Conditions: Community-acquired Pneumonia (CAP) Hospital-acquired Pneumonia (HAP)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 138
Healthy volunteers: no

Brief summary:
This was a study of the safety and efficacy of ceftobiprole medocaril compared with intravenous (IV) standard-of-care cephalosporin treatment with or without vancomycin in pediatric patients with either hospital-acquired bacterial pneumonia (HAP) or community-acquired bacterial pneumonia (CAP) requiring hospitalization, and requiring intravenous (IV) antibiotic therapy.

Detailed description:
This was a randomized, investigator-blind, active-controlled multi-center study to evaluate the safety, tolerability, pharmacokinetics and efficacy of ceftobiprole medocaril compared with IV standard-of-care cephalosporin treatment with or without vancomycin in pediatric patients aged 3 months to less than 18 years with HAP or CAP requiring hospitalization and therapy with IV antibiotics. Randomization was stratified by four age groups (3 months to \< 2 years; 2 years to \< 6 years; 6 years to \< 12 years; 12 years to \< 18 years), and by diagnosis of HAP or CAP.

Arms:
arm 1: Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, an advanced-generation cephalosporin developed for IV administration. Ceftobiprole is characterized by potent, broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative pathogens. arm 2: Ceftriaxone was used as standard-of-care cephalosporin for the treatment of CAP. It is a third-generation cephalosporin with activity against typical bacterial pathogens of CAP requiring hospitalization, and is widely used for the treatment of various bacterial infections in neonates, infants, children, and adults.

Ceftazidime was used as standard-of-care cephalosporin for the treatment of HAP. It is also a third-generation cephalosporin, but with broader activity against Gram-negative aerobic bacilli, including Pseudomonas aeruginosa.

Vancomycin is a glycopeptide antibiotic that is active against staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA). At the discretion of the blinded investigator, patients received vancomycin in addition to the IV standard-of-care cephalosporin when MRSA was suspected or confirmed.

Interventions: intervention 1: ceftobiprole medocaril intervention 2: IV standard-of-care cephalosporin
Intervention descriptions: intervention 1: Ceftobiprole medocaril was administered at age-adjusted doses (10, 15 or 20 mg/kg) and infusion durations (2 or 4 hours) every 8 hours. The maximum dose, regardless of body weight, was 500 mg ceftobiprole every 8 hours (maximum total daily dose of 1500 mg ceftobiprole).

After a minimum of 3 days of IV treatment, patients with sufficient improvement in disease signs and symptoms could be switched to an age-appropriate oral antibiotic to complete a total minimum of 7 days and a total maximum of 14 days' antibiotic treatment. intervention 2: Ceftriaxone was administered at 50 to 80 mg/kg IV as a single daily dose, up to a maximum dose of 2 g/day. The actual dose of ceftriaxone within this dose range was determined by the blinded investigator prior to first study drug administration and was not modified during subsequent study days.

After a minimum of 3 days of IV treatment, patients with sufficient improvement in disease signs and symptoms could be switched to an age-appropriate oral antibiotic to complete a total minimum of 7 days and a total maximum of 14 days' antibiotic treatment.

At the discretion of the blinded investigator, patients received vancomycin at a dose of 10 to 15 mg/kg IV every 6 hours, up to a maximum dose of 2 g/day, in addition to the IV standard-of-care cephalosporin when MRSA was suspected or confirmed.

Protocol document:
Prot_000.pdf: 
NCT03439124 
 
 
 
 
CLINICAL STUDY PROTOCOL 
BPR-PIP-002 
A multicentre, randomized, investigator-blind, active-controlled study to evaluate 
the safety, tolerability, pharmacokinetics and efficacy of ceftobiprole versus 
intravenous standard-of-care cephalosporin treatment with or without vancomycin 
in paediatric patients aged from 3 months to less than 18 years with 
hospital-acquired pneumonia or community-acquired pneumonia requiring 
hospitalisation 
 
Protocol Number/Version: 
BPR-PIP-002 / 3.0 
Compound: 
Ceftobiprole medocaril 
Phase of development: 
Phase 3 
EudraCT number: 
2013-004615-45 
Date: 
29 November 2018 
Project Physician: 
 
Project Statistician: 
 
Sponsor: 
Basilea Pharmaceutica International Ltd 
Grenzacherstrasse 487 
CH-4058 Basel, Switzerland 
Tel + 41 61 606 1111 
 
 
 
 
Note: This is an electronically controlled document. 
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 Investiga or, 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. 


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Clinical Study Protocol 
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SPONSOR SIGNATURES 
 
 
Protocol number / Version: BPR-PIP-002 / 3.0 
Study title: 
A multicentre, randomized, investigator-blind, 
active-controlled study to evaluate the safety, tolerability, 
pharmacokinetics and efficacy of ceftobiprole versus 
intravenous standard-of-care cephalosporin treatment with 
or without vancomycin in paediatric patients aged from 
3 months to less than 18 years with hospital-acquired 
pneumonia or community-acquired pneumonia requiring 
hospitalisation 
Compound: 
Ceftobiprole medocaril 
Phase of development: 
Phase 3 
Date: 
29 November 2018 
Project Physician: 
 
Project Statistician: 
 
Sponsor: 
Basilea Pharmaceutica International Ltd 
Grenzacherstrasse 487 
CH-4058 Basel, Switzerland 
Tel + 41 61 606 1111 
 
 
 
 
 
 


Ceftobiprole 
Clinical Study Protocol 
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Version 3.0 
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Protocol synopsis 
 
 
TITLE 
A multicentre, randomized, investigator-blind, active-controlled study 
to evaluate the safety, tolerability, pharmacokinetics and efficacy of 
ceftobiprole 
versus 
intravenous 
standard-of-care 
cephalosporin 
treatment with or without vancomycin in paediatric patients aged from 
3 months to less than 18 years with hospital-acquired pneumonia or 
community-acquired pneumonia requiring hospitalisation 
 
 
SPONSOR 
Basilea Pharmaceutica International Ltd (‘Basilea’) 
STUDY PHASE 
3 
 
 
INDICATIONS 
Treatment of hospital-acquired pneumonia (HAP) excluding ventilator- 
associated pneumonia (VAP), and community-acquired pneumonia 
(CAP). 
 
 
OBJECTIVES 
Primary objective 
To characterise the safety profile of ceftobiprole in paediatric patients 
with HAP or CAP requiring hospitalisation and intravenous (IV) 
antibiotic therapy. 
Secondary objectives 
In paediatric patients with HAP or CAP requiring hospitalisation: 
 
To compare the clinical cure rate and microbiological eradication 
rate at the test-of-cure (TOC) visit between ceftobiprole and IV 
standard-of-care cephalosporin treatment (± vancomycin) 
 
To compare the clinical and microbiological relapse rates at the last 
follow-up (LFU) visit between ceftobiprole and IV standard-of-care 
cephalosporin treatment (± vancomycin) 
 
To  characterise   other   efficacy   measures   of   ceftobiprole 
(e.g., improvement in signs and symptoms of pneumonia, length of 
hospital stay) 
 
To assess the pharmacokinetics (PK) of ceftobiprole 
 
 
STUDY DESIGN 
Randomized, 
investigator-blind, 
active-comparator, 
multiple-fixed 
dose, multicentre study 
PLANNED NUMBER 
OF PARTICIPANTS 
 
 
 
 
NUMBER OF 
CENTRES/ 
LOCATIONS 
138 patients are planned to be randomized 2:1 to ceftobiprole or 
standard-of-care comparator treatment. It is  estimated  that  at  least 
125 of these patients  will  be  evaluable,  comprising  a  minimum  of 
50 patients for each of the age categories < 6 years and ≥ 6 years. There 
is no requirement for a minimum number of patients with each 
infection type (HAP or CAP). 
Approximately 20 European centres; additional centres both within and 
outside Europe may be considered. 
 
 


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INCLUSION 
CRITERIA 
Patients meeting all of the following at Screening: 
1. Male or female aged 3 months to < 18 years 
2. Body weight of at least 5 kg 
3. Diagnosis of either HAP (pneumonia occurring after ≥ 48 hours of 
hospitalisation) or CAP requiring hospitalisation and administration 
of IV antibiotic therapy, characterised by: 
 
Fever (> 38.5 °C) or hypothermia (< 35 °C), and 
 
Leucocytosis or leucopenia (relevant to patient age and 
institutional normal ranges), and 
 
At least two of the following signs or symptoms: cough, lower 
respiratory tract secretions, auscultatory findings of pneumonia, 
dyspnea/tachypnea, increased work of breathing (retractions, 
nasal flaring, or grunting), hypoxaemia/oxygen saturation 
< 92% (on room air) 
Patients with CAP must present with at least one of the following 
conditions: 
 
Admission to an intensive care unit, intermediate care unit, or a 
unit with the ability to provide constant and close monitoring 
and care 
 
Suspected infection with multi-drug resistant pneumococci or 
methicillin-resistant Staphylococcus aureus (MRSA) 
 
History of absent or incomplete pneumococcal vaccination (did 
not receive all vaccinations as per schedule) 
 
Recent clinical diagnosis of influenza with exacerbation of 
fever and respiratory symptoms after initial improvement in the 
symptoms of acute influenza 
 
Failure to clinically improve on initial antibiotic therapy for at 
least 48 hours and need for antibiotic treatment change 
 
Oxygen saturation on room air ≤ 90% 
4. New or progressive imaging findings consistent with bacterial 
pneumonia (e.g., X-ray, ultrasound, or computer tomography) 
5. Requirement for IV antibacterial treatment for pneumonia 
6. Sufficient vascular access to receive IV study drug 
7. Informed consent from the parent or legally acceptable 
representative (LAR) to participate in the study, and child’s assent 
as appropriate 
8. Female patients who are not pregnant or breast-feeding and meet 
one of the following conditions: 
 
Pre-menarcheal, or 
 
A negative serum or urine pregnancy test and willing to use a 
highly reliable method of contraception during the study until 
the LFU visit 
 
 


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EXCLUSION 
CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY-DRUG 
ADMINISTRATION 
Patients meeting any one of the following at Screening: 
1. Known resistance of the causative pathogen to ceftobiprole or IV 
standard-of-care cephalosporin treatment (± vancomycin) 
2. On mechanical ventilation at Screening for more than 48 hours 
3. Chest trauma with severe lung contusion or flail chest 
4. Acute respiratory distress syndrome 
5. Empyema or lung abscess 
6. Anatomical bronchial obstruction 
7. Documented  or  suspected  active  or  currently-treated  pulmonary 
tuberculosis 
8. Documented or suspected atypical bacterial pneumonia, or viral 
pneumonia without bacterial superinfection, or need for antibiotic 
coverage with a macrolide 
9. Known positive result from a rapid diagnostic test for influenza or 
respiratory syncytial virus, unless bacterial pneumonia secondary to 
viral respiratory illness is suspected based on a clinical history of 
exacerbation of fever and respiratory symptoms after initial 
improvement in the symptoms of an acute respiratory infection 
10. Documented  or  suspected   pertussis,   chemical   pneumonitis 
(e.g., aspiration of gastric contents, inhalation injury), or cystic 
fibrosis 
11. Severe immunodeficiency (HIV infection, or congenital or acquired 
immunodeficiency syndrome) 
12. Significant  laboratory  abnormalities  (based  on  local  laboratory 
results) including: 
 
Hematocrit < 20% 
 
Absolute neutrophil count < 0.5 × 109/L 
 
Platelet count < 50 × 109/L 
 
Alanine aminotransferase, aspartate aminotransferase, or total 
bilirubin > 5 × the age-specific upper limit of normal 
 
Creatinine clearance of < 50 mL/min/1.73 m2, or requirement 
for any form of renal dialysis therapy 
13. Use of systemic antimicrobial therapy for more than 24 hours in the 
48 hours before randomization for the current episode of 
pneumonia 
Exception: CAP patients with failure to clinically improve on initial 
antibiotic therapy for  at least 48 hours and  need for  antibiotic 
treatment change (see Inclusion criterion 3) 
14. History of a previous clinically-relevant hypersensitivity or serious 
adverse reaction to beta-lactam antibiotics or to vancomycin 
15. Poorly-controlled  seizure  disorder  (˃  1  seizure  in  the  month 
preceding randomization) 
The study treatments to be administered are: 
1. Ceftobiprole medocaril 10 to 20 mg/kg (age-adjusted) IV q8h. 
2. Comparator for CAP: ceftriaxone 50 to 80 mg/kg IV as a single daily 
dose, up to a maximum dose of 2 g/day. 
 
 


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CONCOMITANT 
MEDICATION 
3. Comparator for HAP: ceftazidime 50 mg/kg IV q8h, up to a 
maximum of 6 g/day. 
4. For patients receiving comparator antibiotics, administration of 
concomitant vancomycin (10 to 15 mg/kg IV every 6 hours, up to a 
maximum dose of 2 g/day) is to be added when MRSA is suspected 
or confirmed. 
Patients who require concomitant treatment with a macrolide during the 
course of the active study-drug treatment period (other than as part of a 
switch to oral antibiotic treatment as outlined below) should be 
withdrawn from the study and treated with an appropriate non-study 
standard-of-care antibiotic regimen. 
After a minimum of 3 days of study treatments (nine infusions of 
ceftobiprole or an equivalent number of doses of standard-of-care 
antibiotic comparator treatment), patients with sufficient improvement 
in disease signs and symptoms (according to predefined criteria) may 
be switched to an oral antibiotic to complete a minimum of 7 days 
antibiotic treatment,  at  the  discretion  of  the  Blinded  Investigator. 
A macrolide may be used for oral switch. The oral antibiotic will be 
recorded as concomitant medication. 
In addition, concomitant treatment for suspected infections by 
Pseudomonas aeruginosa may be added at the discretion of the Blinded 
Investigator. Anti-pseudomonal treatment for both the ceftobiprole and 
standard-of-care comparator group should comprise gentamicin, 
amikacin or tobramycin. 
 
 
BLINDING 
Investigator-blind (at least one Blinded Investigator at each centre acts 
as blinded observer). 
TREATMENT 
DURATION 
MAIN STUDY 
ENDPOINTS 
7–14 days. 
 
Primary endpoint 
Analysis of adverse events (AEs) assessed on each of the first 3 days of 
study-drug treatment, and at the end-of-treatment (EOT), TOC, and 
LFU visits (Safety population). Other timepoints may also be analysed. 
Secondary endpoints 
1. Efficacy: Comparison of clinical cure rates (ITT and CE 
populations) and microbiological eradication rates (mITT and ME 
populations) between ceftobiprole and the comparator at the TOC 
visit; and cure of pneumonia, defined as clinical improvement or 
lack of progression of X-ray abnormalities, as well as resolution of 
clinical pneumonia findings, at study Day 4 and the EOT visit (ITT 
and CE populations). The clinical and microbiological relapse rates 
at the LFU visit will also be compared (ITT, CE, mITT and ME 
populations). 
2. Pharmacokinetics: Descriptive analysis of ceftobiprole plasma 
concentration per time point, based on PK sampling in at least 
15 patients  in  each  of  the  two  age  categories  of  < 6 years  and 
≥ 6 years (PK population). 
 
 


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STATISTICAL 
ANALYSIS 
A total of 138 paediatric patients aged 3 months to < 18 years will be 
enrolled, with a minimum of 50 patients for each of the age categories 
< 6 years and ≥ 6 years. There is no requirement for a minimum number 
of patients with each infection type (HAP or CAP). 
Patients must be diagnosed with HAP or CAP requiring hospitalisation 
and therapy with IV antibiotics. Randomization will be stratified by four 
age groups (3 months to < 2 years; 2 years to < 6 years; 6 years to < 12 
years; 12 years to < 18 years), and by diagnosis of HAP or CAP. 
No formal hypothesis testing will be performed. Descriptive statistics will 
be applied to the primary analysis, with frequency tables used to 
characterise the safety and tolerability profile of ceftobiprole in the safety 
population. 
The secondary analysis of clinical cure rates (ITT and CE populations) 
and microbiological eradication rates (mITT and ME populations) will be 
compared between ceftobiprole and the standard-of-care comparator. 
Clinical cure and microbiological eradication rates at TOC will be 
tabulated for ceftobiprole and comparators and the between-group 
differences will be displayed along with the respective 95% confidence 
intervals (CIs). The between-group differences in the rates of patients 
whose clinical signs and symptoms improved or were cured at Day 4 and 
at EOT will also be displayed, along with the respective 95% CIs. Signs 
and symptoms of pneumonia and overall clinical status will be analysed 
by descriptive statistics. 
Clinical and microbiological relapse will be assessed at the LFU visit and 
will be compared between the treatment groups. Descriptive statistics will 
be applied. Plasma concentrations will be listed and analysed by 
summary descriptive statistics, including mean, median, standard 
deviation, coefficient of variation, and range. Analyses will also be 
presented by age group. 
Analysis populations 
Safety population: all randomized patients who received at least one dose 
of study drug, analysed according to the first treatment actually received. 
Intent-to-treat (ITT) population: all randomized patients, analysed by 
treatment assigned. 
Clinically evaluable (CE) population: patients who received at least 3 
days (nine infusions) of study drug, had a valid clinical outcome 
assessment at TOC, no major protocol violations, and no systemic non- 
study antibiotic therapies. 
Microbiological intent-to-treat (mITT) population: all patients in the 
ITT analysis population with a valid pathogen identified at baseline. 
Microbiologically evaluable (ME) population: all patients in the CE 
analysis population with a valid pathogen at baseline and a 
microbiological assessment at TOC. 
Pharmacokinetic (PK) population: all patients who received at least one 
dose of ceftobiprole and have at least one plasma-concentration 
measurement obtained using the appropriate methodology. 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................... 8 
LIST OF TABLES............................................................................................................... 11 
LIST OF APPENDICES ..................................................................................................... 11 
LIST OF ABBREVIATIONS ............................................................................................. 12 
1 
BACKGROUND AND RATIONALE ....................................................................... 14 
1.1 Disease characteristics and treatment ....................................................................... 14 
1.2 Investigational medicinal products .......................................................................... 14 
1.3 Nonclinical studies with ceftobiprole ...................................................................... 15 
1.3.1 Microbiology ........................................................................................................ 15 
1.3.2 Pharmacokinetics and product metabolism in animals ........................................ 15 
1.3.3 Toxicology................................................................................................................. 16 
1.4 Clinical studies ......................................................................................................... 18 
1.4.1 Pharmacokinetics, product metabolism, and tissue distribution in humans ......... 18 
1.4.2 Pharmacodynamics .................................................................................................... 19 
1.4.3 Susceptibility testing breakpoints......................................................................... 19 
1.4.4 Efficacy in hospital-acquired pneumonia ............................................................. 19 
1.4.5 Efficacy in community-acquired pneumonia ....................................................... 20 
1.4.6 Safety .................................................................................................................... 20 
1.5 Rationale for study design and dosing regimens ..................................................... 21 
1.5.1 Study design rationale .......................................................................................... 21 
1.5.2 Study drug and dose ............................................................................................. 21 
2 
OBJECTIVES OF THE STUDY ................................................................................ 22 
2.1 Primary objective ..................................................................................................... 22 
2.2 Secondary objectives ................................................................................................ 22 
3 
STUDY DESIGN ........................................................................................................ 22 
3.1 Overview of study design and dosing regimens ...................................................... 22 
3.2 Endpoints ................................................................................................................. 23 
3.2.1 Primary endpoint .................................................................................................. 23 
3.2.2 Secondary endpoints ............................................................................................ 23 
3.3 Treatment plan ......................................................................................................... 24 
3.4 Intravenous-to-oral switch ........................................................................................ 24 
3.5 Home continuation of oral antibiotic therapy .......................................................... 25 
3.6 Concomitant and previous medication and treatment .............................................. 25 
3.6.1 Concomitant anti-staphylococcal treatment in patients with HAP or CAP .......... 26 
3.6.2 Anti-pseudomonal treatment in patients with HAP or CAP ................................. 26 
3.6.3 Macrolide treatment in patients with HAP or CAP.............................................. 26 
3.7 End of study definition ............................................................................................. 26 
4 
STUDY POPULATION ............................................................................................. 27 


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4.1 Target population ..................................................................................................... 27 
4.2 Inclusion criteria ...................................................................................................... 27 
4.3 Exclusion criteria ..................................................................................................... 28 
4.4 Discontinuation of treatment .................................................................................... 29 
4.5 Discontinuation from the study ................................................................................ 29 
4.6 Replacement of patients ........................................................................................... 30 
5 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ........................................ 30 
5.1 Summary schedule of assessments........................................................................... 30 
5.2 Study visits ............................................................................................................... 33 
5.2.1 Screening (Days −1 to 1) ...................................................................................... 33 
5.2.2 Start of treatment (Day 1)..................................................................................... 33 
5.2.3 Days 2 to 7 (active treatment) .............................................................................. 34 
5.2.4 Days 8 to 14 (active treatment) ............................................................................ 35 
5.2.5 End-of-treatment (EOT) ....................................................................................... 36 
5.2.6 Test-of-cure (TOC) ............................................................................................... 36 
5.2.7 Last follow-up ...................................................................................................... 37 
5.3 Efficacy evaluations ................................................................................................. 38 
5.3.1 Pneumonia signs and symptoms and requirement for hospitalisation ................. 38 
5.3.2 Clinical outcome of therapy ................................................................................. 39 
5.3.3 Microbiological outcome of therapy .................................................................... 39 
5.4 Microbiology assessments ....................................................................................... 40 
5.5 Pharmacokinetics assessments ................................................................................. 41 
5.5.1 Collection and preparation of plasma samples ..................................................... 41 
5.5.2 Analysis of ceftobiprole concentrations ............................................................... 41 
5.5.3 Pharmacokinetic parameters ................................................................................ 41 
5.6 Safety assessments ................................................................................................... 42 
5.6.1 Adverse events ..................................................................................................... 42 
5.6.2 Safety laboratory tests .......................................................................................... 42 
5.6.3 Vital signs ............................................................................................................. 44 
5.6.4 Oxygen saturation by pulse oximetry................................................................... 44 
5.6.5 Physical examination............................................................................................ 44 
6 
STUDY DRUGS ......................................................................................................... 44 
6.1 Dose and schedule .................................................................................................... 44 
6.1.1 Ceftobiprole medocaril ......................................................................................... 45 
6.1.2 Comparators ......................................................................................................... 45 
6.2 Administration ......................................................................................................... 47 
6.2.1 Ceftobiprole medocaril ......................................................................................... 47 
6.2.2 Comparator antibiotics ......................................................................................... 48 
6.3 Blinding and randomization ..................................................................................... 48 
6.4 Unblinding methods ................................................................................................. 49 


