
3 
ANALYSIS POPULATIONS 
 
3.1 
Pharmacokinetics Population 
Consists of all subjects who receive study drug and have adequate samples for determination of 
time-plasma concentration profiles of ceftobiprole. Subjects may be excluded from the PK analysis if 
they have significant protocol deviations, including eligibility criteria deviations, or if data which may 
influence the PK analysis are unavailable. 
 
3.2 
Safety Population 
All subjects who receive any quantity of the study drug. 
 
 
4 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
 
4.1 
General Considerations 
No formal hypothesis testing will be performed. Summary outputs, where possible, will be 
presented for cohort 1. 
 
 
4.2 
Derived Variables 
The following derived variables will be applied throughout the study: 
 
• 
Baseline is defined as the last available assessment prior to start of study drug administration 
(including unscheduled assessments). 
 
• 
Last/Final for safety is the first available value after study drug administration. 
 
• 
Adverse event duration (in days, hours or fractions of hours) will be calculated as: 
 
o 
(<event end date.time> minus <event onset date.time>) in days or hours. 
If only date is collected: 
o 
((<event end date> minus <event onset date>) + 1) in days 
 
• 
The following algorithm will be used for the study day determination: 
 
o 
Day 1 = Day of study drug administration. The day before day 1 is Day -1. 
o 
Prior to Day 1 the algorithm is (<visit/examination date> minus <date of first study drug 
administration >) 
o 
Day 1 and subsequent days = (<visit/examination date> minus <date of first study drug 
administration >) + 1. 
 
• 
Elapsed Times Between Examination And Treatment Administration will be calculated as 
(<examination date.time> minus <treatment administration date.time>) 
• 
Post-natal age expressed in days will be computed as 
 
((<consent date> minus <date of birth>) + 1) .Gestational age collected by the investigator will 
be used for analysis. 


 
 
BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
• 
Gestational age collected as weeks and days by the investigator will be computed as weeks 
rounded to 1 decimal for analysis. 
 
 
4.3 
Handling of Missing Data and/or Invalid Data and Outliers 
Incomplete/partial dates will be replaced by derived variables and imputed using the following rules: 
 
• 
if the day of the month is missing it is imputed to be the 15th if not in the month of study 
treatment. In case this leads to inconsistencies with other available patient’s data, the imputation 
values will be handled case-by-case. 
• 
if both the day and month are missing, they are imputed to be June 30 if not in year of study 
treatment. In case this leads to inconsistencies with other available patient’s data, the imputation 
values will be handled case-by-case. 
• 
missing years will be left as missing. 
• 
missing times will be replaced by ’00:00’ for start times and ’23:59’ for end times if time is 
required. 
• 
missing minutes will be replace by ‘00’ for start times and ‘59’ for end times times if time is 
required. 
 
5 
STATISTICAL PLAN AND METHODS 
The statistical analysis will be performed using the software package SAS version 9.3 or higher (SAS 
Institute Inc., Cary, NC 27513, USA). Validation will be done by double programming. 
All individual data as well as results of statistical analyses will be presented in individual patient data 
listings and statistical summary tables. 
In general, continuous variables will be summarized using the following standard descriptive summary 
statistics: mean, standard deviation, median, minimum, maximum and number of observations. 
Categorical data will be described using frequency and percentage. Shift tables will be provided, where 
appropriate. One additional decimal point for mean, median, Q1, Q3 and two additional decimal points 
for SD will be used. 
PK parameters will be presented by individual listings and descriptive summary statistics including 
arithmetic and geometric means, arithmetic and geometric coefficients of variation, standard deviation, 
minimum, median, and maximum. 
Percentages will be rounded to one decimal place or more if most results are close to 0 or 100. 
Unscheduled assessments will only be listed and will not be included in the tables, unless otherwise 
specified. Any changes in the planned statistical methods will be documented in the clinical study 
report. 
To assess the relationship between pairs of continuous variables (including PK parameters), the 
Pearson product moment correlation will be computed. This will however, only be applied when each 
variable has at least 5 non-missing observations. This correlation computation will apply to Cmax, AUC, 
CLs, Vss, t1/2, gestational and post-natal age, weight, BMI, BSA, and calculated creatinine clearance. 
The following international dictionaries will be used for medical coding: 
• Medical History events: MedDRA (version 20.1) 
• Medications: WHO Drug Dictionary Enhanced (March 2018 B2 version) 
• Adverse events: MedDRA (version 20.1) 
Data from all participating study centers will be combined for analysis. 
 
 
 
 
 
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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
 
 
5.1 
Background Characteristics 
5.1.1 Patient disposition 
Enrollment and disposition data will be presented for each patient in data listings and summarized by 
frequency tables. 
Patient enrollment eligibility and inclusion and exclusion criteria deviations will be presented in data 
listings. 
5.1.2 Protocol deviations 
All protocol deviations reported by the clinical team will be presented in a data listing sorted by center, 
category and patient. 
Protocol deviations captured in the database such as: 
• Non-adherence to study inclusion and exclusion criteria 
• Failure to obtain informed consent prior to beginning the study 
• Wrong study treatment received, or an incorrect dose 
• Other data deviations as observed upon review of the data 
 
Major protocol deviations are defined as those that could potentially bias either the PK or safety 
conclusions of the study. All other protocol deviations are defined as minor protocol deviations. 
Protocol deviations will be reviewed prior to database lock and classified as major or minor based on 
medical review. 
 
