Clinical trial NCT03138733
Conditions: Staphylococcus Aureus Bacteremia
Keywords: Ceftobiprole, daptomycin, Staphylococcus aureus Bacteremia, bloodstream infection
Sponsor: Basilea Pharmaceutica
Start date: 2018-08-26; Completion date: 2022-03-11
Enrollment: 390 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to compare the efficacy and safety of ceftobiprole medocaril versus a comparator in the treatment of patients with complicated Staphylococcus aureus bacteremia (SAB).

Detailed description:
Patients were randomized 1:1 to ceftobiprole or the comparator regimen. Randomization was stratified by study site, dialysis status, and prior antibacterial treatment use within 7 days before randomization.

The three phases of the study were:

1. Screening assessments of up to 72 hours prior to randomization
2. Randomization and subsequent active treatment with intravenous (i.v.) study drug (ceftobiprole or daptomycin ± aztreonam).
3. Post-treatment, comprising an end of trial (EOT) visit (within 72 hours of last study-drug administration), Day 35 (± 3 days), Day 42 (± 3 days), and a post-treatment evaluation (PTE) visit on Day 70 (± 5 days) post-randomization.

Arms: arm 1: Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) arm 2: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards), with or without aztreonam
Interventions: intervention 1: Ceftobiprole medocaril intervention 2: Daptomycin
Intervention descriptions: intervention 1: Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) as a 2 h infusion intervention 2: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
BPR-CS-009
Ceftobiprole medocaril
A randomized, double-blind, multi-center study to establish the efficacy and 
safety of ceftobiprole medocaril compared to daptomycin in the treatment of 
Staphylococcus aureus bacteremia, including infective endocarditis
Protocol Number/Version:
BPR-CS-009 / Version 9.0
Compound
Ceftobiprole medocaril
Phase of Development
3
IND number:
64,407
EudraCT number:
2017-001699-43
Date: 
27 February 2020
Sponsor:
Basilea Pharmaceutica International Ltd.
Grenzacherstrasse 487
CH-4058 Basel/Switzerland
Tel + 41 61 606 1111
Confidentiality statement
All information contained in this document is confidential and proprietary information of Basilea 
Pharmaceutica International Ltd (‘Basilea’). This information is provided to you on a confidential basis as an 
investigator or potential investigator, for review by you, and for potential future discussion with an applicable 
Independent Ethics Committee / Institutional Review Board as needed. It may otherwise not be disclosed by 
you to any third party other than those members of your staff who have a need to know, without prior written 
authorization from Basilea, except to the extent necessary to obtain informed consent from potential 
participants in the clinical study to which the document refers. If it is determined that disclosure to another third 
party is required by applicable law or regulations, the person to whom the information is disclosed must be 
informed that the information is confidential, and that it may not be further disclosed without prior written 
authorization from Basilea.


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SPONSOR SIGNATURES
Protocol Number/Version:
BPR-CS-009 / Version 9.0
Protocol title
A randomized, double-blind, multi-center study to establish 
the efficacy and safety of ceftobiprole medocaril compared 
to daptomycin in the treatment of Staphylococcus aureus
bacteremia, including infective endocarditis
Compound
Ceftobiprole medocaril
Phase of Development
3
Date: 
27 February 2020
Sponsor:
Basilea Pharmaceutica International Ltd.
Grenzacherstrasse 487
CH-4058 Basel/Switzerland
Tel + 41 61 606 1111


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Protocol Synopsis
TITLE
A randomized, double-blind, multi-center study to establish the
efficacy and safety of ceftobiprole medocaril compared to daptomycin
in the treatment of Staphylococcus aureus bacteremia, including
infective endocarditis
SPONSOR:
Basilea Pharmaceutica International Ltd. (hereinafter ‘Basilea’)
STUDY PHASE:
3
INDICATION:
Staphylococcus aureus bacteremia, including infective endocarditis
U.S. IND NUMBER:
64,407
EUDRACT NUMBER:
2017-001699-43
PROTOCOL NUMBER:
BPR-CS-009 Version 9.0
OBJECTIVES 
Primary objective
To demonstrate the non-inferiority of ceftobiprole to daptomycin for overall success as assessed by 
an independent Data Review Committee (DRC) in the treatment of S. aureus bacteremia (SAB), 
including infective endocarditis (IE), at the post-treatment evaluation (PTE) visit* in the modified 
intent-to-treat (mITT) population.
Secondary objectives