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6.5 Drug accountability and compliance check ............................................................. 50 
6.6 Packaging and labelling ........................................................................................... 50 
7 
PATIENT SAFETY .................................................................................................... 51 
7.1 Definitions ................................................................................................................ 51 
7.1.1 Adverse occurrence .............................................................................................. 51 
7.1.2 Adverse event ....................................................................................................... 51 
7.1.3 Serious adverse event ........................................................................................... 51 
7.2 Evaluation of adverse events .................................................................................... 52 
7.2.1 Severity................................................................................................................. 52 
7.2.2 Relationship .......................................................................................................... 52 
7.3 Handling of safety information and collection periods .............................................. 53 
7.3.1 Handling of safety data during the pre-treatment period ...................................... 53 
7.3.2 Handling of safety data during the treatment period and up to the last 
scheduled follow-up ............................................................................................. 53 
7.3.3 Handling of post-study safety data ....................................................................... 55 
7.3.4 Reporting of SAEs to regulatory authorities ........................................................ 55 
7.4 Pregnancy ................................................................................................................. 55 
7.4.1 Contraception for women of childbearing potential ............................................ 55 
7.4.2 Reporting and handling of pregnancies ................................................................ 56 
7.5 Data and Safety Monitoring Board .......................................................................... 56 
8 
STATISTICAL CONSIDERATIONS ........................................................................ 57 
8.1 Sample size justification .......................................................................................... 57 
8.2 Analysis populations ................................................................................................ 57 
8.3 General statistical considerations ............................................................................. 58 
8.4 Presentation of clinical results ................................................................................. 58 
8.5 Analyses of endpoints .............................................................................................. 58 
8.6 Safety analyses ......................................................................................................... 59 
8.7 Pharmacokinetics ..................................................................................................... 59 
8.8 DSMB analysis ........................................................................................................ 59 
9 
STUDY ADMINISTRATION AND REGULATORY ASPECTS .............................. 60 
9.1 Study records ............................................................................................................ 60 
9.1.1 Investigator site file .............................................................................................. 60 
9.1.2 Case report forms ................................................................................................. 60 
9.1.3 Patient source documents ..................................................................................... 60 
9.1.4 Document retention and archiving ....................................................................... 60 
9.1.5 Sample retention ................................................................................................... 61 
9.2 Clinical monitoring .................................................................................................. 61 
9.3 Audits and inspections ............................................................................................. 61 
9.4 Protocol amendments ............................................................................................... 62 


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9.5 Premature termination of the study .......................................................................... 62 
9.6 Publication policy .................................................................................................... 62 
10 ETHICS AND GOOD CLINICAL PRACTICE ........................................................ 63 
10.1 Good Clinical Practice ............................................................................................. 63 
10.2 Informed consent and assent .................................................................................... 63 
10.3 Patient confidentiality and data protection ............................................................... 64 
10.4 Independent Ethics Committees / Institutional Review Boards ................................ 64 
11 REFERENCES ............................................................................................................ 65 
 
LIST OF TABLES 
Table 1 
Ceftobiprole MICs established by EUCAST ................................................ 19 
Table 2 
Summary of treatment and follow-up schedule ............................................ 22 
Table 3 
Study-drug administration ............................................................................. 23 
Table 4 
Schedule of assessments ............................................................................... 31 
Table 5 
Total Infusion volumes in HAP patients treated with ceftazidime and 
vancomycin and maintenance fluid volumes ................................................ 47 
Table 6 
Reconstitution and dilution of ceftobiprole .................................................. 48 
LIST OF APPENDICES 
Appendix 1 Rationale  for  ceftobiprole  dosage  selection  (paediatric  population 
aged 3 months to < 18 years) ........................................................................ 68 
Appendix 2 Criteria for evaluating relationship between adverse events and study 
treatment ....................................................................................................... 72 
Appendix 3 Investigator’s protocol signature page .......................................................... 74 


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LIST OF ABBREVIATIONS 
AE Adverse event 
ALT Alanine aminotransferase 
AST Aspartate aminotransferase 
AUC Area under the concentration curve 
BLQ Below limit of quantitation 
CAP Community-acquired pneumonia 
CFU Colony forming unit 
CI Confidence interval 
Cmax 
Maximum observed plasma concentration 
CRF Case Report Form 
EC Ethics Committee 
DSMB Data and Safety Monitoring Board 
EOT End-of-treatment 
ESRD End-stage renal disease 
GCP Good Clinical Practice 
HAP Hospital-acquired pneumonia 
IB Investigator’s Brochure 
ICH International Conference on Harmonisation 
ICU Intensive care unit 
ITT Intent-to-treat 
IV Intravenous 
IVRS/IWRS Interactive Voice/Web Response System 
LAR Legally acceptable representative 
LC Liquid chromatograph 
LFU Last follow-up 
MCHC Mean corpuscular haemoglobin concentration 
MCV Mean corpuscular volume 
MIC Minimum inhibitory concentration 
MRSA Methicillin-resistant Staphylococcus aureus 
MSSA Methicillin-susceptible Staphylococcus aureus 
MS Mass spectrometry 


Ceftobiprole 
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NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed--effect level 
PBP Penicillin-binding protein 
PIP Paediatric Investigation Plan 
PK Pharmacokinetic(s) 
QC Quality control 
RBC Red blood cell 
SAE Serious adverse event 
SAP Statistical Analysis Plan 
SmPC Summary of Product Characteristics 
T > MIC Time that concentration is above the minimum inhibitory 
concentration 
t1/2 Elimination half-life 
tmax 
Time at which Cmax is observed 
TOC Test-of-cure 
VAP Ventilator-associated pneumonia 
Vss Volume of distribution at steady state 
WBC White blood cell 


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1 BACKGROUND AND RATIONALE 
1.1 
Disease characteristics and treatment 
Pneumonia is a leading cause of morbidity and mortality in children in developed 
countries (Lynch 2010, Shann 1999). Most cases of paediatric pneumonia are caused by 
viruses, typical bacteria, or atypical bacteria, with viral aetiology more common in 
younger patients, atypical bacteria (such as mycoplasma and chlamydia) most common in 
patients aged 5–15 years, and Streptococcus pneumoniae the most frequently identified of 
the typical bacteria (Lynch 2010, Michelow 2004). 
The clinical signs and symptoms of viral and bacterial pneumonia are similar in children 
and cannot be reliably distinguished by use of any currently known combination of 
diagnostic tests (Lynch 2010). Viral diagnostic tests are reliable, commonly used, and 
may justify withholding antibacterial therapy (Bradley 2011), however, viral infection 
can predispose paediatric patients to bacterial co-infection (Woods 2013). In severe cases 
where a bacterial aetiology is suspected, therapy is generally empiric because pathogen 
identification often requires impractical invasive sampling (Blumer 1995). Accordingly, 
it is important to use antimicrobials that provide broad-spectrum antibacterial activity 
(Tam 2013, Parker 1995). 
In adults, ceftobiprole is approved in the European Union (EU) for the treatment of 
hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia (VAP), 
and for community-acquired pneumonia (CAP). In the paediatric population, the safety 
and efficacy of ceftobiprole have not yet been established. 
This study is part of the approved EU Paediatric Investigation Plan (PIP) P/0083/2014 
dated 4 April 2014 (see Appendix 1). 
1.2 
Investigational medicinal products 
The treatment regimens to be administered are: 
 Ceftobiprole   medocaril   sodium   (ceftobiprole)   10   to   20   mg/kg   administered 
intravenously (IV) q8h, age-adjusted for dose and infusion duration. 
 Comparator for CAP: ceftriaxone 50 to 80 mg/kg IV as a single daily dose, up to a 
maximum dose of 2 g/day. 
 Comparator for HAP: ceftazidime 50 mg/kg IV q8h, up to a maximum of 6 g/day. 
 In patients receiving comparator antibiotics, administration of concomitant 
vancomycin (10 to 15 mg/kg IV q6h, up to a maximum dose of 2 g/day) is to be 
added when methicillin-resistant Staphylococcus aureus (MRSA) is suspected or 
confirmed. 
After a minimum of 3 days of treatment with systemic antibiotics (nine infusions of 
ceftobiprole or an equivalent number of doses of standard-of-care antibiotic comparator 
treatment), patients with sufficient improvement in disease signs and symptoms 
(according to pre-defined criteria) may be switched to an oral antibiotic (age-appropriate 
for the paediatric  patient)  to  complete  a  minimum  of  7 days  antibiotic  treatment. 
A macrolide may be used for oral switch. The oral antibiotic will be recorded as a 
concomitant medication. 


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1.3 
Nonclinical studies with ceftobiprole 
1.3.1 
Microbiology 
Ceftobiprole has a strong affinity for several penicillin-binding proteins (PBPs), 
including PBP2a and PBP2x, which mediate resistance to other beta-lactams in 
staphylococci  and  pneumococci,  respectively  (Hebeisen 2001,  Lovering 2012, 
Davies 2007, Davies 2010, Henry 2013, Entenza 2002). In contrast to earlier generation 
cephalosporins, ceftobiprole effectively prevents the intracellular growth of both MSSA 
and MRSA strains in macrophages and keratinocytes, due in part to its ability to better 
bind PBP2a under both neutral and acidic pH conditions (Lemaire 2009). Ceftobiprole 
also binds to and saturates several other essential PBPs (Davies 2010, Henry 2013), 
distinguishing it from other available beta-lactams, and is stable to hydrolysis by the 
S. aureus PC1 Class A beta-lactamase, conserving its activity against staphylococci 
(Queenan 2007). 
Ceftobiprole is also relatively stable against AmpC cephalosporinases and common class 
A beta-lactamases produced by Gram-negative bacteria, but not to extended-spectrum 
beta-lactamases (ESBLs), carbapenemases, or OXA beta-lactamases (Queenan 2007). 
In vitro single- and multiple-passage selection studies performed with several Gram- 
positive pathogens, including MRSA, demonstrated a very low propensity for resistance 
after exposure to ceftobiprole (Queenan 2007, Bogdanovich 2006, Queenan 2005, 
Kosowska 2005, Bogdanovich 2005, Queenan 2010), which is due to ceftobiprole’s 
unique ability to bind to multiple target sites. 
No emergence of resistance was seen throughout the extensive clinical development 
program and no minimum inhibitory concentration (MIC) shifts were seen in surveillance 
studies. 
In vitro, ceftobiprole has shown a bactericidal mode of action against methicillin- 
susceptible S. aureus (MSSA), MRSA and many other resistant S. aureus strains, 
including 
glycopeptide-intermediate 
(GISA), 
vancomycin-intermediate 
(VISA), 
vancomycin-resistant (VRSA), daptomycin non-susceptible, and  linezolid non-
susceptible strains, using both broth microdilution and  time-kill  methods (Borbone 
2010, Leonard 2008, Rouse 2007, Deshpande 2013, Farrell 2014). 
Ceftobiprole also effectively reduced the colony-counts of MSSA and MRSA strains 
tested in an in vitro biofilm model, none of which were affected by daptomycin, 
vancomycin or rifampicin (Abbanat 2014). 
Further details on the microbiology of ceftobiprole are provided in the Investigator’s 
Brochure (IB). 
1.3.2 
Pharmacokinetics and product metabolism in animals 
In animals after single-IV-dose PK studies, ceftobiprole medocaril was rapidly 
metabolised via non-specific esterases to ceftobiprole. The volume of distribution of 
ceftobiprole was restricted to the extracellular compartment, and its elimination occurred 
predominantly by passive glomerular filtration of unchanged ceftobiprole. The in vitro 


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and in vivo metabolic patterns of ceftobiprole in rats, dogs, mice, marmosets, and humans 
were similar, with the ring-open product BAL1029 as the main metabolite. After multiple 
doses to rats, rabbits, marmosets, cynomolgus monkeys, and dogs, high and dose- 
proportional exposures to ceftobiprole in all species were achieved, exceeding the 
expected human therapeutic exposure at the no-observed-adverse-effect level (NOAEL). 
There were no relevant indications of accumulation, differences related to sex, or time- 
dependent PK. 
Whole-body autoradiography in animals demonstrated rapid and large distribution of 
ceftobiprole in all organs without specific accumulation in any organs, with the exception 
of the kidney as excretory organ. Results from a reproductive toxicology study in rats 
indicated that nursing pups were not systemically exposed to ceftobiprole. Protein 
binding of ceftobiprole in plasma in all 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 IV administration of the prodrug. 
Based on in vitro cytochrome P450 inhibition and induction data, the lack of a specific 
enzyme involved in cleavage of the prodrug, and ceftobiprole distribution being restricted 
to the extracellular compartment, the potential of ceftobiprole to exhibit clinically 
relevant enzyme-related drug-drug interactions is small. 
In in vitro studies to determine whether ceftobiprole is a substrate or inhibitor of the 
efflux- or uptake-transporters, ceftobiprole inhibited OATP1B1 and OATP1B3 with 
median inhibitory concentrations of 67.6 µM and 44.1 µM, respectively, and ceftobiprole 
was found to be possibly a weak substrate of the renal uptake transporters OAT1 and 
OCT2. The clinical relevance of these findings is unclear. 
Further details on the nonclinical pharmacology, PK, and PD of ceftobiprole are provided 
in the IB. 
1.3.3 
Toxicology 
The primary targets of toxicity after IV administration in animals 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 resultant renal-tissue damage. This effect is not thought to apply to 
humans, because glomerular filtration of ceftobiprole in humans is much slower, and 
urinary concentrations of ceftobiprole do not approach the limit of solubility. 
 Local tolerance: In 4- and 13-week studies in rats and marmosets, concentration- 
dependent slight-to-moderate local endothelial irritation was observed when 
ceftobiprole medocaril was administered into the vena cava over 4–8 hours at 
concentrations of up to 62 mg/mL. 
In a local tolerability study in rabbits, repeated IV administration of ceftobiprole into 
the auricular vein (8 consecutive days with a 3-minute endothelial contact period per 
day) caused no irritation at ceftobiprole concentrations of 2 and 10 mg/mL (nominal 
ceftobiprole medocaril concentrations of 2.66 and 13.3 mg/mL). 


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Hemolysis, plasma turbidity and precipitation were observed in human, dog, rat and 
marmoset blood at concentrations ≥12.5 mg/mL. 
Ceftobiprole 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 
sensitisation, irritation, or phototoxicity were seen. The antigenic potential of ceftobiprole 
is low. No mutagenic potential was seen in the Ames test or in the Chinese hamster 
ovarian assay. Positive effects in the mouse lymphoma/thymidine kinase and human 
chromosomal aberration tests in vitro were related to the cleavage  product  diacetyl, 
which is rapidly metabolised in vivo; the in vivo mouse micronucleus test and rat 
unscheduled DNA synthesis assays were negative. No genotoxic potential of impurities 
was identified. The convulsive potential after intracerebroventricular administration to 
mice was comparable to that of imipenem. No cardiac or pulmonary toxicities were 
observed. 
Neonatal and juvenile rats (1 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 was 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 NOAEL in juvenile 
animals was 100 mg/kg/day (corresponding to 75 mg/kg/day of ceftobiprole). At the 
NOAEL, a safety margin of 2 to 6 could be demonstrated for the recommended dosing 
regimens in the various age groups from neonates to < 18 years. 
Safety margins based on plasma exposures noted at the NOAEL in animals are 
approximately 1- to 5-fold and 1- to 3-fold for maximum observed plasma concentration 
(Cmax), and 2- to 3-fold and 1- to 2-fold for area under the concentration curve (AUC), 
respectively, for administration of 500 and 1000 mg ceftobiprole, infused to humans over 
2 hours as ceftobiprole medocaril. The safety margins based on ceftobiprole plasma 
concentrations seen at the no-observed-effect level (NOEL) for renal toxicity are 2- to 
7-fold and 1- to 5-fold relative to clinical doses of 500 and 1,000 mg. 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 apply to both single-dose and multiple-dose administrations, as 
ceftobiprole accumulation is negligible with multiple dosing in humans. 
Further details on the nonclinical toxicology of ceftobiprole are provided in the IB. 


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1.4 
Clinical studies 
1.4.1 
Pharmacokinetics, product metabolism, and tissue distribution in humans 
A retrospective population PK analysis of patients in the adult Phase 3 HAP study 
assessed the proportion of the dosing interval during which plasma ceftobiprole levels 
remained above the target MIC (fT>MIC), considering the highest MIC of either 
Gram-positive or Gram-negative microorganisms. This analysis demonstrated that the 
fT>MICs of 51.1% and 62.2% were associated with clinical cure and microbiological 
eradication, respectively (Muller 2014). 
The PK of ceftobiprole in adult patients are predictable, linear, and time-independent 
across the dose range of 125 to 1000 mg, and variability is low (< 30%). Steady-state 
drug concentrations are attained on the first day of dosing (q8h), and no appreciable 
accumulation is observed in patients with normal renal function. 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 
(CLCR). Therefore dosing-regimen adjustments are recommended in adult patients with 
moderate and severe renal impairment, in end-stage renal disease (ESRD) patients and in 
patients with creatinine clearance CLCR > 150 mL/min. At comparable CLCR, the PK of 
ceftobiprole in patients in an intensive care unit (ICU) setting and in patients from the 
HAP and CAP studies are similar to healthy subjects. Given no underlying renal 
impairment, the primary PK/PD driver of ceftobiprole (T>MIC) is unaffected by gender, 
obesity, age, or race, and no dose adjustment is required in these sub-populations. 
The distribution of ceftobiprole in lung epithelial lining fluid, bone, muscle and adipose 
tissue is similar to that of other cephalosporins. 
Following administration of 500 mg ceftobiprole q8h for 7 days, ceftobiprole could not 
be detected in the faeces of healthy subjects, there were no significant changes in the 
aerobic or anaerobic intestinal microflora, and no new colonising aerobic or anaerobic 
bacteria resistant to ceftobiprole were observed. 
In paediatric patients given single doses of ceftobiprole at 15 mg/kg (ages 3 months to 
< 6 years) or 10 mg/kg (ages 6 years to < 12 years), the single-dose PK of ceftobiprole 
were generally within the range of those previously observed in healthy adult subjects 
after a single ceftobiprole 500 mg administration. However, in patients given 7 mg/kg 
(ages 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 to be age-independent from neonates to 
adults. 


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1.4.2 
Pharmacodynamics 
In animal models of efficacy (bacteriostasis), ceftobiprole fT>MICs of > 30% and > 50% 
are required for susceptible Gram-positive and Gram-negative pathogens, respectively, at 
a target MIC of 4 μg/mL. For 1 log-kill in colony forming units (CFU) (bactericidal 
effect) in animal pneumonia and thigh models, the target fT>MIC of 4 g/mL remains 
> 30% for susceptible Gram-positive pathogens, and > 60% for susceptible Gram- 
negative pathogens. 
In adults, the recommended clinical dosing regimen for ceftobiprole is 500 mg q8h, 
administered as a 120-minute IV infusion. A retrospective population PK analysis of 
patients in the Phase 3 HAP study demonstrated that for a 60% fT>MIC of 4 g/mL, the 
probability of target attainment under this regimen is 100% for Gram-positive pathogens 
and > 96% for Gram-negative pathogens. 
1.4.3 
Susceptibility testing breakpoints 
Minimum inhibitory concentration breakpoints for ceftobiprole established by the 
European Committee on Antimicrobial Susceptibility Testing (EUCAST), are shown in 
Table 1. 
Table 1     Ceftobiprole MICs established by EUCAST 
 
Organisms 
MIC breakpoints (mg/L) 
Susceptible (≤ S) 
Resistant (R >) 
Staphylococcus aureus (including MRSA) 
2 
2 
Streptococcus pneumoniae 
0.5 
0.5 
Enterobacteriaceae 
0.25 
0.25 
Pseudomonas aeruginosa 
IE a 
IE a 
Non-species specific breakpoint b 
4 
4 
 
 
a Insufficient evidence. 
b Based on the fT>MIC target of 50% and >90% target attainment rate. 
 
1.4.4 
Efficacy in hospital-acquired pneumonia 
In a Phase 3 HAP study (BAP248/307, Awad 2014), the non-inferiority of ceftobiprole to 
ceftazidime plus linezolid was demonstrated within the pre-specified 15% margin for the 
primary efficacy endpoint of clinical cure rate at the test-of-cure (TOC) visit for all 
subjects in the clinically-evaluable (CE) and intent-to-treat (ITT) analysis sets. The ITT 
analysis set included 391 patients in the ceftobiprole group and 390 patients in the 
comparator group. 
The clinical cure rates at the TOC visit were 69.3% and 71.3% (CE), and 49.9% and 
52.8% (ITT) in the ceftobiprole and linezolid plus ceftazidime groups, respectively. 
Non-inferiority of ceftobiprole to linezolid plus ceftazidime was also demonstrated in the 
pre-specified subgroup of subjects with HAP (excluding VAP) (N=571). Non-inferiority 
of ceftobiprole was not demonstrated in the smaller subset of VAP subjects (N=210). 