5.2 
Demographics and Other Baseline Characteristics 
5.2.1 Demographics 
Descriptive statistics of baseline data will be presented for cohort 1. The following baseline 
demographic data will be presented: 
 
• 
Post-natal Age [days] at Day 1 / Gestational Age [weeks] 
o Continuous summary 
• 
Sex  
o Categorical summary (Male, Female) 
• 
Race 
o Categorical summary (White, Black or African American,  Asian, American Indian or 
Alaska Native, Native Hawaiian or Other Pacific Islander, Other) 
• 
Height [cm] 
o Continuous summary 
• 
Weight [g] 
o Continuous summary 
 
 
 
 
 
 
 
 
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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
5.2.2 Medical history 
Medical history of diseases will be summarized in tables by SOC, and PT, including number of 
subjects and percentage relative to the numbers of subjects in the corresponding study groups. 
 
 
5.3 
Prior and Concomitant Medications 
 
Data concerning concomitant medications and procedures will be collected throughout the study. 
These data will be obtained at scheduled or unscheduled study visits, based on  information 
provided by the subject’s parent or legal guardian. 
 
The coding of medications will be performed using the WHODRUG enhanced dictionary and partial 
start  and/or end dates will be imputed as described in section 4.3. 
 
Medications will be classified based on the observed or imputed start dates into: 
 
• 
A medication is classified as prior if it started and stopped before the reference start 
date of the subject. 
 
• 
A medication is classified as concomitant medication if it started on or after the 
reference start date of the subject. 
 
• 
A medication is classified as ongoing if it started before the reference start date of the 
subject and is still ongoing after the reference start date. 
 
Prior medications, concomitant and ongoing medications will be presented in a listing. 
Concomitant and ongoing medications will be summarized in tables by Anatomical Therapeutic 
Chemical (ATC) level 4 code, and Preferred Term (PT), including number of subjects and percentage 
relative to the numbers of subjects in the corresponding study groups. 
 
5.4 
Treatment Compliance and Exposure 
Exposure to study drug will be summarized. The total dose taken will be presented. 
 
5.4.1.1   Pharmacokinetic analysis 
Plasma concentrations at each time point of measurement will be evaluated by descriptive statistics, 
including arithmetic mean, standard deviation (SD), minimum, maximum, and median. Actual 
sampling times will be used to calculate PK parameters. If ≤ 50% of the values at a given time point 
are BLQ, these values will be set to zero for mean value calculation. If more than 50% of the values 
at a given time point are BLQ, no mean value will be calculated. Mean plasma concentration profiles 
of cohort 1 will be generated according to these criteria. 
For PK evaluation, BLQ-values at infusion start will be set to zero, BLQ-values at the end of the 
sampling period will be disregarded for PK assessment. Single BLQ values during blood sampling will 
be taken as ‘missing values’, if the following sample(s) show a concentration above the BLQ value. 
 
5.5 
Safety Analysis 
Definitions of adverse events (AEs) and serious adverse events (SAEs) as well as information on 
 
 
 
 
 
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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
reporting procedures for AEs/SAEs are provided in the clinical trial protocol. AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA version 20.1) and partial start and/or end 
dates will be imputed as described in section 4.3. 
 
Frequency tables summarizing the incidence and observed number of treatment-emergent adverse 
events by treatment and by System Organ Class and Preferred Term will be prepared with 3 levels 
of detail: 
• 
All adverse events 
 
• 
Adverse events by severity (mild/moderate/severe) 
 
• 
Adverse events by relationship to study drug (not related/related) 
 
An adverse event is classified as treatment emergent if the following conditions are met: 
 
• 
Start date and end date of adverse event is missing. 
• 
Start date is missing but end date is not before reference start date of treatment 
• 
Start date is missing but end date is after reference start date 
• 
Start date is on or after reference start date. 
 
Summary tables for all adverse events and for adverse events by severity will be presented for 
cohort 1. 
 
 
5.6 
Clinical Laboratory Evaluations 
 
The laboratory parameters collected per protocol will be described using summary statistics and shift 
tables. Summary statistics will be presented for absolute values and absolute change from baseline. 
 
Reference ranges (low/high, negative/positive, normal/abnormal) will be presented in shift tables to show 
shifts from baseline values at the different time points. 
 
5.7 
Vital Signs 
The actual and change from baseline values of the following vital signs will be summarized using 
descriptive statistics 
• Systolic blood pressure 
• Diastolic blood pressure 
• Pulse rate 
• Temperature 
• Respiration rate 
 
 
In addition marked reference changes from baseline will be presented for vital signs. Marked 
reference change will be defined as follow: 
• Diastolic Blood Pressure: <60 or >100 mmHg. 
• Systolic Blood Pressure: <80 or >180 mmHg. 
 
 
 
 
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BAL5788/ Ceftobiprole Medocaril 
Clinical Study Protocol 
BPR-PIP-001 
 
 
Protocol Version 5.0 
21 March 2019 
 
 
 
 
• Pulse: <40 or >120 beats/min. 
• Temperature: <36.0 or >38.5 degree Celsius. 
 
 
 
6 
REFERENCES 
• Basilea SOP-GLO-000416 (3.0) Statistical Analysis Plan 
• Basilea LIS-GLO-000412 (3.0) Preferred Units and Marked Factors 
• EMEA. CPMP/ICH/363/96: Note for Guidance on Statistical Principles for Clinical Trials - ICH 
Topic E9. London: EMEA; 1998. 
• Integrated Addendum to ICH E6 (R1), GUIDELINE FOR GOOD CLINICAL PRACTICE E6 (R2), 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use, 9 November 2016. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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