To compare ceftobiprole with daptomycin with respect to:
1. All-cause mortality through Day 70 (PTE visit) and Day 28 in the intent-to-treat (ITT) and 
mITT populations.
2. Microbiological eradication rates (negative blood culture for S. aureus) at Day 4, Day 8, and 
the end-of-treatment (EOT) and PTE visits.
3. Overall success rates in the mITT, ITT, and clinically evaluable (CE) populations:
a) at the EOT and PTE visits (ITT and CE populations only)
b) at the EOT and PTE visits, for IE vs non-IE SAB
c) at the EOT and PTE visits, by renal-function status
4. Development of new metastatic foci, or other complications of SAB, after Day 7.
5. Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-culture-
negative for S. aureus, obtained at least 24 h after the first negative blood-culture.
6. Safety and tolerability (Safety population).

To assess the pharmacokinetics (PK) of ceftobiprole.
                                                
* The PTE visit will be performed 70 days (± 5 days) after randomization.


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STUDY DESIGN
Randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-center study in 
adult hospitalized (in a hospital or equivalent medical confinement or clinical research unit) patients
with SAB, including IE.
In the first part of the study, the maximum duration of study antibacterial treatment was limited to 
28 days. Following an interim safety analysis, this treatment duration is extended up to 42 days (i.e., 
21–42 days).
PLANNED SAMPLE SIZE
Approximately 390 patients will be randomized at a 1:1 ratio to ceftobiprole or daptomycin.
PATIENT INCLUSION CRITERIA
Patients meeting all of inclusion criteria 1–5 and at least one of inclusion criteria 6–11 will be 
eligible for enrollment.
1. Male or female ≥ 18 years of age.
2. Informed consent signed by the patient (or by their legally acceptable representative, if 
appropriate) indicating that they understand the purpose of, and procedures required for, the 
study and are willing to participate in the study.
3. SAB, based on at least one S. aureus-positive blood culture obtained within the 72 h prior to 
randomization:
(a) identified by culture laboratory report, or
(b)positive diagnostic test for S. aureus (e.g., polymerase chain reaction [PCR], tube coagulase 
test and fluorescent in situ hybridization [FISH]) obtained from a blood culture.
Note: The microbiological work-up of the blood culture may:

Occur prior to informed consent to participation in the study (see Section 5.2.1 and Table 7).

Be undertaken either on-site or in an external microbiology laboratory specifically appointed for 
the purposes of this study.

Use a diagnostic test:
–
routinely performed locally for the detection of S. aureus from blood cultures
or
–
provided to the laboratory for the purpose of this study, if the test has regulatory approval in 
the country where the test is being performed
Regardless of diagnostic method, every effort should be made to isolate and send all unique organisms 
from blood to the Central Microbiology Laboratory; this applies particularly to the S. aureus isolated 
from blood at the Screening visit. The Central Microbiology Laboratory will re-identify all isolates, 
with the results to be used to determine whether the patient meets the study inclusion criteria. 
Nevertheless, patients without a Central Microbiology Laboratory assessment may be included in the 
mITT population if there is unequivocal documented evidence of a baseline blood culture positive for 
S. aureus at the local laboratory.