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1.4.5 
Efficacy in community-acquired pneumonia 
The results of the Phase 3 CAP-3001 study (Nicholson 2012) demonstrated the non-
inferiority of ceftobiprole 500 mg administered q8h as a 2-hour infusion to treatment 
with ceftriaxone with or without linezolid for subjects hospitalized with CAP within the 
pre-specified margin of 10% for the primary efficacy endpoint of clinical cure rate at the 
TOC visit. ITT analysis set comprised  314  patients  in  the  ceftobiprole  group  and 
324 patients in the comparator group. 
The clinical cure rates at the TOC visit in the ceftobiprole and ceftriaxone with or without 
linezolid groups, respectively, were 86.6% and 87.4% in the clinically evaluable (CE) 
analysis set, and 76.4% and 79.3% in the ITT analysis set. The respective clinical cure 
rates in patients in PORT Risk Classes ≥ III (PSI score ≥ 71) were 86.5% and 86.3% 
(ITT), and 79.1% and 78.5% (CE). 
1.4.6 
Safety 
The  current  safety  experience  from  clinical  studies  of   ceftobiprole   comprises 
3037 subjects (1404 from Phase 3 pneumonia studies, 1633 from Phase 2 and Phase 3 
cSSTI studies, and 511 subjects from Phase 1 studies). The observed safety profile is 
consistent with that of the cephalosporin class as a whole. 
The most common adverse reactions, occurring in ≥ 3% of patients treated with 
ceftobiprole were nausea, vomiting, diarrhoea, infusion-site reactions, hypersensitivity 
(including urticaria, pruritic rash, and drug hypersensitivity), and dysgeusia. 
Less frequently reported, but more serious adverse reactions included thrombocytopenia, 
agranulocytosis, anaphylaxis, Clostridium difficile colitis, convulsion, agitation 
(including anxiety, panic attacks, and nightmares), and renal failure. 
In a previous clinical study in 64 paediatric patients age 3 months to 17 years (study 
CSI-1006), ceftobiprole was administered IV 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 patients). 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 patients discontinued due to a treatment-emergent AE. 
In terms of local tolerability, 1 moderate catheter-site-related reaction was observed in a 
child in the age group 2 to < 6 years (ceftobiprole 15 mg/kg) and 1 mild phlebitis in a 
child in the age group 3 months to < 2 years (ceftobiprole 15 mg/kg). Overall, the 
available preclinical and clinical data suggest that the expected risk of local irritation in 
the paediatric population with ceftobiprole is acceptable, but should be carefully 
monitored. 
Detailed warnings and precautions related to ceftobiprole are provided in the IB. 
The safety profiles of the standard-of-care comparators in children are well characterised 
due to their use over many years, and are described in the respective SmPCs. 


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1.5 
Rationale for study design and dosing regimens 
1.5.1 
Study design rationale 
The study design is adequate to identify the most common AEs associated with 
ceftobiprole in the two age groups of patients < 6 years and ≥ 6 years, and adequate to 
describe the efficacy of ceftobiprole in paediatric patients with HAP or CAP. Blood 
sampling is minimal, but adequate to monitor safety and provide PK information through 
PK sampling. Safety measures include the selection of clinics experienced in paediatric 
care. 
Treatment of 92 patients (the Safety population) with ceftobiprole will yield a > 95% 
probability of observing at least one AE type if the actual probability of this event is 
> 3.2%. 
In addition, the investigator-blinded nature of the study will allow for an unbiased 
assessment of the safety profiles of the study treatments. 
The dosing regimen of ceftobiprole (10 to 20 mg/kg, up to a maximum of 500 mg, given 
q8h as 2-hour or 4-hour infusions) provides adequate exposure for eradication of 
pathogens likely to be present in the enrolled patients. The selected comparator 
antibiotics and regimens are standard-of-care cephalosporin treatments, with the addition 
of vancomycin if MRSA is suspected or confirmed. 
 
1.5.2 
Study drug and dose 
1.5.2.1 Ceftobiprole medocaril 
Patients will receive 10 to 20 mg/kg ceftobiprole, up to a maximum of 500 mg, 
administered as 2-hour or 4-hour continuous-rate infusions of ceftobiprole medocaril q8h, 
for a minimum of 3 days. Treatment may be prolonged up to a maximum of 14 days. 
The age-adjusted ceftobiprole medocaril doses and infusion times are provided in 
Section 6.1.1. 
A detailed dosing rationale is provided in Appendix 1. In summary, the planned dose of 
ceftobiprole is based on the results of study CSI-1006, in which paediatric patients aged 
3 months to < 18 years received 7 to 15 mg/kg as a 2-hour infusion. In addition, the 
dosing regimen (dose, dosing interval and infusion duration) was designed for paediatric 
patients aged 3 months to < 18 years to ensure that the fT>MIC at 4 µg/mL is > 50%, and 
to maintain the exposure within the adult well-tolerated range and below the NOAEL in 
the juvenile rat study TOX8611 for the corresponding age groups. 
1.5.2.2 Comparators 
The dosing regimens for the the standard-of-care comparators are provided in 
Section 6.1.2. 


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2 
OBJECTIVES OF THE STUDY 
2.1 
Primary objective 
The primary objective of this study is to characterise the safety profile of ceftobiprole in 
paediatric patients with HAP or CAP requiring hospitalisation and IV antibiotic therapy. 
2.2 
Secondary objectives 
The secondary objectives of this study are in paediatric patients with HAP or CAP 
requiring hospitalisation: 
 To compare the clinical cure rate and microbiological eradication rate at the TOC visit 
between    ceftobiprole    and     IV     standard-of-care     cephalosporin     treatment 
(± vancomycin) 
 To compare the clinical and microbiological relapse rates at the last follow-up (LFU) 
visit  between  ceftobiprole   and   IV   standard-of-care   cephalosporin   treatment 
(± vancomycin) 
 To characterise other efficacy measures of ceftobiprole (e.g., improvement in signs 
and symptoms of pneumonia, length of hospital stay) 
 To assess the PK of ceftobiprole 
 
3 STUDY DESIGN 
3.1 
Overview of study design and dosing regimens 
This is a randomized, investigator-blind, multiple-fixed dose, active-controlled 
multicentre study to be carried out in 138 paediatric patients (minimum of 125 evaluable 
patients) aged 3 months to < 18 years diagnosed with either HAP or CAP requiring 
hospitalisation and treatment with systemic antibiotics. 
Randomization will be stratified by four age groups ( 3 months to < 2 years; 2 years to 
< 6 years; 6 years to < 12 years; 12 years to < 18 years), and by diagnosis of HAP or 
CAP. Patients will be randomized 2:1 within each group to receive either ceftobiprole or 
the comparator standard-of-care IV cephalosporin antibiotic (ceftazidime with or without 
vancomycin for patients with HAP; ceftriaxone with or without vancomycin for patients 
with CAP). At least 50 patients are planned to be enrolled in each of the age categories < 
6 years and ≥ 6 years (see Sections 6.3 and 8.1). There is no requirement for a minimum 
number of patients with each infection type (HAP or CAP). 
Table 2     Summary of treatment and follow-up schedule 
 
 
Study phase 
 
1 
2 
3 
4 
Pre-treatment 
Active treatment 
Post-treatment 
Follow-up 
 
Screening and 
randomization 
 
Day −1 
Baseline 
Study drug 
followed by 
optional oral 
treatment 
From Day 1 
At least 7 days, 
up to 14 days. 
 
End of treatment 
(EOT) 
 
Within 24 hours 
after last treatment 
 
Test-of-cure 
(TOC) 
 
7–14 days after last 
treatment 
 
Last follow-up 
(LFU) 
 
28–35 days after 
last treatment 
 


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The study comprises the following phases (Table 2): 
 A pre-dosing screening phase of up to 24 hours 
 A treatment phase of 7 days, with possible prolongation up to 14 days, with IV 
administration of ceftobiprole or appropriate comparator treatment, with the option 
for oral switch after a minimum of 3 days (nine infusions) of IV treatment 
 A post-treatment TOC assessment 7 to 14 days after the last treatment 
 An LFU assessment 28 to 35 days after the last treatment to monitor relapse of 
pneumonia, and safety 
The total duration of the study for each patient is approximately 5–7 weeks. 
Study assessments are summarised in the Schedule of assessments (Table 4) and outlined 
in more detail in Section 5. After randomization and during active treatment, patients will 
receive ceftobiprole or standard-of-care comparator (± vancomycin) according to the 
schedule outlined in Table 3. 
Table 3 
Study-drug administration 
 
Study drug 
Dose 
Concentration 
Frequency 
Infusion 
Maximum 
(mg/kg) 
(mg/mL) 
duration (h) 
daily dose 
(mg) 
Ceftobiprole 
10–20 
2–4 
q8h 
2–4 
1500 
Ceftriaxone 
50–80 
20 
q24h 
0.5 
2000 
Ceftazidime 
50 
20 
q8h 
0.5 
6000 
Vancomycin 
10–15 
4 
q6h 
1 
2000 
 
3.2 
Endpoints 
3.2.1 
Primary endpoint 
Analysis of adverse events (AEs) assessed on each of the first 3 days of study-drug 
treatment, and at the end-of-treatment (EOT), TOC, and LFU visits (Safety population). 
Other timepoints may also be analysed. 
3.2.2 
Secondary endpoints 
1. Efficacy: Comparison of clinical cure rates (ITT and CE populations) and 
microbiological eradication rates (mITT and ME populations) between ceftobiprole 
and the comparator at the TOC and LFU visits; and cure of pneumonia, defined as 
clinical improvement or lack of progression of X-ray abnormalities, as well as 
resolution of clinical pneumonia findings at study Day 4 and the EOT visit (ITT and 
CE populations). The clinical and microbiological relapse rates at the LFU visit will 
also be compared (ITT, CE, mITT and ME populations). 
2. Pharmacokinetics: Descriptive analysis of ceftobiprole plasma concentration per time 
point, based on PK sampling in at least 15 patients in each of the two age categories 
of < 6 years and ≥ 6 years (PK population). 


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3.3 
Treatment plan 
Once a patient is randomized, IV study medication should be administered as soon as 
possible, with preferably no more than 6 hours between randomization and first study-
drug administration. Pharmacy and centre staff will be unblinded to treatment. Each 
centre will implement a Study Blinding Plan to ensure that blinded investigators 
remain blinded to the assigned treatment (see Section 6.3). 
Details of the study treatments to be administered, including dosages, are provided in 
Section 1.2. 
Patients will receive IV antibiotics for at least 3 days (9 infusions); at the discretion of the 
Blinded Investigator, patients may switch to oral antibiotics after 3 days (9 infusions) if 
they meet standardized criteria of clinical improvement (see Section 3.4). 
Treatment (IV or oral) will continue for a minimum of 4 additional days (total of 7 days 
treatment). If required, a prolongation of treatment, up to a total of 14 days of treatment, 
is possible. 
Patients who require concomitant treatment with a macrolide during the course of the 
active IV study drug treatment period (other than as part of a switch to oral antibiotic 
treatment, see Section 3.4) should be withdrawn from the study and treated with an 
appropriate non-study standard-of-care antibiotic regimen. 
3.4 
Intravenous-to-oral switch 
After a minimum of 3 days of study treatment (nine infusions of ceftobiprole or an 
equivalent number of doses of standard-of-care antibiotic comparator treatment), patients 
with sufficient improvement in disease signs and symptoms may be switched to an oral 
antibiotic to complete a minimum of 7 days antibiotic treatment, at the discretion of the 
Blinded Investigator. 
No oral formulations of the study antibiotics are available. The choice of oral antibiotic 
will be at the discretion of the Blinded Investigator, taking into consideration local 
standards of care and antibiotic susceptibility patterns. 
Recommended options for an oral switch are penicillins (amoxicillin ± clavulanate), 
cephalosporins (cefuroxime axetil, cefaclor, cephalexine), macrolides (erythromycin, 
azithromycin, clarithromycin, roxithromycin), clindamycin, and linezolid. 
The oral antibiotic is to be recorded as a concomitant medication. 
All of the following criteria must be met for at least 24 hours at the time of the IV to oral 
antibiotic switch: 
1. The patient has a normally functioning gastrointestinal tract and the ability to 
swallow an age-appropriate formulation of the intended oral antibiotic. 
2. The patient demonstrates clinical improvement such that, in the opinion of the 
Blinded Investigator, a step-down to oral antibiotic therapy is medically appropriate. 


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3. Either: 
(a) The causative pathogen for pneumonia has been identified and confirmed as 
susceptible to the intended oral antibiotic regimen. 
or 
(b) In the opinion of the Blinded Investigator, and based on local antibiotic 
susceptibility data, likely causative pathogens for the relevant type of pneumonia 
(HAP or CAP) are expected to be susceptible to the intended oral antibiotic 
regimen. 
4. The patient has stable (or baseline) mental status. 
5. The patient displays appropriate appetite and activity level. 
6. Oxygen saturation > 92% on room air by pulse oximetry on at least four separate 
occasions within 24 hours, with no measurements indicating oxygen saturation ≤ 92%. 
7. Body temperature < 37.8 °C on at least four separate occasions within 24 hours, with 
no measurement indicating temperature > 37.8 °C. 
3.5 
Home continuation of oral antibiotic therapy 
Patients switched to oral antibiotic therapy may remain inpatients, or be discharged home 
to be followed up as outpatients, at the discretion of the Blinded Investigator. 
All of the following criteria must be met for home continuation of antibiotic treatment: 
1. The  patient  demonstrates  clinical  improvement  such  that,  in  the  opinion  of  the 
Blinded Investigator, home discharge is medically appropriate. 
2. The Blinded Investigator considers the patient’s parent(s) or legally acceptable 
representative (LAR) capable of administering, or supervising the administration of, 
(as appropriate to the patient’s age) oral antibiotics in accordance with the dosing 
instructions. 
3. The patient is able to comply with taking the medication. 
4. The Blinded Investigator considers the patient’s home environment to be safe, with 
continuous, adequate, and appropriate care by a competent adult available at all times. 
5. Instructions  for  promptly  returning  to  the  study  centre  in  the  event  of  clinical 
deterioration are provided to the patient’s parent(s) or LAR. 
3.6 
Concomitant and previous medication and treatment 
All medication given to the patient during the course of the study is to be recorded in the 
case report form (CRF); information to be recorded includes 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 must also be 
recorded in the CRF. 
Medication given within 14 days before Screening up to the start of study drug dosing is 
defined as prior medication; if given after the start of study drug dosing, up to the LFU 
visit safety assessment 28 to 35 days after the EOT visit, it is defined as concomitant 
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As described in the following sections, patients may receive treatment for suspected or 
proven infection with Pseudomonas aeruginosa (see Section 3.6.2), in addition to 
ceftobiprole or standard-of-care comparator antibiotics (plus vancomycin), if clinically 
required. Patients may also receive non-antimicrobial medication and treatment. Patients 
who require concomitant treatment with a macrolide during the course of the active study 
drug treatment period (other than as part of a switch to oral antibiotic treatment) should 
be withdrawn from study treatment (see Section 4.4). Oral macrolides are permitted for 
patients switching from IV study drug to oral standard-of-care antibiotics, according 
to predefined criteria after at least 9  infusions  of  IV  study  drug  administration 
(see Section 3.4). 
3.6.1 
Concomitant anti-staphylococcal treatment in patients with HAP or CAP 
In patients receiving comparator antibiotics, vancomycin is added when MRSA is 
suspected or confirmed (see Sections 6.1.2.1 and 6.1.2.2). Patients treated with 
ceftobiprole are not to receive concomitant vancomycin or other anti-staphylococcal 
treatment as part of the study medication (see Section 6.1.1). 
Patients treated with ceftobiprole who require additional anti-staphylococcal treatment 
(e.g., due to clinical failure), or patients in the standard-of-care comparator group who 
require anti-staphylococcal treatment other than vancomycin, should be discontinued 
from the study and treated as clinically indicated. 
3.6.2 
Anti-pseudomonal treatment in patients with HAP or CAP 
Anti-pseudomonal treatment may be added to ceftobiprole treatment and/or standard-of- 
care comparator treatment if clinically indicated (see Section 3.3). 
Anti-pseudomonal treatment for both the ceftobiprole and standard-of-care comparator 
group should comprise: 
 amikacin: 15–22.5 mg/kg per day in 1–3 divided doses 
 gentamicin: 4.5–7.5 mg/kg per day in 1 dose (preferred) to 2 divided doses 
 tobramycin: 6–7.5 mg/kg per day in 3–4 equally divided doses 
3.6.3 
Macrolide treatment in patients with HAP or CAP 
Patients with documented or suspected atypical bacterial pneumonia are to be excluded 
from the study (see Section 4.3). 
Patients who require concomitant treatment with a macrolide during the course of the 
active IV study drug treatment period (other than as part of a switch to oral antibiotic 
treatment as outlined below) should be withdrawn from the study and treated with an 
appropriate non-study standard-of-care antibiotic regimen. All such cases should be 
classified as clinical failure (see Section 5.3.2). 
The use of an oral macrolide for IV to oral switch according to predefined criteria after at 
least 72 hours of IV study drug administration (see Section 3.4) is permitted. 
3.7 
End of study definition 
The end of the study is defined as the completion of the last study-related contact with 
any patient (last patient last visit). 


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4 STUDY POPULATION 
4.1 
Target population 
The target population comprises male or female paediatric patients aged 3 months to 
< 18 years with HAP or CAP requiring hospitalisation and treatment with IV antibiotics. 
4.2 
Inclusion criteria 
Patients meeting all of the following at Screening: 
1. Male or female aged 3 months to < 18 years 
2. Body weight of at least 5 kg 
3. Diagnosis of either HAP (pneumonia occurring after ≥ 48 hours of hospitalisation) or 
CAP requiring hospitalisation and administration of IV antibiotic therapy, 
characterised by: 
 Fever (> 38.5°C) or hypothermia (< 35°C), and 
 Leucocytosis or leucopenia (relevant to patient age and institutional normal 
ranges), and 
 At least two of the following signs or symptoms: cough, lower respiratory tract 
secretions, auscultatory findings of pneumonia, dyspnea/tachypnea, increased 
work of breathing (retractions, nasal flaring, or grunting), hypoxaemia/oxygen 
saturation < 92% (on room air) 
Patients with CAP must present with at least one of the following conditions: 
 Admission to an intensive care unit (ICU), intermediate care unit, or a unit with 
the ability to provide constant and close monitoring and care 
 Suspected infection with multi-drug resistant pneumococci or MRSA 
 History of absent or incomplete pneumococcal vaccination (did not receive all 
vaccinations as per schedule) 
 Recent clinical diagnosis of influenza with exacerbation of fever and respiratory 
symptoms after initial improvement in the symptoms of acute influenza 
 Failure to clinically improve on initial antibiotic therapy for at least 48 hours and 
need for antibiotic treatment change 
 Oxygen saturation on room air ≤ 90% 
4. New or progressive imaging findings consistent with bacterial pneumonia (e.g., X-ray, 
ultrasound, or computer tomography) 
5. Requirement for intravenous antibacterial treatment for pneumonia 
6. Sufficient vascular access to receive IV study drug 
7. Informed consent from the parent or legally acceptable representative to participate in 
the study, and child’s assent as appropriate 
8. Female patients who are not pregnant or breast-feeding and meet one of the following 
conditions: 
 Pre-menarcheal, or 
 A negative serum or urine pregnancy test and willing to use a highly reliable 
method of contraception during the study until the LFU visit 


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4.3 
Exclusion criteria 
Patients meeting any one of the following at Screening: 
1. Known resistance of the causative pathogen to ceftobiprole or IV standard-of-care 
cephalosporin treatment (± vancomycin) 
2. On mechanical ventilation at the time of Screening for more than 48 hours 
3. Chest trauma with severe lung contusion or flail chest 
4. Acute respiratory distress syndrome 
5. Empyema or lung abscess 
6. Anatomical bronchial obstruction 
7. Documented or suspected active or currently-treated pulmonary tuberculosis 
8. Documented or suspected atypical bacterial pneumonia, or viral pneumonia without 
bacterial superinfection, or need for antibiotic coverage with a macrolide 
9. Known positive result from a rapid diagnostic test for influenza or respiratory syncytial 
virus, unless bacterial pneumonia secondary to viral respiratory illness is suspected 
based on a clinical history of exacerbation of fever and respiratory symptoms after 
initial improvement in the symptoms of an acute respiratory infection 
10. Documented or suspected pertussis, chemical pneumonitis (e.g., aspiration of gastric 
contents, inhalation injury), or cystic fibrosis 
11. Severe immunodeficiency (HIV infection, or congenital or acquired immunodeficiency 
syndrome) 
12. Significant laboratory abnormalities (based on local laboratory results) including: 
 Hematocrit < 20% 
 Absolute neutrophil count < 0.5 × 109/L 
 Platelet count < 50 × 109/L 
 Alanine aminotransferase, aspartate aminotransferase, or total bilirubin > 5 × the 
age-specific upper limit of normal 
 Creatinine clearance of < 50 mL/min/1.73 m2, or requirement for any form of 
renal dialysis therapy 
13. Use of systemic antimicrobial therapy for more than 24 hours in the 48 hours before 
randomization for the current episode of pneumonia. 
Exception: CAP patients with failure to clinically improve on initial antibiotic therapy 
for at least 48 hours and need for antibiotic treatment change (see Inclusion criterion 3) 
14. History of a previous clinically-relevant hypersensitivity or serious adverse reaction to 
beta-lactam antibiotics or to vancomycin 
15. Poorly-controlled seizure disorder (˃ 1 seizure in the month preceding randomization) 


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4.4 
Discontinuation of treatment 
Patients who require concomitant treatment with a macrolide during the course of the 
active IV study drug treatment period (other than as part of a switch to oral antibiotic 
treatment as outlined below) should be withdrawn from the study and treated with an 
appropriate non-study standard-of-care antibiotic regimen. If possible, these patients 
should complete EOT, TOC, and LFU assessments. 
A patient must be discontinued from study treatment if any of the following events occur: 
 no adequate response to the antibiotic treatment within 3 days of treatment 
 need for the use of macrolides concomitant to study drug treatment 
 pregnancy 
All  reasons  for  discontinuation  of  treatment  must  be  recorded  by  the  Blinded 
Investigator. In addition to those above, such reasons may include: 
 adverse event 
 abnormal laboratory value 
 abnormal test procedure result 
 intercurrent illness that prevents or interfere with further administration of treatment 
 death 
 protocol deviation 
 lost to follow-up 
 administrative/logistical reasons 
For all patients who discontinue study treatment, AE monitoring must be continued up to 
and including an LFU visit 28 to 35 days after EOT. 
Patients who discontinue from study treatment should be encouraged to remain on study 
to complete the post-treatment EOT, TOC, and LFU visits. 
For patients who fail to return for EOT, TOC, or LFU visits, the Blinded Investigator 
must make every effort to contact the patient (by telephone or mail correspondence). The 
outcome of this contact must be documented by the Blinded Investigator in the patient’s 
source documents. The reasons for failing to return for the visits must be recorded in the 
case report form (CRF). 
4.5 
Discontinuation from the study 
Patients may withdraw from the study at any time and for any reason. Parents or LARs 
may also withdraw consent for the patient’s participation at any time and for any reason. 
The Blinded Investigator may also withdraw patients (e.g., in case of treatment failure, 
adverse reactions, poor compliance, or for administrative reasons). 
If patients are withdrawn, the date of withdrawal, the number of infusions completed up 
to that date, and the reason for withdrawal must be recorded in the CRF. If an infusion is 
stopped, the exact time of the termination must be recorded in the CRF. 
Blinded  Investigators  are  encouraged  to  recommend  that  patients  discontinued  from 
treatment complete the EOT, TOC, and LFU assessments. 


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4.6 
Replacement of patients 
The following patients are to be replaced: 
 Patients failing screening procedures are to be replaced. 
 Patients who discontinue participation in the study for any reason after randomization 
but before receiving the first dose of study drug are to be replaced. 
The following patients are not to be replaced: 
 Patients who discontinue participation in the study for any reason after receiving the 
first dose of study drug are not to be replaced. 
Patients who fail screening procedures, patients discontinued from the study, and patients 
who have completed the study, are not permitted to re-enroll in the study. 
 
5 SCHEDULE OF ASSESSMENTS AND PROCEDURES 
5.1 
Summary schedule of assessments 
Table 4 presents a summary of the assessments to be performed from Screening to the 
final post-treatment visit. 


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Table 4 
Schedule of assessments 
 
Assessment 
Study Day 
Screening 
Day −1 to 1 
Active treatment 
Day 1 
Days 2–3 
Day 4 
Days 5–7 
Day 8–14 
EOT* 
TOC 
7–14 days 
after EOT 
LFU** 
28–35 days 
after EOT 
Written informed consent1 
X 
Inclusion/exclusion criteria 
X 
Medical history and demographics 
X 
Prior medications2 
X 
Pregnancy test3 
X 
X 
Physical examination 
X 
X 
X 
Laboratory tests4 
X 
X 
X 
X 
Haptoglobin5 
X 
X 
X 
Direct antiglobulin (Coombs) test6 
X 
X 
Vital signs and pulse oximetry7 
X 
X 
X 
X 
X 
X 
X 
X 
Pneumonia signs and symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical pneumonia outcome assessment8 
X 
X 
Study medication 
X 
X 
X 
X 
X 
Eligibility for IV to oral switch 
X 
X 
X 
Concomitant medication9 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events10 
◄----- continuous from time of first study drug administration------► 
Imaging11 
X 
Microbiological sampling12 
X 
X 
X 
X 
Overall microbiological outcome 
X 
X 
Overall clinical outcome13 
X 
X 
PK sampling14 
X 
Treatment/hospitalisation setting 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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1     The informed consent form (and the assent form where appropriate) must be signed before any study procedures take place (see Section 10.2). 
2     Prior medications taken up to 14 days before Screening are to be recorded. 
3  Pregnancy testing must be conducted for all menarcheal female patients. If results of the pregnancy test are positive at Screening, the patient must not be randomized in 
the study. 
4    Laboratory tests include haematology, biochemistry, and urinalysis (see Section 5.6.2). 
5     For children aged 6 years and older and in younger patients not treated with vancomycin. 
6     For children aged 6 years and older and in younger patients not treated with vancomycin. 
7 Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures) and pulse oximetry must be recorded three times daily 
during the active study drug treatment period. Vital signs and pulse oximetry must also be obtained at the EOT visit and the TOC visit. Weight will be assessed at 
Screening, and EOT. Height is to be assessed only at Screening (See Sections 5.6.3 and 5.6.4). 
8     On Day 4 and at the EOT visit, the Blinded Investigator must make an overall clinical assessment of pneumonia as being worsened, unchanged, improved, or cured. 
9     All medications taken since the recording of prior medications, and medications continued at entry into the study, should be recorded as concomitant therapy. 
10 Non-serious changes in, or worsening of, a patient’s condition that occur between informed consent and first study-drug administration are to be collected as pre-dose 
medical history. If any such occurrence is considered to be serious, it will additionally be reported following the procedures of an SAE, to allow for an assessment of 
serious procedure-related events. All AEs occurring from the time of first study-drug administration to the LFU visit must be collected in accordance with the 
procedures outlined in Section 7. 
11 Screening imaging (e.g., X-ray, ultrasound, or computer tomography) does not need to be repeated if it was performed within 24 hours of informed consent; post- 
baseline imaging may be obtained as clinically indicated. 
12 Blood samples for culture and Gram stain are to be obtained at Screening if feasible. Post-baseline blood cultures should be obtained as clinically indicated according to 
local practice during therapy, at EOT, and at the TOC. At the LFU visit, sampling is only to be undertaken if considered necessary by the Blinded Investigator to 
evaluate microbiological relapse (need for further antibiotic treatment). 
13 At the TOC visit, the Blinded Investigator must rate the overall clinical outcome of therapy as clinical cure, clinical failure, or clinically unevaluable. At the LFU visit, 
for patients with TOC outcomes of clinical cure, an assessment of relapse must be performed (see Section 5.2.7). 
14  Blood samples (200–300 µL) are to be taken on Day 3 at the following time points: Children aged 2 years and older – pre-dose, and at 2h (end of infusion), 4h, 6h, and 
8h after start of infusion; children aged less than 2 years – pre-dose and at 4h (end of infusion), 6h, and 8h after start of infusion. 
* EOT assessment is to be performed within 24 hours after the last study drug administration. If a patient withdraws prematurely, EOT visit laboratory/safety tests are to 
be conducted within 1 week of patient's withdrawal. 
** The LFU visit will be performed by telephone contact unless an examination is needed to evaluate relapse or abnormalities at the TOC assessment (see Section 5.2.7). 
The overall clinical outcome of relapse will only be assessed for patients with an outcome of ‘clinical cure’, and the assessment of microbiological relapse will only be 
performed for patients with outcomes of ‘microbiological eradication’ or ‘presumed microbiological eradication’. 


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5.2 
Study visits 
5.2.1 
Screening (Days −1 to 1) 
The parents or LARs must provide written informed consent for patients to participate in 
the study before any study-specific procedures are carried out. Age-appropriate assent 
procedures for the paediatric patients may also be necessary, as described in Section 10.2. 
Once informed consent (and assent, as applicable) is obtained, patients are considered 
enrolled in the study and are to be screened within 24 hours prior to the first dose of study 
medication. Screening evaluations and dosing may be performed  on  the  same  day 
(Day 1). Analyses required as part of the screening process which have been performed 
within the 24 hours prior to dosing do not need to be repeated, regardless of whether they 
were performed before or after signing of the ICF. 
Screening will comprise: 
 Medical history and demographics 
 Review and recording of medication given within the previous 14 days 
 Pregnancy testing must be conducted on all menarcheal female patients 
 Physical examination 
 Safety laboratory tests (central laboratory, see Section 5.6.2). Local laboratory results 
may be used for inclusion and exclusion criteria. 
 Vital signs (including height and weight, body temperature, respiratory rate, 
pulse rate, and systolic and diastolic blood pressures) (see Section 5.6.3) 
 Measurement of oxygen saturation (pulse oximetry; see Section 5.6.4) 
 Rating of the signs and symptoms of pneumonia (see Section 5.3.1) 
 Chest imaging (e.g., X-ray, ultrasound, or computer tomography), unless this has been 
performed within 24 hours of informed consent 
 Collection and culture of microbiological respiratory samples (and blood culture 
if clinically indicated) (see Section 5.4) 
 Treatment setting/hospitalisation (ICU or other ward) 
Based on the screening results, the investigator will review all enrolment criteria, 
including laboratory test results, to ensure patient eligibility. 
5.2.2 
Start of treatment (Day 1) 
Patients will be randomized to treatment with ceftobiprole or comparator. Start of study 
drug administration should be performed as soon as possible thereafter, and no later than 
6 hours after randomization. 
Clinical signs and symptoms of pneumonia are to be rated by the Blinded Investigator 
before the start of dosing (see Section 5.3.1). 
Ceftobiprole medocaril will be reconstituted, diluted for IV administration, and 
administered as described in Section 6.2. Comparator antibiotics will be administered 
according to the manufacturer’s instructions, the Pharmacy Manual, and consistent with 
local standard practice. The dates and exact start and stop times of all infusions must be 
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Anti-staphylococcal treatment should be given as described in Section 3.6.1. Anti-
pseudomonal treatment may be given as indicated (see Section 3.6.2). 
Vital signs and measurement of oxygen saturation (pulse oximetry) must be recorded 
before the start of the first dose of study drug, and every 8 hours thereafter (see Section 
Table 4 and Section 5.6.4). 
Changes in medication must be recorded. Information on the treatment setting (ICU or 
other ward) must be documented in the CRF. Adverse events must be monitored and 
recorded by the Blinded Investigator on Day 1 and throughout the study (see Table 4 and 
Section 7). 
Additional microbiological sampling or chest X-rays will not be required for study 
purposes, however, results from microbiological blood culture or respiratory sampling or 
from additional chest X-rays performed in the context of routine clinical care must be 
documented in the CRF. 
5.2.3 
Days 2 to 7 (active treatment) 
All days 2–7 
The Blinded Investigator must rate the clinical signs and symptoms of pneumonia on 
each day (during a study-drug-free interval in the morning in order to maintain blinding) 
(see Section 5.3.1). Vital signs and measurement of oxygen saturation (pulse oximetry) 
must be recorded before the first dose of antibiotics is given, and every 8 hours thereafter. 
Changes in medication must be recorded. Information on the treatment setting (ICU or 
other ward, or from Day 4, ambulatory treatment) must be documented in the CRF. AEs 
must be monitored and recorded by the Blinded Investigator (see Table 4 and Section 7). 
Additional microbiological sampling or chest X-rays is not required for study purposes, 
however, results from microbiological blood culture or respiratory sampling or from 
additional chest X-rays performed in the context of routine clinical care must be 
documented in the CRF. 
Blood samples must be obtained for  the  determination  of  plasma  levels  on  Day  3 
(see Section 5.5.1 for instructions on sample preparation). From study Day 4 onwards 
(after a minimum of 3 days (9 infusions) of treatment with systemic study antibiotics) 
patients will be assessed daily by the Blinded Investigator for eligibility for an IV to oral 
switch. 
If IV study antibiotics are given from Day 4 or later (see below), ceftobiprole medocaril 
or comparator antibiotics are to be administered as on Day 1 (see Section 5.2.2). The 
dates and exact start and stop times of all infusions must be recorded in the CRF. 
If oral antibiotics are given from Day 4 or later, the dates and times of administration 
must be recorded in the CRF (see Section 3.4). 
Anti-pseudomonal treatment may be given as indicated (see Section 3.6.2). 


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Day 4 only 
After 3 days (9 infusions) of treatment with IV study antibiotics, if clinical signs and 
symptoms are absent or improved, the Blinded Investigator may consider switching the 
patient from systemic to oral antibiotic therapy (see Section 3.4). In the absence of 
substantial clinical improvement, the Blinded Investigator should consider changes in 
therapy or withdrawal of the patient from the study. 
On Day 4, a physical examination must be performed, and the Blinded Investigator must 
also make an overall clinical assessment of pneumonia as being worsened, unchanged, 
improved or cured. 
Safety laboratory tests must also be obtained on Day 4 (see Section 5.6.2). 
5.2.4 
Days 8 to 14 (active treatment) 
Clinical signs and symptoms of pneumonia must be rated by the Blinded Investigator 
each day (see Section 5.3.1). If clinical signs and symptoms are absent or sufficiently 
improved on Day 8, the Blinded Investigator may consider stopping antibiotic therapy at 
any time after treatment for a minimum of 7 days. 
If antibiotic therapy is continued, clinical signs and symptoms of pneumonia must be 
rated by the Blinded Investigator each subsequent day (during a study drug free interval 
in the morning in order to maintain blinding) (see Section 5.3.1). Whenever clinical signs 
and symptoms are absent or improved, the Blinded Investigator may consider stopping 
antibiotic therapy. 
Patients are to be assessed daily by the Blinded Investigator for eligibility for an IV to 
oral switch. 
If IV study antibiotics are given from Day 4 or later, ceftobiprole medocaril or 
comparator antibiotics are to be administered as on Day 1 (see Section 5.2.2). The dates 
and exact start and stop times of all infusions must be recorded in the CRF. 
If oral antibiotics are given from Day 4 or later, the dates and times of administration 
must be recorded in the CRF (see Section 3.4). 
Anti-pseudomonal treatment may be given as indicated (see Section 3.6.2). 
Vital signs and measurement of oxygen saturation (pulse oximetry) must be recorded 
before the start of the first dose of study drug administration, and every 8 hours 
thereafter. 
Any other changes in medication must be recorded. Information on the treatment setting 
(ICU, other ward, or ambulatory treatment) must be documented in the CRF. AEs must 
be monitored and recorded by the Blinded Investigator (see Table 4 and Section 7). 
Additional microbiological sampling or chest X-rays are not required for study purposes, 
however, results from microbiological blood culture or respiratory sampling or from 
additional chest X-rays performed in the context of routine clinical care must be 
documented in the CRF. 
The maximum duration of study drug administration is 14 days. 


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5.2.5 
End-of-treatment (EOT) 
EOT assessments are to be performed within 24 hours after administration of the last 
dose of IV or oral antibiotics. The recommended minimum duration of antibiotic intake is 
7 days (including both study drug and oral switch, as applicable). The maximum duration 
of study drug administration (if no oral switch is used) is 14 days. 
A physical examination (including body weight) must be performed. 
The Blinded Investigator must rate the  clinical  signs  and  symptoms  of  pneumonia 
(see Section 5.3.1). The Blinded Investigator must also make an overall clinical 
assessment of pneumonia as being worsened, unchanged, improved or cured. 
Vital signs and pulse oximetry results must be recorded, and blood and urine samples for 
laboratory safety tests must be obtained at this visit. Pregnancy testing must be conducted 
on all menarcheal female patients. 
Where possible, microbiological samples should be collected and cultured as described in 
Section 5.4. 
Changes in medication must be recorded. Information on the  treatment  setting 
(ICU, other ward, or ambulatory treatment) must be documented in the CRF. AEs must 
be monitored and recorded by the Blinded Investigator at the EOT visit (see Table 4 and 
Section 7). 
Chest X-rays are not required for study purposes, however, results from additional chest 
X-rays performed in the context of routine clinical care must be documented in the CRF. 
5.2.6 
Test-of-cure (TOC) 
TOC assessments must be performed 7 to 14 days after the EOT evaluation. The Blinded 
Investigator must rate the clinical signs and symptoms of pneumonia, and the overall 
clinical outcome of therapy (see Section 5.3.2). 
Vital signs and pulse oximetry results must be recorded, and blood and urine samples for 
laboratory safety tests must be obtained at this visit. 
Where possible, microbiological samples should be collected and cultured as described in 
Section 5.4. 
Overall microbiological outcome will be assessed by the Blinded Investigator in 
accordance with the definitions in Section 5.3.3. 
Changes in medication must be recorded. Information on the  treatment  setting 
(ICU, other ward, or ambulatory treatment) must be documented in the CRF. AEs must 
be monitored and recorded by the Blinded Investigator at the TOC visit (see Table 4 and 
Section 7). 
Chest X-rays will not be required for study purposes, however, results from additional 
chest X-rays performed in the context of routine clinical care must be documented in 
the CRF. 


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5.2.7 
Last follow-up 
An LFU assessment must be performed 28 to 35 days after the EOT evaluation for all 
patients, and may comprise a clinic visit or a telephone contact conducted by medically 
qualified staff as appropriate. Information on the treatment setting (ICU, other ward, or 
ambulatory treatment) must be documented in the CRF. 
The LFU visit must include monitoring and recording of AEs (see Section 7) and 
concomitant medications for all patients. 
For patients with TOC outcomes of clinical cure an assessment of relapse must be 
performed as follows: 
 If a clinic visit is scheduled, the Blinded Investigator is to evaluate signs and 
symptoms of pneumonia (see Section 5.3.1) and the need for further antibiotic therapy 
for pneumonia, and record the outcome as ‘clinical relapse’ or ‘clinical cure 
maintained’. 
 If the patient (or a parent/LAR) denies any signs and symptoms of respiratory illness 
in a telephone interview, and requests no medical attention, the outcome is to be 
classified as ‘clinical cure maintained’. 
 If the patient (or a parent/LAR) reports or confirms signs and symptoms of respiratory 
illness in a telephone interview, a clinic visit is to be scheduled for evaluation of the 
signs and symptoms of pneumonia. If the patient does not attend the clinic visit, 
further telephone contact must be attempted in order to establish recovery (absence of 
respiratory illness) without antibiotic therapy (outcome: ‘clinical cure maintained’) or 
if systemic antibiotics were used for the treatment of pneumonia (outcome: ‘clinical 
relapse’). 
Chest X-rays are to be obtained, if clinically indicated, in relapsing patients who require 
further antibiotic therapy for pneumonia at the discretion of the Blinded Investigator. 
Where possible, microbiological samples should also be collected and cultured. Blood 
culture sampling is only to be undertaken if considered necessary by the Blinded 
Investigator, to evaluate microbiological relapse (see Section 5.4). 
If applicable, overall microbiological outcome will be assessed by the Blinded 
Investigator in accordance with the definitions in Section 5.3.3. 


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5.3 
Efficacy evaluations 
5.3.1 
Pneumonia signs and symptoms and requirement for hospitalisation 
The Blinded Investigator is to rate the following 10 signs and symptoms as ‘absent’ or 
‘present’ at baseline (pre-dose), and as ‘absent’, ‘improved’, ‘unchanged’, or ‘worsened’, 
on every day of active treatment, and at the EOT and TOC visits: 
1.  Fever* (> 38.5 °C) 
2. Hypothermia 
3. Tachypnea corresponding to 
Age 3 months to < 1 year: > 50 breaths per minute 
Age 1 year to < 5 years: > 40 breaths per minute 
Age ≥ 5 Years: 
> 20 breaths per minute 
4. Dyspnoea 
5. Retractions (suprasternal, intercostal or subcostal) 
6. Grunting 
7. Nasal flaring 
8. Apnoea 
9. Altered mental status 
10. Hypoxemia (pulse oximetry measurement ≤ 92% on room air) 
At Day 4, and EOT assessments, the Blinded Investigator must also rate the clinical 
outcome of pneumonia compared to baseline, as: 
 Cured: no signs or symptoms of pneumonia are detectable 
 Improved: clinically relevant improvement in overall signs and symptoms 
 Unchanged: no change from baseline, or minor change not judged to be clinically 
relevant 
 Worsened: clinically relevant increase in the overall severity of signs and symptoms 
The date of discharge from hospital must be recorded in the CRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*  Body temperature may be axillary, oral, rectal, tympanic or by skin temperature (e.g., by a patch); 
however, for each patient, only one method should be used consistently throughout the study. 


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5.3.2 
Clinical outcome of therapy 
At the TOC visit, the Blinded Investigator must rate the overall clinical outcome as: 
 Clinical cure: signs and symptoms of pneumonia normalized or improved to an 
extent that further antibiotic therapy is not necessary, stabilization or improvement of 
chest X-rays post-baseline if these are available 
 Clinical failure: persistence of clinically relevant signs and symptoms of pneumonia, 
and a need for continued or additional antibiotics (including macrolides) to treat 
respiratory illness 
 Clinically unevaluable: unable to examine the patient or to determine disease status 
within 7 to 14 days after EOT 
At the LFU visit (see Section 5.2.7), the Blinded Investigator must assess relapse in 
patients with a TOC clinical outcome of ‘clinical cure’ as follows: 
 Clinical cure maintained: no further antimicrobial therapy was necessary for 
treatment of the infection. 
 Clinical relapse: signs and symptoms of CAP or HAP (see Section 5.3.1) reappeared 
such that additional antimicrobial therapy was necessary. 
 Clinically unevaluable: absence of clinical assessments at LFU, or concomitant 
treatment with a systemic antibiotic active against Gram-positive or Gram-negative 
bacteria, administered for a reason other than the CAP or HAP. 
At the LFU assessment, the TOC clinical outcomes of ‘clinical failure’ or ‘clinically 
unevaluable’ will be carried forward to the LFU outcome assessment. 
5.3.3 
Microbiological outcome of therapy 
The   microbiological   outcome   of   therapy   is   to   be   based   on   the   results   from 
microbiological cultures at the EOT and TOC visits, as follows: 
 Microbiological eradication: causative pathogen isolated at baseline is no longer 
detected in valid samples obtained. 
 Presumed microbiological eradication: causative pathogen isolated at baseline, but 
no valid sample obtained or required post-therapy because of clinical improvement 
(clinical outcome of cure). 
 Microbiological persistence: same causative pathogen isolated at baseline and in 
valid samples obtained at EOT and/or TOC. 
 Superinfection: different pathogens, potentially causative, isolated at baseline and in 
valid samples obtained at EOT and/or TOC, or a new potentially causative pathogen 
isolated at EOT or TOC in the absence of an isolated pre-treatment pathogen. 
 Microbiologically non-evaluable: no causative pathogen isolated at baseline, or 
unable to obtain valid sample at EOT or TOC in cases of clinical failure or in 
clinically unevaluable patients. 


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At the LFU visit, (see Section 5.2.7), the Blinded Investigator must assess relapse in 
patients with a TOC assessment of ‘microbiological eradication’ or ‘presumed 
microbiological eradication’ as follows: 
 Microbiological eradication maintained: microbiological eradication at the TOC 
visit and no growth at the LFU visit of a potential pathogen from a valid culture taken 
at the original site of infection. 
 Presumed microbiological eradication maintained: microbiological eradication or 
presumed microbiological eradication at the TOC visit and no growth at the LFU visit 
of a potential pathogen from any valid culture taken at the original site of infection, 
and no clinical relapse. 
 Microbiological relapse: growth of the original pathogen at the original site of 
infection, with or without the presence of clinical signs or symptoms of infection. 
 Presumed microbiological relapse: no growth of a potential pathogen from any valid 
culture taken at the original site of infection, in the presence of clinical signs or 
symptoms of infection 
 Superinfection: different potentially causative pathogens isolated at baseline and in 
valid samples obtained at the LFU visit, or a new potentially causative pathogen 
isolated at the LFU visit in the absence of a pathogen isolated at baseline. 
 Microbiologically non-evaluable: no pathogen isolated at baseline, or absence of 
clinical determination at TOC, or ‘Other’ (specified by the Blinded Investigator). 
At the LFU assessment, (see Section 5.2.7), TOC microbiological outcomes of 
‘microbiological persistence’, ‘superinfection’ or ‘microbiologically non-evaluable’ will 
be carried forward to the LFU outcome assessment. 
5.4 
Microbiology assessments 
Blood samples for culture and Gram stain are to be obtained at Screening if feasible. 
Post-baseline blood cultures should be obtained as clinically indicated according to local 
practice during therapy, at EOT, and at the TOC visit. At the LFU visit, sampling is only 
to be undertaken if considered necessary by the Blinded Investigator to evaluate 
microbiological relapse (need for further antibiotic treatment). 
Sputum samples for culture and Gram stain are to be obtained at Screening, at EOT, and 
at the TOC and LFU visits for patients able to produce sputum. The numbers of white 
blood cells and epithelial cells in each sputum sample must be recorded (for details, see 
the Microbiology Manual). 
Tracheal aspirates or broncho-alveolar lavage samples for culture and Gram stain may be 
used if obtained in patients requiring mechanical ventilation or who undergo 
bronchoscopy that is clinically indicated. 
Potential pathogens from any culture are to be stored and shipped to a central laboratory. 
The Microbiology Manual describes the procedures for collection, culture, susceptibility 
testing, storage, and shipping of microbiology samples. 


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5.5 
Pharmacokinetics assessments 
5.5.1 
Collection and preparation of plasma samples 
Blood samples of 200 to 300  µL are  to be  obtained for PK analysis from at least 
15 patients in each of the two age categories of < 6 years and ≥ 6 years on Day 3 at the 
following time points: 
 Children aged 2 years and older: pre-dose, and at 2h (end of infusion), 4h, 6h, and 8h 
after start of infusion 
 Children aged less than 2 years: pre-dose and at 4h (end of infusion), 6h, and 8h after 
start of infusion 
Blood sampling should be performed after the daily visit of the Blinded Investigator in 
order to maintain the blind. The date and exact times of blood sampling must be recorded 
in the CRF. 
Blood for PK analysis should be collected by heel prick or fingertip prick or by regular 
venous puncture or through an existing arterial line, depending on age and according to 
local practice. 
Blood must be collected in pre-chilled tubes containing EDTA as an anticoagulant, and 
containing citric acid. Samples must be centrifuged, and the supernatant frozen. Samples 
must be stored and shipped to as described in the Pharmacokinetics Manual. 
5.5.2 
Analysis of ceftobiprole concentrations 
Plasma will be analysed for concentrations of ceftobiprole, and if applicable for 
concentrations of ceftobiprole medocaril and the open-ring metabolite (BAL1029). The 
analysis must 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 must be prepared in blank and pre-tested 
human plasma, and will be subject to the same assay procedure as experimental samples. 
The limit of quantification is to be defined as the lowest concentration of analyte in a 
human plasma sample, which can be quantitatively determined with inter-assay precision 
and accuracy of 100 ± 20%. Lower found concentrations must 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 patient 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. 
5.5.3 
Pharmacokinetic parameters 
Concentrations of ceftobiprole, ceftobiprole medocaril, and metabolite in plasma will be 
determined; these results will be analysed by use of descriptive statistics. 


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5.6 
Safety assessments 
The Blinded Investigator must evaluate patient safety by monitoring and recording all 
AEs and serious adverse events (SAEs), physical examination, vital signs, and laboratory 
tests (see Table 4). Safety assessments must be performed at intervals indicated in the 
Schedule of Assessments (see Table 4). More frequent assessments may be performed at 
the Blinded Investigator’s discretion, if medically indicated. 
5.6.1 
Adverse events 
See Section 7 for details regarding AE collection and management. 
5.6.2 
Safety laboratory tests 
Blood and urine samples obtained at screening and on Day 4, EOT and the TOC visit 
must be analyzed for the following laboratory parameters: 
Haematology: Haemoglobin concentration,  haematocrit,  red  blood  cell  (RBC) 
count, total and differential white blood cell (WBC) count, platelet 
count, mean corpuscular haemoglobin (MCH), mean corpuscular 
haemoglobin concentration (MCHC), mean corpuscular volume 
(MCV), reticulocyte count. 
In children aged 6 years and older, and in younger patients  not 
treated with vancomycin, additionally direct antiglobulin (Coombs) 
test at screening and TOC. 
Blood chemistry: C-reactive protein, creatinine, alanine amino transferase (ALT), 
aspartate aminotransferase (AST), total bilirubin, sodium, potassium. 
In children aged 6 years and older, and in younger patients  not 
treated with vancomycin, additionally haptoglobin at  screening, 
Day 4, and EOT. 
Urinalysis: 
Dipstick for pH, glucose*, blood*, and protein* 
(*microscopic examination of sediment if positive/strong positive) 
 
Blood draws should be performed according to standard procedures of the institution. 
The choice of site and procedure for blood draws (e.g., heel prick, fingertip prick, venous 
site, or through an indwelling venous or arterial catheter) is to be made by the Blinded 
Investigator. The patient’s age, the accessibility of the puncture site, and  the  blood 
volume required, should all be taken into consideration when selecting the puncture site 
and method. Maximum blood volumes for laboratory testing per visit and over the course 
of the study need to be considered. 
Children with bodyweight ≤ 15 kg (approximately 3–4 years and younger) should always 
be treated with blood-saving methods and small tubes. 
Creatinine clearance is estimated using the Schwartz Estimate. 


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The anticipated blood volume required for safety laboratory and PK assessment using 
regular tubes (S-Monovette®) and technique is: 
 
Haematology 
(mL) 
Biochemistry 
(mL) 
Haptoglobin 
and Coombs 
(mL) 
PK 
(mL) 
Total 
(mL) 
Screening 
2.6 
2.6 
5.2 
10.4 
Day 3 
1.5 
1.5 
Day 4 
2.6 
2.6 
2.6 
7.8 
EOT 
2.6 
2.6 
2.6 
7.8 
TOC 
2.6 
2.6 
2.6 
7.8 
Total 
10.4 
10.4 
13 
1.5 
35.3 
 
The anticipated blood volume required for safety laboratory and PK assessment using 
micro sampling technique and small tubes (Microvette®) is: 
 
Haematology 
(mL) 
Biochemistry 
(mL) 
Haptoglobin 
and Coombs 
(mL) 
PK 
(mL) 
Total 
(mL) 
Screening 
0.5 
0.5 
1.1 
2.1 
Day 3 
1.5 
1.5 
Day 4 
0.5 
0.5 
0.6 
1.6 
EOT 
0.5 
0.5 
0.6 
1.6 
TOC 
0.5 
0.5 
0.5 
1.5 
Total 
2.0 
2.0 
2.8 
1.5 
8.3 
 
Total circulating blood volume and maximal blood volume for laboratory testing based 
on body weight: 
 
Total circulating 
blood volume 
(mL) 
Maximum total 
blood volume 
for testing 
(mL) 
Maximum per visit 
blood volume 
for testing 
(mL) 
5 kg 
400 
12 
4 
10 kg 
800 
24 
8 
15 kg 
1200 
36 
12 
20 kg 
1600 
48 
16 
 
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
if medically indicated, and followed-up until return to the normal range, stabilization, 
and/or until an adequate explanation of the abnormality has been determined. When a 
clear explanation is established this must be recorded in the CRF. Abnormal laboratory 
results should not be recorded as an AE unless the abnormality is associated with a 
clinically relevant condition (see Section 7.3.2.1.1). 


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5.6.3 
Vital signs 
Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and 
diastolic blood pressures) must be recorded at Screening, prior to first administration of 
study drug and thereafter every 8 hours during the active study drug treatment period, and 
at the EOT and TOC clinical assessments. Weight will be assessed at Screening, and the 
EOT visit. Height will be assessed only at Screening. 
Body temperature may be axillary, oral, rectal, tympanic or skin. However, for each 
patient, only one method should be used consistently throughout the study. 
Any clinically significant change in vital signs, or worsening of, a patient’s condition that 
occurs after first study-drug administration must be reported as an AE (see Section 7.1.2). 
5.6.4 
Oxygen saturation by pulse oximetry 
Pulse oximetry measurements must be performed together with the assessment of vital 
signs, at Screening, before administration of the first dose of study drug and every 
8 hours thereafter during the active study drug treatment period, and at the time of 
EOT and TOC assessments (see Table 4). Results of each assessment (as % oxygen 
saturation) must be recorded in the CRF. 
5.6.5 
Physical examination 
Each patient must undergo a physical examination at Screening, at Day 4 and at the EOT 
visit. Abnormalities are to be described in the CRF. 
Any clinically-significant physical change in, or worsening of, a patient’s condition that 
occurs after first study-drug administration must be reported as an AE (see Section 7.1.2). 
 
6 STUDY DRUGS 
6.1 
Dose and schedule 
The intended doses and the schedule of ceftobiprole medocaril and comparator 
cephalosporin antibiotics (ceftazidime or ceftriaxone) may not be modified. Patients 
requiring dose modifications of these antibiotics for safety reasons should be withdrawn 
from the study. 
Vancomycin doses should be modified for patients with renal impairment, and to 
maintain recommended levels of drug exposure (see Section 6.1.2.3). 
On each treatment day, study-drug administration should occur within ±1 h from the 
scheduled time point for ≤ q6h dose regimens, and ±2 h from the scheduled time point for 
> q6h dose regimens. 


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6.1.1 
Ceftobiprole medocaril 
Patients are to receive IV infusions of ceftobiprole (given as ceftobiprole medocaril) q8h 
at age-adjusted doses and infusion durations as follows: 
 3 months to < 2 years:      20 mg/kg as 4-hour infusions 
 2 years to < 6 years:         20 mg/kg as 2-hour infusions 
 6 years to < 12 years:       15 mg/kg as 2-hour infusions 
 12 years to < 18 years:     10 mg/kg as 2-hour infusions 
Note: the maximum dose, regardless of body weight, is 500 mg ceftobiprole q8h 
(maximum total daily dose of 1500 mg ceftobiprole). 
To limit the infusion volume for patients < 12 years of age, ceftobiprole medocaril is to 
be administered at a concentration of 4 mg/mL ceftobiprole using dextrose 5% as carrier 
solution (see Section 6.2.1). 
For patients aged 12 years to < 18 years, ceftobiprole medocaril is to be administered at a 
concentration of 2 mg/mL ceftobiprole, which reflects the use in adults. 
Criteria that permit a switch from IV to oral antibiotics therapy, and the recommended 
oral antibiotics, are described in Section 3.4. 
Treatment of suspected infections by P. aeruginosa may be added at the discretion of the 
Blinded Investigator, in accordance with local practice (Section 3.6.2). Patients requiring 
concomitant treatment with a macrolide should be considered as clinical failures and 
withdrawn from study treatment, as described in Section 4.4. 
6.1.2 
Comparators 
6.1.2.1 Standard-of-care comparator for CAP 
The standard-of-care comparator antibiotic treatment is IV ceftriaxone 50–80 mg/kg 
administered once daily up to a maximum dose of 2 g/day. The actual dose of ceftriaxone 
within a dose range of 50 to 80 mg/kg (maximum dose of 2 g/d) is to be determined by 
the Blinded Investigator prior to first study drug administration. The dose administered 
on Day 1 should be not be modified throughout subsequent study days. Ceftriaxone is to 
be administered at a concentration of 20 mg/mL in all age groups. 
Optional: 
 Patients should receive vancomycin at a recommended dose of 10–15 mg/kg every 
6 hours (40 to 60 mg/kg per day) as an IV infusion, in addition to IV standard-of-care 
cephalosporin (comparator) antibiotic treatment when MRSA is suspected or 
confirmed, or at the discretion of the Blinded Investigator. Vancomycin serum 
concentrations should be monitored in all patients receiving vancomycin and the 
dosage adjusted as needed in order to maintain serum concentrations within the 
therapeutic window (see Section 6.1.2.3). Vancomycin dosage in patients with 
impaired renal function should be modified in accordance with the approved product 


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label. The adjustment of vancomycin dose levels will be performed by the unblinded 
investigators. Vancomycin is to be administered at a concentration of 4 mg/mL in all 
age groups. 
 Anti-pseudomonal treatment is described in Section 3.6.2. 
Withdrawal of patients requiring treatment with a macrolide is described in Section 4.4. 
Criteria that permit a switch from IV to oral antibiotics therapy, and the recommended 
oral antibiotics, are described in Section 3.4. 
6.1.2.2 Standard-of-care comparator for HAP 
The  standard-of-care  comparator  antibiotic  treatment  is  IV  ceftazidime  50  mg/kg 
administered every 8 hours up to a maximum of 6 g/day. 
Optional: 
 All patients should receive vancomycin at a recommended dose of 10–15 mg/kg q6h 
(40–60 mg/kg per day) as an IV infusion, in addition to IV ceftazidime when MRSA 
is suspected or confirmed, or at the discretion of the Blinded Investigator. 
Vancomycin serum concentrations should be monitored in all patients receiving 
vancomycin and the dosage adjusted as needed in order to maintain serum 
concentrations within the therapeutic window (see Section 6.1.2.3). Vancomycin 
dosage in patients with impaired renal function should be modified in accordance 
with the approved product label. The adjustment of vancomycin dose levels will be 
performed by the unblinded investigators. Vancomycin is to be administered at a 
concentration of 4 mg/mL for all age groups. 
In the event of scheduling conflicts, the order of administration should always be 
ceftazidime, followed by vancomycin. 
Vancomycin must not be given together with ceftazidime in the same line; the line 
must be flushed when vancomycin is given directly after ceftazidime. 
 Anti-pseudomonal treatment is described in Section 3.6.2. 
Withdrawal of patients requiring treatment with a macrolide is described in Section 4.4. 
Criteria that permit a switch from IV to oral antibiotics therapy, and the recommended 
oral antibiotics, are described in Section 3.4. 
6.1.2.3 Monitoring of vancomycin serum concentrations 
The serum concentration of vancomycin should be monitored at the second day of 
treatment immediately prior to the next dose (trough level). Therapeutic steady-state 
trough vancomycin blood levels should be maintained at 15–20 mg/L. 
The concentrations should normally be monitored two or three times per week. 
The  adjustment  of  vancomycin  dose  levels  is  to  be  performed  by  the  unblinded 
investigators. 


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6.2 
Administration 
The highest total infusion volume in this study occurs in HAP patients treated with 
ceftazidime and vancomycin. This highest possible infusion volume remains in all 
instances below the maintenance need for water in parenteral fluid therapy calculated by 
the Holliday-Segar formula (see Table 5) (Holliday 1957). 
Table 5 
Total Infusion volumes in HAP patients treated with ceftazidime and 
vancomycin and maintenance fluid volumes 
 
Age group 
Body weight (kg)* 
Infusion volume (mL) 
Maintenance fluid 
volume (mL)** 
3 months to < 2 years 
2 years to < 6 years 
6 years to < 12 years 
12 years to < 18 years 
5–12 
10–28 
16–62 
30–92 
113–270 
225–630 
360–800 
675–800 
500–1100 
1000–1660 
1300–2340 
1700–2940 
*   Range from the 5th percentile for the lowest age up to the 95th percentile of the highest age. 
** 100 mL/kg for the first 10 kg body weight, 50 mL/kg for the second 10 kg body weight, and 20 mL/kg for the 
remaining body weight. 
 
6.2.1 
Ceftobiprole medocaril 
Details on study drug preparation and administration are provided in the Pharmacy 
Manual. Procedures can be briefly summarized as follows: 
Ceftobiprole medocaril is to be administered intravenously, depending on age, as follows 
 3 months to < 12 years: ceftobiprole medocaril administered at a concentration of 
4 mg/mL ceftobiprole using dextrose 5% as carrier solution 
 12 years to < 18 years: ceftobiprole medocaril administered at a concentration of 
2 mg/mL ceftobiprole using either physiological saline (NaCl 0.9%) or dextrose 5% 
as carrier solution 
Ceftobiprole medocaril will be supplied in vials containing 500 mg ceftobiprole 
(corresponding to 667 mg of ceftobiprole medocaril) as lyophilized powder and must be 
reconstituted and diluted as shown in Table 6. 


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Table 6 
Reconstitution and dilution of ceftobiprole 
 
Age Group 3 months to < 12 years 
Age Group 12 years to < 18 years 
Step 1: 
Reconstitution 
10 mL dextrose 5% 
Concentration of the reconstituted solution: 
50 mg/mL ceftobiprole. 
Stability of the reconstituted solution: 
 1 hour at room temperature 
 Up to 24 hours in a refrigerator at 2 °C to 
8 °C 
10 mL dextrose 5% 
Concentration of the reconstituted solution: 
50 mg/mL ceftobiprole. 
Stability of the reconstituted solution: 
 1 hour at room temperature 
 Up to 24 hours in a refrigerator at 2 °C to 
8 °C 
Step 2: 
Dilution 
Dextrose 5% to achieve a ceftobiprole 
concentration of 4 mg/mL in the final 
solution for infusion. 
Stability of the solution for infusion: 
24 hours at 2 °C to 8 °C plus 12 hours at 
room temperature, including the infusion into 
the patient. 
Note: 
Reconstitution, dilution and infusion 
including an up to 4-hour infusion period 
must be completed within 24 hours. 
Only dextrose 5% is permitted for 
reconstitution and dilution. 
Either physiological saline (NaCl 0.9%) or 
dextrose 5% to achieve a ceftobiprole 
concentration of 2 mg/mL in the final 
solution for infusion 
Stability of the solution for infusion: 
8 hours at room temperature 
96 hours in a refrigerator at 2 °C to 8 °C 
 
Reconstituted and infusion solutions should 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. 
The reconstituted and infusion solutions should not be frozen, and should not be exposed 
to direct sunlight before infusion. 
If the infusion solution is stored in the refrigerator, it should be equilibrated to room 
temperature prior to administration. The infusion solution does not need to be protected 
from light during administration. 
Further details of study drug administration are described in the Pharmacy Manual. 
6.2.2 
Comparator antibiotics 
Comparator antibiotics must be administered according to the manufacturers’ 
instructions, and as described in Section 6.1.2. 
6.3 
Blinding and randomization 
This is an investigator-blind study. 
There is to be at least one Blinded Investigator at each centre who does not know the 
patient’s assigned treatment. This blinded observer is to conduct the clinical assessments, 


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including with reference to the criteria for switching to oral study drug. The assessments 
are to be made in the patient ward when no study drugs are being administered. The 
remaining investigators, study team, patients, their parents, and the pharmacy staff, are 
unblinded. A Blinding Management Plan must be established at each centre. 
Patients are to be randomized with stratification by diagnosis of HAP or CAP and age as 
described in Section 3.1. Within each group, patients are to be randomized 2:1 to receive 
ceftobiprole or comparator antibiotics ceftazidime ± vancomycin (for HAP)  or 
ceftriaxone ± vancomycin (for CAP). Randomization will be carried out using a central 
Interactive Voice Response System (IVRS) and/or Interactive Web-based Response 
System (IWRS) based on a computer-generated randomization schedule prepared by the 
Sponsor before the study. 
The following personnel will have access to the randomization list and the identity of the 
study drugs. 
 those responsible for labelling, packaging, and respective documentation 
 those performing PK analyses 
 those setting up the random scheme and IVRS/IWRS 
 the unblinded centre study team, including unblinded investigators at each centre 
 the unblinded pharmacist or delegate responsible for blinded study-drug preparation 
and documentation 
 those required to break the blind for expedited reporting purposes to health authorities 
and other relevant institutions 
 those responsible for clinical monitoring (unblinded Monitor) and his/ her supervisor 
(unblinded monitoring report review) 
 the unblinded data manager responsible for cleaning unblinded infusion and PK data 
 the  unblinded  statistician,  if  required  for  safety  reasons,  producing  the  interim 
analysis and Data and Safety Monitoring Board (DSMB) outputs 
These personnel must not disclose any details of the randomization scheme or the 
treatment code of study drugs. 
6.4 
Unblinding methods 
Individual treatment codes for each randomized patient will be available to Blinded 
Investigators from the IVRS/IWRS system. The Blinded Investigator is responsible for 
monitoring and recording AEs. 
The treatment code should only be broken in medical emergencies; it is advisable to 
contact the medical monitor prior to breaking the blind. The Blinded Investigator must 
record the reason for unblinding in the patient’s records/source documents. 
In order to maintain the investigator-blinded nature of the study, the allocation of the 
investigational product(s) for the patient must not be communicated further, unless 
required for the treatment and/or surveillance of the patient. Adverse events and SAEs 
must be reported as outlined in Section 7. Serious adverse event reporting is to be 
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Sponsor/designee. The Sponsor/designee might break the blind via IVRS/IWRS for 
regulatory reporting purposes. This must be fully documented, and only the minimum 
number of staff necessary are to have access to the unblinded information. 
Detailed handling instructions are provided in the IVRS/IWRS Manual. 
Systematic unblinding of the clinical database will occur after database lock as described 
in the Data Management Plan and Statistical Analysis Plan (SAP). 
6.5 
Drug accountability and compliance check 
Compliance will be assessed by direct observation of each patient during infusion of the 
study medication, and by measurement of ceftobiprole concentrations in plasma. 
A Drug Dispensing Log must be kept current and should contain the following 
information for ceftobiprole, ceftriaxone, ceftazidime, and vancomycin: 
 The identification of the patient to whom the drug was dispensed 
 The date(s), time and quantity of the drug dispensed to the patient 
 The initials of the person who dispensed the drug 
The inventory must be available for inspection by the unblinded clinical monitor. Drug 
supplies, including partially used or empty containers and the dispensing logs, must be 
maintained for verification by the unblinded clinical monitor. 
When requested in writing by Basilea, unused drug supplies may be destroyed by the 
unblinded investigator. Records shall be maintained by the unblinded investigator of any 
such alternate disposition of the test drug. These records must show the identification and 
quantity of each unit disposed of, the method of destruction (taking into account the 
requirements of local law), and the person who disposed of the test substance. Such 
records shall be submitted to Basilea. 
6.6 
Packaging and labelling 
Study drug vials (including ceftobiprole, ceftriaxone, ceftazidime, and vancomycin,) will 
be supplied by Basilea to the unblinded investigator or to the Unblinded Pharmacist. 
Basilea will ensure that the study medication and certificates of analysis are available 
before the start of the study. 
Study drug for IV administration will be presented as vials of sterile lyophilized 
ceftobiprole medocaril (BAL5788) containing the equivalent of 500 mg ceftobiprole 
which will be reconstituted and diluted as described in Section 6.2.1. The lyophilisate 
will be stored in a refrigerator (2°C to 8°C). 
The study drug vial labels will identify, e.g., the Sponsor, study number, vial contents, 
batch number and expiry date as per applicable guidelines. 
Study drug must be kept in a secure location under adequate storage conditions. Further 
details on handling, preparation, and administration of IV ceftobiprole are described in 
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7 
PATIENT SAFETY 
7.1 
Definitions 
7.1.1 
Adverse occurrence 
An adverse occurrence is any untoward medical occurrence taking place after informed 
consent and before first study-drug administration. 
7.1.2 
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. 
7.1.2.1 Treatment-emergent adverse event 
A treatment-emergent adverse event is any AE which occurs from the start of first dosing 
up to and including the scheduled LFU visit. 
7.1.3 
Serious adverse event 
A serious adverse event (SAE) is any AE that meets one or more of the following criteria: 
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the Sponsor is appropriate, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
patient, or may require intervention to prevent one of the outcomes listed in the 
definitions above. These situations should also usually be considered serious. 
Examples of such events include intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, and development of drug dependency or drug abuse. 
It should be noted that: 
 Death is considered an outcome of an AE. Whenever possible the underlying cause of 
death must be reported as the AE. 
 A life-threatening SAE is any adverse experience that places the patient at risk of 
death at the time of its occurrence, i.e., it does not include a reaction that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalisation is defined as any inpatient admission, even if for less than 
24 hours. For chronic or long-term inpatients, inpatient admission also includes 
transfer within the hospital to an acute/intensive care inpatient unit (e.g., from a 
medical floor to the coronary care unit, or from the neurological floor to the 
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The following hospitalisations, whether planned before or during the study, should 
not be considered SAEs: 
– Routine treatment or monitoring of the HAP or CAP, not associated with any 
deterioration in condition (e.g., hospitalisations related to study procedures, such 
as study-drug administration, PK assessments, etc). 
– Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the HAP or CAP and has not worsened. 
– Admission to a hospital or other institution for general care, not associated with 
any deterioration in condition. 
– Treatment on an emergency outpatient basis for an event which does not meet any 
of the above definitions of ‘serious’, and does not result in hospital admission. 
7.1.3.1 Suspected unexpected serious adverse reaction 
A suspected unexpected serious adverse reaction (SUSAR) is any SAE considered to be 
related to the study treatment and for which the nature or severity is not consistent with 
the applicable reference safety information (i.e., regardless of whether the nature or 
severity of an SAE has been previously observed/documented). 
Note: Expectedness of SAEs will be assessed by the Sponsor against the applicable 
reference safety information. 
7.2 
Evaluation of adverse events 
7.2.1 
Severity 
The intensity of an AE will be graded on the following three-point scale: 
 Mild: discomfort but no disruption of normal daily activity 
 Moderate: discomfort sufficient to reduce or affect daily activity 
 Severe: inability to work or to perform normal daily activities 
7.2.2 
Relationship 
The  relationship  of  AEs  to  the  study  treatment  must  be  assessed  by  the  Blinded 
Investigator as one of the following: 
 not related 
 unlikely 
 possible 
 probable 
Appendix 2 provides criteria for relationship assessments. 
According to the Sponsor’s criteria for causality assessment, a causal relationship will be 
suspected for all AEs reported with a relationship of ‘possible’ or ‘probable’, and those 
with missing or unknown relationships. 


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7.3 
Handling of safety information and collection periods 
7.3.1 
Handling of safety data during the pre-treatment period 
Any relevant change in, or worsening of, a patient’s condition occurring after consent, 
but prior to the start of first study-drug administration, must be recorded in the CRF as 
pre-dose medical history. 
If a change in, or worsening of,  a  patient’s  condition  is  considered  to  be  serious 
(i.e., meets one or more of the criteria for an SAE in Section 7.1.3), this information must 
also be reported to the Sponsor’s safety representative, using the same forms and 
procedures as for an SAE (see Section 7.3.2.2). 
7.3.2 
Handling of safety data during the treatment period and up to the last 
scheduled follow-up 
From the start of first dosing up to and including the LFU visit, any change in, or 
worsening of, the patient’s condition must be collected and reported in the CRF as an AE 
(see Section 7.3.2.1). Serious adverse events must be additionally reported and recorded 
on SAE report forms (see Section 7.3.2.2). 
7.3.2.1 Adverse event management 
The Blinded Investigator or the physician in attendance should administer therapy as 
clinically indicated for any AE/SAE that occurs. 
7.3.2.1.1 Data collection 
All AEs directly observed (physical examination, laboratory test, or other assessments), 
mentioned by the patient, or reported by the patient upon non-directive questioning, must 
be recorded on the AE pages of the CRF. 
The Blinded Investigator should consider reports from the parents, LARs or caregivers 
when recording AEs. 
All AEs must be recorded in the English language in the CRF and should include the 
following information: 
1. Term. If possible, a diagnosis should be documented rather than signs and symptoms, 
using self-explanatory and concise medical terminology. 
Note: Use of the AE term ‘disease progression’/‘lack of efficacy’, or equivalent 
terms, should be avoided. Instead, a diagnosis, signs, or symptoms should be used to 
describe the worsening of the HAP or CAP. 
2. Duration (start and end dates). 
3. Severity grade (three-point scale, see Section 7.2.1). 
4. Relationship to study treatment (see Section 7.2.2 and Appendix 2). 
5. Action(s) taken with regards to the study treatment or additional treatments given for 
the event. 
6. Whether the event is an SAE (see Section 7.1.3). 
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Abnormal laboratory results should not be recorded as an AE unless the abnormal result 
meets one or more of the following criteria: 
 induces clinical signs or symptoms which require therapy or additional diagnostic 
evaluation 
 requires changes in study drug dosing or discontinuation of study participation 
 is considered clinically significant 
Signs, symptoms or diagnosis associated with these abnormal results must be recorded on 
the AEs page of the CRF. 
Adverse events must also be reported in the source document with at least the nature of 
the event, the start and end date, the relationship to the study drug, and the treatment (if 
applicable). 
7.3.2.1.2 Follow-up 
Once an AE is detected, it must be proactively followed at each visit (or more frequently 
if necessary) for any changes in severity, relationship to the study drug, interventions 
required for treatment, and the event’s outcome. 
All AEs must be followed-up until they have returned to baseline status or have 
stabilised, or until the scheduled LFU visit. 
In addition, an AE which remains unresolved after completion of the study (including the 
scheduled LFU visit) and meets one or more of the criteria listed below, requires detailed 
evaluation, follow-up and, if necessary, specific medical treatment until the AE is 
resolved or a reasonable explanation for its persistence is found: 
 an AE evaluated as related to the study drug 
 an AE that led to a patient withdrawal from the study 
 an SAE 
These cases must be followed-up on the CRF unless otherwise agreed with the Sponsor. 
7.3.2.2 
Serious adverse event recording and reporting 
In addition to being reported and followed-up as AEs (see Section 7.3.2.1), SAEs must be 
reported to the Sponsor’s safety representative listed below, within 24 hours of awareness 
of the event. 
The Blinded Investigator must complete the ‘Serious Adverse Event Report Form’ in 
English, and send the completed, signed form by fax or email to: 
 
 
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 


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Such preliminary reports must be followed by detailed anonymised descriptions, which 
may include copies of hospital case reports, autopsy reports, and other documents if 
requested and applicable. 
The original SAE Report Form and the correspondence to the Sponsor reporting the 
SAE (fax confirmation sheet/email) must be kept at the study centre in the Investigator 
Site File (ISF). 
7.3.3 
Handling of post-study safety data 
Any AE occurring after the LFU visit which is considered to be both: 
 serious (i.e., meets one or more of the criteria listed for SAEs, see Section 7.1.3), and 
 related to the study drug (see Section 7.2.2 and Appendix 2) 
should be reported to the Sponsor’s designated safety representative using the same forms 
and procedures as for an SAE (see Section 7.3.2.2). 
Events occurring after the LFU visit should not be reported in the CRF. 
7.3.4 
Reporting of SAEs to regulatory authorities 
7.3.4.1 
Sponsor’s responsibilities 
The Sponsor’s safety representative must ensure the reporting of SUSARs and any 
expeditable SAEs to regulatory Authorities in accordance with applicable law. 
In the event of a SUSAR, the Sponsor will ensure that all investigators involved in all 
studies with ceftobiprole medocaril are informed. 
7.3.4.2 Investigator’s responsibilities 
The Blinded Investigator is responsible for informing the local Independent Ethics 
Committee / Institutional Review Board (IEC/IRB), and any other applicable bodies, of 
SUSARs and any other expeditable SAEs, in accordance with applicable laws. This 
activity may be delegated. 
7.4 
Pregnancy 
7.4.1 
Contraception for women of childbearing potential 
There are no adequate and well-controlled studies with ceftobiprole in pregnant women. 
Animal studies do not indicate direct harmful effects with respect to pregnancy, 
embryonal/fetal development, parturition, or post-natal development. As no data in 
exposed human pregnancies are available, ceftobiprole should not be used during 
pregnancy. 
The Blinded Investigator must make every effort to ensure that a clinical study patient 
does not become pregnant during the study. This should be done, and documented, as 
part of the consent process, by explaining clearly to the patient the potential dangers of 
becoming pregnant, and providing each patient with information about appropriate 
medically-approved effective contraception (see below). 
Pregnancy testing must be conducted on all menarcheal female patients prior to 
administration of the first dose of study drug. If results of the pregnancy test are positive, 
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Female  patients  of  childbearing   potential   who   enrol   in   this   study   must   agree 
(in consultation with their parents and doctors, as applicable) to use a highly reliable 
method of contraception during the study. Such methods may include: 
 Intrauterine device (IUD) 
 Combined (oestrogen- and progesterone-containing) hormonal contraception (oral, 
vaginal ring or transdermal patch) with an ethinylestradiol dose of at least 30 µg, plus 
use of male condoms (preferably with spermicides), female condoms, a female 
diaphragm or a cervical cap 
 Total sexual abstinence 
7.4.2 
Reporting and handling of pregnancies 
Female patients must inform the Blinded Investigator within 24 hours if they have any 
concerns about possible reduction of contraceptive effectivity (e.g., forgotten pill or 
vomiting) during the study. In these cases the patients must return to the study centre as 
soon as possible, but not later than 24 hours, after the Blinded Investigator is informed. 
Female patients must inform the Blinded Investigator if they become pregnant during the 
study. The study drug must be discontinued immediately when a patient becomes 
pregnant. The patient must be monitored until conclusion of the pregnancy and infants 
must be followed-up at least for 8 weeks after delivery. 
The Blinded Investigator must immediately notify the Sponsor’s safety representative 
about any pregnancy by submitting a Pregnancy Report Form, in accordance with the 
requirements (timelines and contact details) of an SAE (see Section 7.3.2.2). In addition, 
pregnancy-related adverse outcomes must also be reported as AEs or SAEs (see Section 
7.3.2). Note that an induced abortion which is not required by an AE does not constitute 
an SAE. 
The Blinded Investigator must notify the local IEC/IRB about any pregnancies resulting 
in an adverse outcome, in accordance with applicable laws and regulations. 
7.5 
Data and Safety Monitoring Board 
The composition, roles and responsibilities of the DSMB are described in a separate 
DSMB Charter. Briefly, members of the DSMB will review patient data for periodic 
scheduled data review meetings. 
An interim analysis of safety data will be performed by the DSMB after randomization of 
approximately 50 patients. The Blinded Investigator will remain blinded to the assigned 
treatment during this analysis (see Section 8.8). 


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8 STATISTICAL CONSIDERATIONS 
8.1 
Sample size justification 
The randomization of 138 patients is expected to give at least 125 evaluable patients 
(at least 92 receiving ceftobiprole and at least 46 receiving the comparator, assuming 
approximately a 10% dropout rate from randomization to the EOT and TOC visits). 
At least 50 patients are planned to be enrolled in each of the age categories < 6 years and 
≥ 6 years. There is no requirement for a minimum number of patients with each infection 
type (HAP or CAP). 
Treatment   of   92   patients   (safety   population)   with   ceftobiprole   will   yield   a 
> 95% probability of observing at least one AE type if the actual probability of this event 
is > 3.2%. 
In an age-related analysis, if at least 33 patients receiving ceftobiprole are aged < 6 years 
and at least 33 are aged ≥ 6 years, this will yield a 95% probability of observing at least 
one AE type in each of the two age groups if the actual probability of this event is 
> 8.7%. 
At least 33 patients on ceftobiprole and at least 17 patients on IV standard-of-care 
cephalosporin treatment must be included in the age categories < 6 years (Groups 1, 2, 5 
and 6) and ≥ 6 years (Groups 3, 4, 7 and 8; see Section 8.3). 
8.2 
Analysis populations 
The analysis populations are defined as follows: 
Safety population: all randomized patients who received at least one dose of study drug, 
analysed according to the first treatment actually received. 
Intent-to-treat (ITT) population: all randomized patients, analysed by treatment 
assigned. 
Clinically Evaluable (CE) population: patients who received at least 3 days (9 infusions) 
of study drug, had a valid clinical outcome assessment at TOC, no major protocol 
violations, and no systemic non-study antibiotic therapy. 
Microbiological intent-to-treat (mITT) population: all patients in the ITT analysis 
population with a valid pathogen identified at baseline. 
Microbiologically Evaluable (ME) population: all patients in the CE analysis population 
with a valid pathogen at baseline and a microbiological assessment at TOC. 
Pharmacokinetic (PK) population: all patients who received at least one dose of 
ceftobiprole and have at least one plasma concentration measurement obtained by the 
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8.3 
General statistical considerations 
Study results will be presented by infection type, and if applicable by age group within 
each infection type, as follows: 
 Group 1:  Patients aged 3 months to < 2 years with CAP 
 Group 2:  Patients aged 2 years     to < 6 years with CAP 
 Group 3:  Patients aged 6 years     to < 12 years with CAP 
 Group 4:  Patients aged 12 years   to < 18 years with CAP 
 Group 5:  Patients aged 3 months to < 2 years with HAP 
 Group 6:  Patients aged 2 years     to < 6 years with HAP 
 Group 7:  Patients aged 6 years     to < 12 years with HAP 
 Group 8:  Patients aged 12 years   to < 18 years with HAP 
No formal hypothesis testing will be performed. Descriptive statistics will be applied to 
the primary variable, with frequency tables used to characterise the safety profile of 
ceftobiprole, and the numbers of patients with adverse changes in laboratory test results, 
vital signs, and physical examination results. 
The secondary variable of clinical cure will be compared between ceftobiprole and the 
standard-of-care comparator IV antibiotic treatment. The between-group difference, 
along with the respective 95% CI, will be displayed at the study time points Day 4, EOT, 
and TOC. 
8.4 
Presentation of clinical results 
Presence of disease signs and symptoms at baseline, changes in disease signs and 
symptoms and in overall clinical status, clinical outcomes at TOC, microbiological 
outcomes at TOC, and findings at the LFU visit will be presented in individual patient 
listings, and summarized by descriptive statistics. 
8.5 
Analyses of endpoints 
The primary endpoint of the study (see Section 3.2.1) is analysis of AEs assessed on each 
of the first 3 days of study-drug treatment, and at the EOT, TOC, and LFU visits (Safety 
population). Other timepoints may also be analysed. 
The secondary endpoints (see Section 3.2.2) are: 
1. Efficacy: Comparison of clinical cure rates (ITT and CE populations) and 
microbiological eradication rates (mITT and ME populations) between ceftobiprole 
and the comparator at the TOC visit; and cure of pneumonia, defined as clinical 
improvement or lack of progression of X-ray abnormalities, as well as resolution of 
clinical pneumonia findings, at study Day 4 and the EOT visit (ITT and CE 
populations). The clinical and microbiological relapse rates at the LFU visit will also 
be compared (ITT, CE, mITT and ME populations). 


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2. Pharmacokinetics: Descriptive analysis of ceftobiprole plasma concentration per time 
point, based on PK sampling in at least 15 patients in each of the two age categories 
of < 6 years and ≥ 6 years (PK population). 
Clinical cure rates at TOC (see Section 5.3.2) in all patients (HAP and CAP alone and/or 
combined) will be tabulated for ceftobiprole and the comparators, and the between-group 
difference will be displayed along with the respective 95% CI. 
The between-group difference in clinical cure rates at TOC will be displayed, along with 
the respective 95% CI. The between-group difference in the percentages of patients rated 
as improved or cured regarding their clinical signs and symptoms at study Day 4 and 
EOT (see Section 5.3) will be also be displayed, along with the respective 95% CI. 
Changes from baseline in signs and symptoms and in overall clinical status (see Section 
5.3.1) will be analysed by descriptive statistics. Duration of hospitalisation, defined as the 
time from start of study drug therapy to discharge, will be analysed by descriptive 
statistics and by a time to event analysis. 
A full Statistical Analysis Plan (SAP) will be prepared before database lock. 
8.6 
Safety analyses 
The incidence of AEs will be displayed by MedDRA System Organ Class and Preferred 
Term. In addition, listings will be provided by individual patient. Vital signs will be listed 
and summarised by mean and standard deviation. 
Laboratory test values will be presented in individual patient listings, with flagging of 
values outside the normal ranges and marked normal ranges, by frequency tables for each 
parameter showing the numbers of patients with values outside normal ranges and 
marked normal ranges, and by shift tables for each parameter showing the numbers of 
patients with adverse changes from baseline. 
Vital signs data and abnormalities at physical examination will be presented in individual 
patient listings. 
8.7 
Pharmacokinetics 
Ceftobiprole plasma concentrations at each time point of measurement will be evaluated 
by descriptive statistics. 
Pharmacokinetic data will be presented by individual listings and descriptive summary 
statistics. 
8.8 
DSMB analysis 
An interim analysis of safety data will be performed by the DSMB after randomization of 
approximately 50 patients. The Blinded Investigator will remain blinded to the assigned 
treatment during this analysis (see Section 7.5). 


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9 
STUDY ADMINISTRATION AND REGULATORY ASPECTS 
9.1 
Study records 
The investigators (blinded and unblinded) must maintain adequate and accurate records 
to enable the conduct of the study to be fully documented and the study data to be 
subsequently verified. 
9.1.1 
Investigator site file 
The ISF must contain all essential documents as required by ICH E6 and applicable 
regulations, including the protocol and any subsequent amendments, CRFs, Query Forms, 
documented IEC/IRB approvals, documented regulatory approvals, sample informed 
consent forms, drug records, staff curriculum vitae, and other appropriate 
documents/correspondence. 
9.1.2 
Case report forms 
For each patient enrolled in the study, including patients who do not complete the study 
and patients for whom a CRF is initiated during screening but are not randomized, a CRF 
must be completed and signed (manually or electronically) by the investigator (blinded 
and unblinded) or authorized centre staff. If a patient withdraws from the study, the 
reason must be noted on the CRF. If a patient is withdrawn from the study because of an 
AE, thorough efforts should be made to clearly document the outcome. 
The investigator (blinded and unblinded) should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported to the Sponsor in the CRFs and in all 
required reports. 
If the CRF is to be the source document for certain data, this must be discussed and 
agreed with the Sponsor in advance, and clearly documented. 
9.1.3 
Patient source documents 
Patient source documents used to record key efficacy/safety parameters, independent of 
the CRFs, may include, but are not limited to, patient hospital/clinic records, physicians’ 
and nurses’ notes, appointment books, original laboratory reports, X-ray, pathology and 
special assessment reports, signed informed consent/assent forms, consultant letters, and 
patient screening and enrollment logs. Source documents are part of the study documents, 
and must be maintained and made available upon request for clinical monitoring visits, 
audits or inspections. 
9.1.4 
Document retention and archiving 
The Principal 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 Principal Investigator when the study documents can be destroyed, subject to 
applicable regulations. 
These files must be made available for audits and inspection, upon reasonable request, to 
the authorized representative of the Sponsor, or to regulatory authorities. 


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Should the Principal Investigator wish to assign the study records to another party, or 
move them to another location, the Sponsor must be notified in advance. 
If the Principal Investigator cannot guarantee the archiving requirement at the 
investigational centre for any or all of the study documents, arrangements must be made 
between the Principal Investigator and the Sponsor for appropriate storage. 
9.1.5 
Sample retention 
All samples taken will be stored for up to 5 years for future medical and/or scientific 
research projects related to ceftobiprole. Informed consent must be obtained for this 
purpose, authorizing the Sponsor to use their study information and samples for future 
research projects. 
After a maximum of 5 years, all stored samples will be safely destroyed. 
9.2 
Clinical monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s Meeting,  the 
Sponsor will review the protocol, CRFs and other study documentation with the 
investigators (blinded and unblinded) and the centre staff. 
The Monitor (blinded and unblinded) must visit the investigator (blinded and unblinded) 
and the study facilities on a regular basis throughout the study to verify adherence to 
Good Clinical Practice (GCP) and the protocol, and the completeness, consistency and 
accuracy of the data being entered into the CRFs. The unblinded monitor must also 
ensure that the study drug is being stored, dispensed, and accounted for according to 
specifications. 
The Principal Investigator must ensure that the monitors have direct access to all required 
study data (source documents) during the regular monitoring visits. This includes all 
patient records needed to verify the entries in the CRFs. 
The investigator (blinded and unblinded) must cooperate with the Monitors to ensure that 
any protocol deviations or other issues detected in the course of monitoring visits are 
resolved. 
Monitoring reports (blinded and unblinded) must be written after each monitoring visit, 
per centre and per visit. These monitoring reports must be reviewed and approved by the 
respective supervisors (blinded and unblinded) of the Monitors. 
Monitoring instructions are provided in the Clinical Monitoring Plan. 
9.3 
Audits and inspections 
The study may be audited at any time, with appropriate notification, by qualified 
personnel from the Sponsor or its designees, to assess compliance with the protocol, 
GCP, and regulatory requirements. These audits may also be conducted for quality 
assurance purposes, to ensure that complete and accurate data are submitted, and that all 
AEs are being identified and reported in compliance with the protocol and applicable 
regulations. The study may also be inspected by regulatory authority inspectors, after 
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In the event of an audit or an inspection, the investigators must ensure that direct access 
to all study documentation, including source documents, is granted to the auditors or 
inspectors. 
9.4 
Protocol amendments 
Protocol amendments must be prepared by a representative of the Sponsor, and be 
reviewed and approved by the Project Physician and the Project Statistician. 
All protocol amendments must be submitted to the appropriate IEC/IRB for information 
and approval in accordance with applicable laws and regulations, and to regulatory 
agencies if required. 
Approval of a protocol amendment must be awaited before changes are implemented, 
with the exception of changes necessary to eliminate an immediate hazard to study 
participants, or changes involving only logistical or administrative aspects of the study 
(e.g., changes to monitors, changes to telephone numbers). 
9.5 
Premature termination of the study 
The Sponsor reserves the right to terminate the study at any time. An investigator has the 
right to terminate his or her participation to the study at any time. Should either of these 
events occur, both parties will arrange the necessary procedures after review and 
consultation. 
If the study is to be terminated early, the Sponsor and the investigators must ensure that 
adequate consideration is given to the protection of the interests of all patients enrolled in 
the study. 
9.6 
Publication policy 
The Sponsor is committed to registering all therapeutic studies in a publicly accessible 
clinical trial registry (e.g., www.clinicaltrials.gov), and will ensure that results of these 
studies will be made available to the medical community consistent with applicable laws 
and regulations. 
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 is to be determined by mutual agreement. 
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 must 
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 an investigator. 


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10 
ETHICS AND GOOD CLINICAL PRACTICE 
10.1 
Good Clinical Practice 
The study must be conducted in compliance with this protocol, ICH E6 and any relevant 
supplementary guidance on GCP, and applicable laws and regulations. 
10.2 
Informed consent and assent 
It is the responsibility of the investigators, or a person designated by the investigators 
(if acceptable under local regulations), to obtain prior written informed consent from the 
subject’s parent(s) or LAR 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 LAR that they are completely free to refuse 
consent for the subject to enter the study, and to withdraw the subject 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 centre. 
If appropriate, the subject’s assent to participation in the study should be obtained by the 
investigator, at the same time as consent is obtained from the parent(s)/LAR. It is the 
responsibility of the investigator, after consultation with the parent(s)/LAR, to determine 
whether the subject is capable of forming an opinion and assessing the information 
provided about the study in order to agree to participate. This determination should not be 
based solely on the subject’s age, but should also take into account other factors, 
including the subject’s developmental stage, intellectual capacities, and life experience. 
Appropriate forms for obtaining the subject’s assent to participation in the study will be 
provided by the Sponsor/designee, and reviewed by the IEC/IRB responsible for 
oversight of the study centre. 
If the parent(s) or LAR 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 LAR 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 LAR. 
The CRFs 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 LARs 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. Where the subject’s assent has 
been given, this should also be obtained again after the new information has been 
explained to the subject in appropriate terms. 


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10.3 
Patient confidentiality and data protection 
The investigator (blinded and unblinded) must ensure that patient anonymity is 
maintained, and that patients’ identities are protected from unauthorized parties. This 
includes any electronic data generated during the study. In the CRF, or other documents 
submitted to the Sponsor, patients must be identified only by an identification code, and 
not by name. The investigators must keep a confidential patient identification code list, as 
described in Section 8.3.21 of ICH E6. 
The Sponsor is responsible for ensuring compliance with all applicable data protection 
laws. 
10.4 
Independent Ethics Committees / Institutional Review Boards 
This protocol and any accompanying material provided to the patient, including patient 
information sheets or descriptions of the study used to obtain informed consent, as well 
as any advertising material and information about any compensation provided to the 
patient, must be submitted to an IEC/IRB operating in compliance with ICH E6 and any 
relevant supplementary guidance on GCP, and with applicable laws and regulations. 
Approval from the IEC/IRB must be obtained and documented before starting the study. 
Amendments made to the protocol after receipt of IEC/IRB approval must also be 
submitted to the IEC/IRB in accordance with local procedures and applicable laws and 
regulations. 


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11 
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Agents Chemother 2008; 52: 2974–6. 
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anti-methicillin-resistant Staphylococcus aureus (MRSA) activity of ceftobiprole. 
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(Lynch 2010) Lynch T, Bialy L, Kellner JD, et al. A systematic review on the diagnosis 
of pediatric bacterial pneumonia: when gold is bronze. PLoS One 5:e11989. 
(Michelow 2004) Michelow IC,, Olsen K, Lozano J, et al. Epidemiology and clinical 
characteristics of community-acquired pneumonia in hospitalized children. 
Pediatrics 2004; 113:701–7. 
(Muller 2014) Muller AE, Punt N, Mouton JW. Exposure to ceftobiprole is associated 
with microbiological eradication and clinical cure in patients with nosocomial 
pneumonia. Antimicrob Agents Chemother 2014;58:2512–4. 
(Nicholson 2012) Nicholson SC, Welte T, File TM, Jr., et al. A randomised, double-blind 
trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid 
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(Noel 2008a) Noel GJ, Bush K, Bagchi P, et al. A randomized, double-blind trial 
comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the 
treatment of patients with complicated skin and skin-structure infections. Clin 
Infect Dis. 2008; 46: 647–55. 
(Noel 2008b) Noel GJ, Strauss RS, Amsler K, et al. Results of a double-blind, 
randomized trial of ceftobiprole treatment of complicated skin and skin structure 
infections caused by gram-positive bacteria. Antimicrob Agents Chemother. 2008; 
52: 37–44. 
(Parker 1995) Parker EM, Hutchison M, Blumer JL. The pharmacokinetics of 
meropenem in infants and children: a population analysis. Antimicrob Agents 
Chemother 1995; 36 (Suppl A):63–71. 
(Queenan 2005) Queenan AM and Bush K. Johnson & Johnson Pharmaceutical Res. and 
Dev. L.L.C. Poster Abstract C1-55: Ceftobiprole: Effect on AmpC β-Lactamase 
Induction and Resistance Frequency in Gram-Negative Bacteria. ICAAC 2005 
[data on file]. 
(Queenan 2007) Queenan AM, Shang W, Kania M, et al. Interactions of ceftobiprole with 
beta-lactamases from molecular classes A to D. Antimicrob Agents Chemother 
2007; 51: 3089–95. 
(Queenan 2010) Queenan AM, Shang W, Bush K, et al. Differential selection of single- 
step AmpC or efflux mutants of Pseudomonas aeruginosa by using cefepime, 
ceftazidime, or ceftobiprole. Antimicrob Agents Chemother 2010; 54: 4092–7. 
(Rouse 2007) Rouse MS, Steckelberg JM, and Patel R. In vitro activity of ceftobiprole, 
daptomycin, linezolid, and vancomycin against methicillin-resistant staphylococci 
associated with endocarditis and bone and joint infection. Diagn Microbiol Infect 
Dis 2007; 58: 363–5. 
(Shann 1999) Shann F, Steinhoff MC. 1999. Vaccines for children in rich and poor 
countries. Lancet 354 Suppl 2:S7–S11. 
(Tam 2013) Tam PY. 2013. Approach to common bacterial infections: community- 
acquired pneumonia. Pediatr Clin North Amer 60:437–53. 
(TOX8611) Ceftobiprole medocaril (BAL5788): A subcutaneous toxicity study in 
neonatal and juvenile albino rats. Charles River Laboratories Preclinical Services 
Montreal Inc. Study No. 901275. Document ID No. EDMS-PSDB-9243880; 
J&JPRD (12 Nov 2008). 
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Appendix 1 Rationale for ceftobiprole dosage selection (paediatric population aged 
3 months to < 18 years) 
Overview 
The ceftobiprole doses selected for this study are: 
 
Age group 
Dosing regimen up to a maximum of 500 mg 
3 months to < 2 years 
20 mg/kg as a 4-h infusion q8h 
2 years to < 6 years 
20 mg/kg as a 2-h infusion q8h 
6 years to < 12 years 
15 mg/kg as a 2-h infusion q8h 
12 years to < 18 years 
10 mg/kg as a 2-h infusion q8h 
 
The selection of this dosing regimen was based on the following five considerations: 
1. The level of drug exposure that have been demonstrated to be effective in treating 
HAP and CAP (in adults) 
2. The pharmacokinetic and safety results of a previous single-dose study in paediatric 
subjects aged 3 months to < 18 years (study CSI-1006) 
3. Adverse event profile of ceftobiprole in adults 
4. The results of a toxicity study in juvenile animals 
5. Pharmacokinetic modeling results 
Target drug exposure and efficacy considerations 
Ceftobiprole is a cephalosporin and belongs to the beta-lactam class of antibiotics. For 
beta-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 efficacy*. 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 studies† and in the 
Phase 3 studies in nosocomial pneumonia (BAP248/307)‡ and in community-acquired 
pneumonia (CAP-3001)§. 
Accordingly, considering that ceftobiprole will be used as a broad-spectrum antibiotic, a 
dosing regimen leading to 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. 
 
 
 
 
 
* Craig. Does the dose matter? Clin Infect Dis 2001;33:233–237 
†  Craig. In vivo pharmacodynamics of ceftobiprole against multiple bacterial pathogens in murine thigh and lung 
infection models. Antimicrob Agents Chemother 2008; 52:3492–3496 
‡ Muller. %ft.>MIC predicts probability of clinical outcome in the treatment of nosocomial pneumonia by ceftobiprole. 
ECCMID 2013 Poster P904 
§  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 hours with limited accumulation after 
repeated every 8-hour (q8h) administration. The pharmacokinetics 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 adverse events (AEs) being dysgeusia, nausea 
and vomiting. In pooled safety data from 2 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 q8 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/kg/day [TOX8611]. 
The corresponding exposures are summarized in Table A1. 
Table A1   Exposure to ceftobiprole at the NOAEL in juvenile rats 
 
 
100 mg/kg/day s.c. 
Female rats 
Male rats 
 
Study day 
Approximate 
Cmax 
AUC0-8h 
Cmax 
AUC0-8h 
post-partum 
human equivalent age 
(µg/mL) 
(µg.h/mL) 
(µg/mL) 
(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 
Experience in the paediatric population 
Study CSI-1006 evaluated the pharmacokinetics 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 4 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). 


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In the pharmacokinetic evaluable subset, ceftobiprole volume of distribution and 
systemic clearance increased with age to reach almost healthy-adult historical values in 
the 12 to < 18 years age group [CSI-1006]. 
At the doses administered in this study 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 
pharmacokinetics 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., 62.3%–90.1% [CSI-1004]. 
However, at the doses investigated, in each age group there were children underexposed 
in terms of the PD target [CSI-1006]. Observed pharmacokinetic and pharmacodynamic 
parameters corrected by the free fraction in the different age groups are presented in 
Table A2. 
Table A2 Observed pharmacokinetic  and  pharmacodynamics  parameters 
corrected by the free fraction in the different age groups (study CSI-
1006) 
 
 
Ceftobiprole dose administered as 2-h infusion (single dose) 
 
Age group 
3 months to 
< 2 years 
2 years to 
< 6 years 
6 years to 
< 12 years 
12 years to 
< 18 years 
Investigated doses 
15 mg/kg 
15 mg/kg 
10 mg/kg 
7 mg/kg 
T1/2 (h) 
2.1 (1.1-4.1) 
2.0 (1.6-2.8) 
2.1 (1.5-3.2) 
2.4 (1.9-1.2) 
fCmax (µg/mL) 
18.9 (8.22-41.2) 
22.9 (12.8-35.9) 
21.2 (16.7-26.8) 
14.2 (7.36-19.4) 
fAUC0-8h (µg.h/mL) 
60.4 (25.2-124) 
65.7 (34.0-101) 
61.0 (33.9-77.0) 
45.4 (28.1-61.1) 
fT>MIC = 4 µg/mL (h) 
5.3 (2.8-7.5) 
5.3 (3.4-7.4) 
5.0 (3.5-6.7) 
4.5 (3.0-6.0) 
Number of subjects 
below the target of 
50% of dosing interval 
2 out of 16 
3 out of 15 
1 out of 15 
4 out of 15 
The safety profile observed in study CSI-1006 after single-dose administration of 
ceftobiprole (7 mg/kg to 15 mg/kg) in paediatric subjects receiving other systemic 
antibiotic therapy was generally similar that observed in adults. No new or unexpected 
safety signals associated with study drug were detected. Thirty-one subjects (48%) 
reported at least 1 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 [CSI-1006]. 
Pharmacokinetic modeling 
The modeling strategy was to optimize the dosing regimen (dose, dosing interval and 
infusion duration) for paediatric subjects 3 months – < 18 years in order to maximize 
fT>MIC=4 µg/mL and maintain exposure in the range well tolerated range by adults, and 
below the exposure at the NOAEL in the juvenile rat study [TOX8611] for the 
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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 regimens for paediatric subjects of various age groups are 
summarized in Table A3. 
Table A3   Predicted exposure to ceftobiprole in the various age groups 3 months 
to < 18 years 
 
Age group 
3 months to 
< 2 years 
2 years to 
< 6 years 
6 years to 
< 12 years 
12 years to 
< 18 years 
Number of subjects 
16 
15 
15 
15 
Recommended regimen* 
20 mg/kg 
20 mg/kg 
15 mg/kg over 
10 mg/kg over 
over 4-h q8h 
over 2-h q8h 
2-h q8h 
2-h q8h 
ft>MIC=4 µg/Ml below 50% 
0 
0 
0 
1 
of dosing interval 
Above highest adult Cmax 
0 
0 
0 
0 
Above highest adult AUC 
1 
0 
0 
0 
Above exposure (Cmax and 
AUC) at NOAEL 
0 
0 
0 
0 
* Up to a maximum of 500 mg. 


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Appendix 2 Criteria for evaluating relationship between adverse events and study 
treatment 
NOT RELATED 
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. (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. 
UNLIKELY 
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 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 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 ‘not related’ or 
‘unlikely’, nor the criteria for ‘probable’. An AE would be considered possible if, or 
when e.g.: 
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 
three 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 reappear. 
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 
must be regarded as strong evidence of probable relationship to study drug. 
A causal relationship is suspected for all AEs/SAEs reported with a relationship of 
‘possible’ or ‘probable’ and those with missing or unknown relationships. 


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Appendix 3 
Investigator’s protocol signature page 
BASILEA 
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
Protocol 
BPR-PIP-002 Version 3.0 
Basilea Product: 
Ceftobiprole 
 
 
A multicentre, randomized, investigator-blind, active-controlled study to 
evaluate the safety, tolerability, pharmacokinetics and efficacy of 
Protocol Title: 
ceftobiprole versus intravenous standard-of-care cephalosporin treatment 
with or without vancomycin in paediatric patients aged from 3 months to 
less than 18 years with hospital-acquired pneumonia or community- 
acquired pneumonia requiring hospitalisation 
 
 
Basilea Pharmaceutica International Ltd 
Approval Date: 
29 November 2018 
By (Project Physician): 
 
MPH 
 
 
Name of Principal Investigator: 
Study Centre: 
I agree to the conditions relating to this study as set out in the above named Protocol and Study 
Procedures. I fully understand that any changes instituted by the investigator(s) without previous 
discussion with the Sponsor’s Project Clinician, Clinical Pharmacologist and Biostatistician (only 
if required) would constitute a violation of the protocol, including any ancillary studies or 
procedures performed on study subjects (other than those procedures necessary for the well-being 
of the subjects). 
I agree to follow International Conference on Harmonisation (ICH) guidelines for good clinical 
practice (GCP), including the EU Clinical Trial Directive 2001/20/EC and specifically, obtain 
approval from the Ethics Committee prior to study start, allow direct access to source documents 
and agree to inspection by auditors from Basilea and regulatory authorities, as required by ICH 
GCP. I will ensure that the investigational product(s) supplied by the Sponsor will be used only as 
described in the above named protocol; if any other use is desired, written permission must be 
obtained from the Sponsor. 
I acknowledge that I have read the protocol for this study, and I agree to carry out all of its 
terms in accordance with applicable laws and regulations. 
To be signed by Principal Investigator and Sub-Investigators (at minimum): 
Please print names and dates next to the corresponding signatures 
 
 
Signature 
Name 
Date 
 
 
 
 
Principal Investigator 
 
 
 
Sub/Co-Investigator 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Ceftobiprole 
BPR-PIP-002 
Sponsor: 
Study title: 
Study number: 
SAP version: 
Name/Title 
Confidentiality statement: 
(basilea) 
PHAIIMACEUTICA 
Basilea Pharmaceutica International Ltd. 
Version 2.0 
02 March 2020 
A multicentre, randomized, investigator-blind, 
active-controlled study to evaluate the safety, 
tolerability, pharmacokinetics and efficacy of 
ceftobiprole versus intravenous standard-of-care 
cephalosporin treatment with or without vancomycin 
in paediatric patients aged from 3 months to less than 
18 years with hospital-acquired pneumonia or 
community-acquired pneumonia requiring 
hospitalisation 
BPR-PIP-002 
Final 2.0 - 02 March 2020 
Date 
03NIIY	ioio 
o")dll-ft ?o'2o 
03 
Signature 
•
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.
Confidential - Proprietary information of Basilea Pharmaceutica International Ltd. 
1/15 
NCT03439124


Statistical Analysis Plan 
Ceftobiprole  
BPR-PIP-002  
 
Version 2.0 
02 March 2020 
 
 
 
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2/15 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS..................................................................................................................................... 3 
1 
Introduction ...................................................................................................................................................... 4 
1.1 Change from planned analysis ............................................................................................................... 4 
2 
Study Objectives, endpoints and Design......................................................................................................... 4 
2.1 Study Objectives ..................................................................................................................................... 4 
2.1.1 
Primary objective ....................................................................................................................... 4 
2.1.2 
Secondary objectives ................................................................................................................. 4 
2.2 Study Endpoints ...................................................................................................................................... 4 
2.2.1 
Primary endpoint ........................................................................................................................ 4 
2.2.2 
Secondary endpoints ................................................................................................................. 4 
2.3 Study Design ........................................................................................................................................... 5 
2.3.1 
Study design and sample size ................................................................................................... 5 
2.3.2 
Assessments.............................................................................................................................. 5 
2.3.3 
Interim analyses ......................................................................................................................... 8 
3 
Analysis populations ........................................................................................................................................ 8 
3.1 Safety Population .................................................................................................................................... 8 
3.2 Intent-to-treat (ITT) Population ............................................................................................................... 8 
3.3 Clinically Evaluable (CE) Population ...................................................................................................... 8 
3.4 Microbiological Intent-to-treat (mITT) Population ................................................................................... 8 
3.5 Microbiologically Evaluable (ME) Population .......................................................................................... 8 
3.6 Pharmacokinetic (PK) Population ........................................................................................................... 8 
4 
Statistical Considerations and analysis ........................................................................................................... 8 
4.1 General Considerations .......................................................................................................................... 8 
4.2 Derived Variables.................................................................................................................................... 9 
4.3 Handling of Missing Data and/or Invalid Data and Outliers .................................................................... 9 
4.4 Handling of Mis-stratification and Incorrect Treatment ......................................................................... 10 
4.5 Valid Pathogens .................................................................................................................................... 10 
5 
Statistical plan and methods ......................................................................................................................... 12 
5.1 Background Characteristics .................................................................................................................. 12 
5.1.1 
Patient disposition .................................................................................................................... 12 
5.1.2 
Protocol deviations .................................................................................................................. 12 
5.2 Demographics and Other Baseline Characteristics .............................................................................. 12 
5.2.1 
Demographics .......................................................................................................................... 12 
5.2.2 
Medical history ......................................................................................................................... 13 
5.3 Prior and Concomitant Medications ...................................................................................................... 13 
5.4 Treatment Compliance and Exposure .................................................................................................. 13 
5.5 Primary and secondary endpoint analysis ............................................................................................ 14 
5.5.1 
Primary endpoint analysis ........................................................................................................ 14 
5.5.2 
Secondary endpoint analysis ................................................................................................... 14 
5.6 Safety Analysis ..................................................................................................................................... 15 
5.7 Clinical Laboratory Evaluations ............................................................................................................ 15 
5.8 Vital Signs ............................................................................................................................................. 15 
5.9 Physical Examination ............................................................................................................................ 15 
6 
References .................................................................................................................................................... 15 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
CAP 
Community-acquired Pneumonia 
CE 
Clinically Evaluable 
CI 
Confidence Interval 
DSMB 
Data and Safety Monitoring Board 
EOT 
End-of-treatment 
HAP 
Hospital-acquired Pneumonia 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFU 
Last Follow-up 
ME 
Microbiologically Evaluable 
mITT 
Microbiological Intent-to-treat 
PIP 
Paediatric Investigation Plan 
PK 
Pharmacokinetic(s) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TOC 
Test-of-cure 
WBC 
White Blood Cell Count 
 
 
 


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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-002, version 3.0, dated 29 Nov 2018. The SAP version 1.0 has been 
amended to reflect the changes introduced in this latest version of the protocol. 
 
1.1 
Change from planned analysis 
Considering the number of patients in the mITT and ME analysis populations, the microbiological 
data will only be listed. 
 
2 
STUDY OBJECTIVES, ENDPOINTS AND DESIGN 
2.1 
Study Objectives 
2.1.1 Primary objective 
The primary objective of this study is to characterise the safety profile of ceftobiprole in paediatric 
patients with hospital-acquired pneumonia (HAP) or community-acquired pneumonia (CAP) requiring 
hospitalisation and IV antibiotic therapy. 
2.1.2 Secondary objectives 
The secondary objectives of this study in paediatric patients with HAP or CAP requiring hospitalisation 
are: 
• 
To compare the clinical cure rate and microbiological eradication rate at the test-of-cure (TOC) 
visit between ceftobiprole and intravenous (IV) standard-of-care cephalosporin treatment 
(± vancomycin) 
• 
To compare the clinical and microbiological relapse rates at the last follow-up (LFU) visit between 
ceftobiprole and IV standard-of-care cephalosporin treatment (± vancomycin) 
• 
To characterise other efficacy measures of ceftobiprole (e.g., improvement in signs and 
symptoms of pneumonia, length of hospital stay) 
• 
To assess the pharmacokinetics (PK) of ceftobiprole 
2.2 
Study Endpoints 
2.2.1 Primary endpoint 
The primary endpoint is: 
Analysis of adverse events (AEs) assessed on each of the first 3 days of study-drug treatment, and at 
the end-of-treatment (EOT), TOC, and LFU visits (Safety population). Other timepoints may also be 
analysed. 
2.2.2 Secondary endpoints 
Secondary endpoints are: 
2.2.2.1 Efficacy 
• 
Comparison of clinical cure rates (intent-to-treat [ITT] and clinically evaluable [CE] populations) 
between ceftobiprole and the comparator at the TOC and LFU visits 


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• 
Comparison 
of 
microbiological 
eradication 
rates 
(microbiological 
ITT 
[mITT] 
and 
microbiologically evaluable [ME] populations) between ceftobiprole and the comparator at the 
TOC and LFU visits 
• 
Comparison of clinical response at study Day 4 and at the EOT visit (ITT and CE populations) 
• 
Comparison of the clinical and microbiological relapse rates at the LFU visit (ITT, CE, mITT, and 
ME populations) 
2.2.2.2 Pharmacokinetics 
• 
Descriptive analysis of ceftobiprole plasma concentration per time point, based on PK sampling 
in at least 15 patients in each of the two age categories of <6 years and ≥6 years (PK population). 
2.3 
Study Design 
2.3.1 Study design and sample size 
This is a randomized, investigator-blind, multiple-fixed dose, active-controlled multicentre study to be 
carried out in 138 paediatric patients (minimum of 125 evaluable patients) aged 3 months to <18 years, 
diagnosed with either HAP or CAP, requiring hospitalisation and treatment with systemic antibiotics. 
Randomization will be stratified by four age groups (3 months to <2 years; 2 years to <6 years; 6 years 
to <12 years; 12 years to <18 years), and by diagnosis of HAP or CAP. Patients will be randomized 2:1 
within each group to receive either ceftobiprole or the comparator standard-of-care IV cephalosporin 
antibiotic (ceftazidime with or without vancomycin for patients with HAP; ceftriaxone with or without 
vancomycin for patients with CAP). At least 50 patients are planned to be enrolled in each of the age 
categories <6 years and ≥6 years. There is no requirement for a minimum number of patients with each 
infection type (HAP or CAP) 
2.3.2 Assessments 
Table 1 presents a summary of the schedule of assessments that are to be performed from Screening 
to the final post-treatment visit. 
Table 1:  
Schedule of Assessments 
Assessment 
Study 
Day 
Screening 
Active treatment 
EOT* 
TOC 
LFU** 
Day −1 to 
1 
Day 1 
Days 
2–3 
Day 
4 
Days 
5–7 
Day 
8–14 
 
7–14 days 
after EOT 
28–35 days  
after EOT 
Written informed 
consent1 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
Prior medications2 
X 
 
 
 
 
 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
X 
 
 
Physical examination  
X 
 
 
X 
 
 
X 
 
 
Laboratory tests4 
X 
 
 
X 
 
 
X 
X 
 
Haptoglobin5 
X 
 
 
X 
 
 
X 
 
 
Direct antiglobulin 
(Coombs) test6 
X 
 
 
 
 
 
 
X 
 
Vital signs and pulse 
oximetry7 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Pneumonia signs and 
symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical pneumonia 
outcome assessment8 
 
 
 
X 
 
 
X 
 
 
Study medication 
 
X 
X 
X 
X 
X 
 
 
 
Eligibility for IV to oral 
switch 
 
 
 
X 
X 
X 
 
 
 
Concomitant 
medication9 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events10 
 
◄----- continuous from time of first study drug administration------► 
Imaging11 
X 
 
 
 
 
 
 
 
 
Microbiological 
sampling12 
X 
 
 
 
 
 
X 
X 
X 
Overall 
microbiological 
outcome 
 
 
 
 
 
 
 
X 
X 
Overall clinical 
outcome13 
 
 
 
 
 
 
 
X 
X 
PK sampling14 
 
 
X 
 
 
 
 
 
 
Treatment/hospitalisat
ion setting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 The informed consent form (and the assent form where appropriate) must be signed before any study procedures 
take place. 
2  Prior medications taken up to 14 days before Screening are to be recorded. 
3  Pregnancy testing must be conducted for all menarcheal female patients. If results of the pregnancy test are positive 
at Screening, the patient must not be randomized in the study. 
4  Laboratory tests include haematology, biochemistry, and urinalysis. 
5  For children aged 6 years and older and in younger patients not treated with vancomycin. 
6  For children aged 6 years and older and in younger patients not treated with vancomycin. 
7  Vital signs (including body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures) and 
pulse oximetry must be recorded three times daily during the active study drug treatment period. Vital signs and 
pulse oximetry must also be obtained at the EOT visit and the TOC visit. Weight will be assessed at Screening, and 
EOT. Height is to be assessed only at Screening. 
8 On Day 4 and at the EOT visit, the Blinded Investigator must make an overall clinical assessment of pneumonia as 
being worsened, unchanged, improved, or cured. 
9  All medications taken since the recording of prior medications, and medications continued at entry into the study, 
should be recorded as concomitant therapy. 
10  Non-serious changes in, or worsening of, a patient’s condition that occur between informed consent and first study-
drug administration are to be collected as pre-dose medical history. If any such occurrence is considered to be 
serious, it will additionally be reported following the procedures of an SAE, to allow for an assessment of serious 
procedure-related events. All AEs occurring from the time of first study-drug administration to the LFU visit must be 
collected in accordance with the procedures outlined in the protocol. 
11 Screening imaging (e.g., X-ray, ultrasound, or computer tomography) does not need to be repeated if it was 
performed within 24 hours of informed consent; post-baseline imaging may be obtained as clinically indicated. 
12 Blood samples for culture and Gram stain are to be obtained at Screening if feasible. Post-baseline blood cultures 
should be obtained as clinically indicated according to local practice during therapy, at EOT, and at the TOC. At the 
LFU visit, sampling is only to be undertaken if considered necessary by the Blinded Investigator to evaluate 
microbiological relapse (need for further antibiotic treatment). 
13 At the TOC visit, the Blinded Investigator must rate the overall clinical outcome of therapy as clinical cure, clinical 
failure, or clinically unevaluable. At the LFU visit, for patients with TOC outcomes of clinical cure, an assessment of 
relapse must be performed. 
14  Blood samples (200–300 µL) are to be taken on Day 3 at the following time points: Children aged 2 years and older 
– pre-dose, and at 2h (end of infusion), 4h, 6h, and 8h after start of infusion; children aged less than 2 years – pre-
dose and at 4h (end of infusion), 6h, and 8h after start of infusion. 


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* EOT assessment is to be performed within 24 hours after the last study drug administration. If a patient withdraws 
prematurely, EOT visit laboratory/safety tests are to be conducted within 1 week of patient's withdrawal. 
** The LFU visit will be performed by telephone contact unless an examination is needed to evaluate relapse or 
abnormalities at the TOC assessment. The overall clinical outcome of relapse will only be assessed for patients 
with an outcome of ‘clinical cure’, and the assessment of microbiological relapse will only be performed for patients 
with outcomes of ‘microbiological eradication’ or ‘presumed microbiological eradication’. 
 
 
 


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2.3.3 Interim analyses 
An interim analysis of safety data will be performed by the Data Safety Monitoring Board (DSMB) after 
randomization of approximately 50 patients. The interim analysis as documented in the DSMB charter 
will focus on the safety of the subjects while the final analysis which is described in this document will 
include safety as well as efficacy endpoints. 
In order to maintain blinding during the interim analyses, the following approaches will be adopted: 
• 
Treatment groups will be identified by codes (A and B) in the interim analyses 
• 
Blinded and unblinded statisticians/programmers will be assigned to the study 
• 
Datasets that could lead to unblinding (EX, LB and PK) will only be available to the unblinded 
members of the team 
The timing of data cut, analysis populations and other relevant information for the interim analysis can 
be found in the DSMB Charter for this study. 
 
3 
ANALYSIS POPULATIONS 
3.1 
Safety Population 
All randomized patients who received at least one dose of study drug, analysed according to the first 
treatment actually received. 
3.2 
Intent-to-treat (ITT) Population 
All randomized patients, analysed by treatment assigned. Should ITT and safety populations be 
identical, then all analyses would be performed for the ITT/safety population.    
3.3 
Clinically Evaluable (CE) Population 
The CE population will be the subset of patients in the ITT population who have complied with 
important aspects of the study until TOC visit, i.e., with no major protocol deviations (e.g., had a valid 
clinical outcome assessment at TOC, no systemic non-study antibiotic therapy, etc…).  
Major protocol deviations will be identified prior to the database lock and study unblinding. 
3.4 
Microbiological Intent-to-treat (mITT) Population 
All patients in the ITT analysis population with a valid pathogen identified at baseline. 
3.5 
Microbiologically Evaluable (ME) Population 
All patients in the CE analysis population with a valid pathogen at baseline and a microbiological 
assessment at TOC. 
3.6 
Pharmacokinetic (PK) Population 
All patients who received at least one dose of ceftobiprole and have at least one plasma concentration 
measurement obtained by the appropriate methodology. 
 
4 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
4.1 
General Considerations 
Study results will be presented according to the following groups: 


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• 
Group 1: Patients aged 3 months to <2 years with CAP 
• 
Group 2: Patients aged 2 years to <6 years with CAP 
• 
Group 3: Patients aged 6 years to <12 years with CAP 
• 
Group 4: Patients aged 12 years to <18 years with CAP 
• 
CAP Overall 
• 
HAP Overall 
No formal hypothesis testing will be performed. Descriptive statistics will be applied to the primary 
variable, with frequency tables used to characterise the safety profile of ceftobiprole, and the numbers 
of patients with adverse changes in laboratory test results, vital signs, and physical examination results. 
The secondary variable of clinical cure will be compared between ceftobiprole and the standard-of-
care comparator IV antibiotic treatment. The between-group difference, along with the respective 
95% CI, will be displayed at the study time points Day 4, EOT, and TOC. 
4.2 
Derived Variables 
The following derived variables will be applied throughout the study: 
 
• 
Baseline is defined as the last available assessment prior to first dose intake (including 
unscheduled assessments). 
 
• 
Last/Final for safety is the first available value after treatment or, if not available, then 
immediately before last treatment (but not before first treatment). 
 
• 
Adverse event duration (in days) will be calculated as (the times will not be considered): Event 
end date - Event onset date + 1. 
 
• 
The following algorithm will be used for the study day determination: 
 
o 
Day 1 = Day of first 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. 
 
 
• 
To reflect the birth date collection requirement for paediatric studies, age, expressed in years, 
will be calculated as follow: 
 
o 
if full date of birth collected:  integer part of (consent date - date of birth)/365.25. 
o 
if only year of birth collected: consent year - year of birth 
 
• 
Duration of exposure (in days) will be calculated as: Date of last study drug administration – 
Date of first study drug administration + 1. 
 
4.3 
Handling of Missing Data and/or Invalid Data and Outliers 
When calculating the clinical outcome of therapy, subjects assessed as clinically unevaluable or 
withdrawn from the study before the TOC visit but after at least one treatment with study drug will be 
counted as clinical failure. 


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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 treatment. In 
case this leads to inconsistencies with other available patient’s data, the imputation values will 
be handled on a case-by-case basis. 
• 
If both the day and month are missing, they are imputed to be June 30 if not in year of treatment. 
In case this leads to inconsistencies with other available patient’s data, the imputation values 
will be handled on a case-by-case basis. 
• 
Missing years will be left as missing. 
• 
Missing time will be replaced by ’00:00’ for start times and ’23:59’ for end times if time is 
required. 
• 
Missing minutes will be replaced by ‘00’ for start times and ‘59’ for end times times if time is 
required. 
4.4 
Handling of Mis-stratification and Incorrect Treatment 
In the case that a patient is stratified into the wrong stratum during randomization, the patient will be 
analysed based on the actual stratum depending on age and diagnosis. However, in the case that a 
patient is treated with a treatment other than the randomized treatment, the analyses will proceed as 
follows: 
• 
For the Safety population, the patient will be analysed according to actual treatment received. 
• 
For the ITT population, the patient will be analysed according to the treatment the patient was 
randomized to. 
• 
For the CE and ME populations, the patient will be excluded from analysis. 
4.5 
Valid Pathogens 
For assignment to the ME or the mITT population, the following pathogens will be considered: 
• 
Staphylococcus aureus  
• 
Streptococcus pneumoniae  
• 
Streptococcus species  
• 
Pseudomonas aeruginosa  
• 
Escherichia coli  
• 
Moraxella catarrhalis 
• 
Klebsiella species  
• 
Haemophilus influenzae  
• 
Haemophilus parainfluenzae 
• 
Mycoplasma pneumoniae 
• 
Chlamydia pneumoniae 
• 
Burkholderia cepacia complex 
• 
Bordetella pertussis 
• 
Enterobacter species  
• 
Citrobacter species  
• 
Prevotella species 
• 
Nocardia species  
• 
Legionella species 
• 
Serratia species 
• 
Acinetobacter calcoaceticus 
• 
Acinetobacter baumannii 


Statistical Analysis Plan 
Ceftobiprole  
BPR-PIP-002  
 
Version 2.0 
02 March 2020 
 
 
 
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• 
Stenotrophomonas maltophilia 
 
This list is not exhaustive and may be updated prior to database lock. A listing of subjects with any 
identified pathogens will be provided. 
 


Statistical Analysis Plan 
Ceftobiprole  
BPR-PIP-002  
 
Version 2.0 
02 March 2020 
 
 
 
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd. 
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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). 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. 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. 
The following international dictionaries will be used for medical coding: 
• Medical History events:  MedDRA (version 20.1 or above) 
• Medications:  WHO Drug Dictionary Enhanced (March 2017 version or above) 
• Adverse events:  MedDRA (version 20.1 or above) 
• Concomitant procedures:  MedDRA (version 20.1 or above) 
Data from all participating study centers will be combined for analysis. 
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. 
Inclusion and exclusion criteria deviations and patient enrollment eligibility will be presented by dose 
cohort and patient in data listings. 
5.1.2 Protocol deviations 
All protocol deviations reported by the clinical team will be tabulated and presented in a data listing 
sorted by center, category and patient.  
Major protocol deviations are defined as those that could potentially bias either the efficacy 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 to 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 by treatment group. The following baseline 
demographic data will be presented: 
• 
Age [years] at consent 
o Continuous summary 
• 
Sex 
o Categorical summary (Male, Female) 
• 
Race 


Statistical Analysis Plan 
Ceftobiprole  
BPR-PIP-002  
 
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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 [kg] 
o Continuous summary 
5.2.2 Medical history 
Medical history of other diseases will be summarized in tables by treatment groups, 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 treatment groups, 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 
The overall exposure to study drug adjusted by baseline weight will be summarized by treatment 
group, age group and infection type. The total dose taken at specific time points and at the end of the 
study will be presented. 
Treatment compliance per administration will be computed as:  
Compliance [%] = (actual dose (mg) / planned dose (mg))*100. 
Overall treatment compliance for intravenous treatment for each subject will be computed as the total 
dose administered (mg) / total planned dose (mg)) *100 and summarized. 


Statistical Analysis Plan 
Ceftobiprole  
BPR-PIP-002  
 
Version 2.0 
02 March 2020 
 
 
 
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In addition, the duration of intravenous and oral treatments (for subjects who switched to oral 
treatment) as well as the time-to-switch will be summarized. 
5.5 
Primary and secondary endpoint analysis 
5.5.1 Primary endpoint analysis 
The primary endpoint of this study is the analysis of adverse events assessed on each of the first 
3 days of study-drug treatment, and at the end-of-treatment, test-of-cure and last follow-up visits. A 
summary table will be presented for all adverse events by treatment group, age group and infection 
type. This will be done for the Safety population. 
Adverse events will be presented cumulatively. In addition, a summary of all adverse events 
experienced while patients are on IV therapy irrespective of when they switch treatment will be 
presented. 
5.5.2 Secondary endpoint analysis 
For the secondary endpoints, some efficacy analysis will be computed based on some pre-planned 
efficacy evaluations which can be found in the study protocol. No formal hypothesis tests are 
planned. 
5.5.2.1 Clinical cure rate 
Clinical cure is defined as signs and symptoms of pneumonia normalized or improved to an extent 
that further antibiotic therapy is not necessary, with lack of progression of chest X-ray abnormalities 
post-baseline if these are available. As the protocol does not require repeat chest X-rays after 
screening unless clinically indicated, patients with clinical improvement without a repeat chest X-ray 
would be considered to have lack of progression of X-ray abnormalities. This endpoint will use the 
difference of proportions to assess the difference in the clinical cure rate between the treatment 
groups at the TOC visit. The 95% confidence interval using the Exact method will also be computed. 
This will be done for both the ITT and the CE populations. All analysis will be done by infection type 
and overall. 
5.5.2.2 Clinical relapse  
The clinical relapse rate and presumed relapse rate (ITT and CE) between treatment groups at the 
LFU visit will also be compared using difference of proportions. The 95% confidence interval will be 
computed using the Exact method.  
5.5.2.3 Other efficacy analysis 
Descriptive statistics will be presented for changes from baseline in signs and symptoms and in 
overall clinical status. Duration of hospitalisation, defined as the time from start of study drug therapy 
to discharge, will also be analysed by descriptive statistics and by a time-to-event analysis. 
Re-hospitalizations will not be considered in the calculation of duration of hospitalization. 
The other efficacy data collected e.g. microbiological assessments alongside any valid pathogens 
and resistance will be listed.  
5.5.2.4 Pharmacokinetic analysis 
Plasma concentrations of ceftobiprole, ceftobiprole medocaril, and open-ring metabolite will be 
summarized by descriptive statistics. This analysis will be done by age group (3 months to <2 years, 
2 years to <6 years, 6 years to <12 years, 12 years to <18 years). 


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Ceftobiprole  
BPR-PIP-002  
 
Version 2.0 
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Further pharmacokinetic data analyses will be described and summarized separately. 
5.6 
Safety Analysis 
Definitions of adverse events (AEs) and serious adverse events (SAEs) as well as information on 
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 or above) 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/unlikely/possible/ probable) 
 
Summary tables for all adverse events and for adverse events by severity will be split by treatment 
group, age groups, infection type and overall. 
5.7 
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. 
Where reference indicators (low/high, negative/positive or normal/abnormal) are present however, 
shift tables will, in addition be presented to show shifts from baseline values at the different time points. 
Adverse changes from baseline to first post-dose results will also be summarized. 
5.8 
Vital Signs 
The actual and change from baseline values of the following vital signs will be summarized using 
descriptive statistics. In addition, change from baseline values for patients with values outside marked 
reference range will also be summarized. 
• 
Systolic blood pressure 
• 
Diastolic blood pressure 
• 
Pulse rate 
• 
Temperature 
• 
Respiration rate 
 
5.9 
Physical Examination 
Abnormal results in physical examinations will be summarized by visit while all data will be listed. 
6 
REFERENCES 
• 
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.