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4. At least one of the following signs or symptoms of bacteremia within the 72 h prior to 
randomization (may be based on measurements obtained before or after informed consent but 
within the 72 h prior to randomization):
(a) fever > 38 °C / 100.4 °F measured orally, > 38.5 °C / 101.3 °F measured tympanically, 
> 37.5° C / 99.5 °F measured by axillary method, or > 39 °C / 102.2 °F measured rectally
(b)white blood cell (WBC) count > 10.0 × 109/L, or < 4.0 × 109/L, or > 10% immature 
neutrophils (bands)
(c) tachycardia (heart rate > 90 bpm)
(d)hypotension (systolic blood pressure < 90 mmHg)
5. Required duration of study antibacterial treatment ≤ 42 days.
6. SAB in patients undergoing chronic intermittent hemodialysis or peritoneal dialysis.
7. Persistent SAB: documented failure of bloodstream clearance, defined as a positive blood culture 
for S. aureus within the 72 h prior to randomization, after prior appropriate anti-staphylococcal 
treatment (except failure under daptomycin therapy) of at least 3 complete days.
8. Other forms of complicated SAB, including the following: 
(a) Acute bacterial skin or skin-structure infections (ABSSSIs)
(b) Metastatic infection of native tissue. Examples include but are not limited to:

Septic arthritis or bacterial joint infection/empyema

Septic or suppurative thrombophlebitis

Visceral soft-tissue abscesses requiring ≤ 42 days of study antibacterial treatment

Septic pulmonary emboli/infarction
Note: The diagnosis of a septic pulmonary embolism will be made by the investigator based on 
clinical symptoms of fever, cough, sputum/hemoptysis in the presence of an extrapulmonary 
infection, sepsis, or risk factors for septic emboli (e.g., intravenous drug use) and will be based on 
the following radiological signs:
Contrast-enhanced CT (preferred):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of cavitation) or wedge-
shaped infiltrates 
–
with/without a feeding vessel sign (vessel leading to the nodule)
–
with/without pleural effusion or features suggestive of pleural empyema
Non-contrast enhanced CT (e.g., in patients with a contraindication for contrast administration):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of cavitation) or wedge-
shaped infiltrates 
–
with/without pleural effusion or features suggestive of pleural empyema
Plain X-ray (e.g., in patients unable to undergo a CT):
Multifocal nodular densities or wedge-shaped infiltrates in varying stages of cavitation with or 
without pleural effusion or features suggestive of pleural empyema


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9. Definite native-valve right-sided IE (RIE) by Modified Duke’s Criteria.
Note: Patients with left-sided infective endocarditis (LIE) are excluded from the study. If LIE is diagnosed 
after onset of study therapy, patients may be maintained in the study. In the event that the investigator 
decides to discontinue the study therapy, the patient will be included in the mITT population and 
considered a failure. 
The minimum requirements for a diagnosis of RIE and LIE (Modified Duke’s Criteria), and the minimum 
diagnostic requirements for other forms of complicated SAB, are provided in Appendix 1 and Appendix 2.
10. Osteomyelitis (including vertebral, sternal, or long-bone osteomyelitis).
11. Epidural or cerebral abscess.
Inclusion criteria 1–7 must be ascertained based on assessments within the 72-h screening window. 
For inclusion criteria 8–11, assessments performed up to 7 days after randomization may be used to 
confirm the diagnosis of complicated SAB.
Patients randomized with suspected complicated SAB who turn out not to meet at least one of 
inclusion criteria 6–11 (i.e., who do not have confirmed complicated SAB), will be considered to 
have uncomplicated bacteremia. These patients will continue in the study. The minimum treatment 
duration target in this study is 21 days; the maximum treatment duration is 42 days.
PATIENT EXCLUSION CRITERIA
Patients meeting any of the following exclusion criteria at Screening will be excluded from the 
study:
1. Treatment with potentially effective (anti-staphylococcal) systemic antibacterial treatment for 
more than 48 h within the 7 days prior to randomization (see Appendix 5).
Exception: Documented failure of bloodstream clearance with prior antistaphylococcal treatment 
(except failure under daptomycin therapy) administered for at least 3 complete days.
2. Bloodstream or non-bloodstream concomitant infections with Gram-negative bacteria that are 
known (at Screening) to be non-susceptible to either ceftobiprole or aztreonam.
3. Confirmed uncomplicated SAB (e.g., catheter-related non-persistent SAB without signs of SAB 
complications, unless the patient has end-stage renal disease and is on intermittent hemodialysis 
or peritoneal dialysis). 
4. Left sided infective endocarditis (known or suspected to be present at the time of randomization)
Note: If LIE is diagnosed after onset of study therapy, patients may be maintained in the study. In the 
event that the investigator decides to discontinue the study therapy, the patient will be included in the 
mITT population and considered a failure. 
5. Prosthetic cardiac valves or valve support rings, cardiac pacemakers, automatic implantable 
cardioverter-defibrillator, or left-ventricular assist devices.
6. Complicated SAB in patients with other foreign body material that cannot be removed within the 
7 days after randomization.
Exceptions:

Patients with non-infected coronary stents may be included regardless of the time of stent 
implantation. 


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
Patients with non-infected (no signs or symptoms of clinical involvement at the time of 
randomization) prosthetic joints, plates, spinal hardware, or other extravascular material may 
be included if implantation of the foreign material was performed at least 60 days before 
randomization.

Patients with non-infected (no signs or symptoms of clinical involvement at the time of 
randomization) intravascular prosthetic material or vena cava filters may be included if 
implantation of the foreign material was performed at least 90 days before randomization.
7. Cardiac native-valve surgery planned within 3 days after randomization.
8. Community- or hospital-acquired pneumonia
Note: The diagnosis of pneumonia will be made by the investigator based on respiratory complaints (e.g., 
cough, dyspnea, purulent secretions, and chest pain) and new or worsening infiltrates suggestive of 
bacterial pneumonia on a chest radiograph or a high-resolution CT. Equivocal findings on a chest 
radiograph should be further assessed by the conduct of a high-resolution chest CT (if feasible) and/or the 
conduct of lung ultrasound to support the presence or absence of a diagnosis of pneumonia.   
9. High probability of death within 7 days due to the underlying SAB or SAB-associated disease, 
or high probability of death within 28 days from an unrelated underlying disease.
10. Clinically-relevant hypersensitivity to -lactam antibacterials or daptomycin.
11. Known infection due to Staphylococcus aureus that exhibits reduced susceptibility to daptomycin 
(minimum inhibitory concentration [MIC] > 1 mg/L), or ceftobiprole (MIC > 2 mg/L).
12. Absolute neutrophil count < 0.5 × 109/L.
13. Either: a) a history of opportunistic infections (e.g., invasive fungal infections or 
cytomegalovirus [CMV]) within 30 days prior to randomization, where the underlying cause of 
these infections is still active (e.g., leukemia, transplant, acquired immunodeficiency syndrome 
[AIDS]); or b) CD4 count < 100 cells/mm3 in patients with AIDS; or c) patients treated with 
cotrimoxazole as prophylaxis for pneumocystis pneumonia.
14. Requirement or expected requirement between randomization and the PTE visit for potentially 
effective (anti-staphylococcal) systemic antibacterial treatment that is unrelated to the treatment 
of SAB, e.g., in the context of planned surgery, gynecological or other procedures requiring 
antibacterial prophylaxis or other anticipated uses of antibacterials such as treatment for acne 
vulgaris.
15. Requirement for continuous renal-replacement therapy at the time of randomization, or high 
likelihood of requirement for continuous renal-replacement therapy during the study period.
Note: Patients undergoing chronic intermittent hemodialysis or peritoneal dialysis are permitted to 
participate in the study.
16. Alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 8 × the upper limit of 
normal, or severe hepatic disease with Child-Pugh class C.
17. Women who are pregnant or nursing.


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18. Women who are of childbearing potential and unwilling to use an acceptable method of birth 
control during the study: female sterilization (bilateral tubal occlusion or oophorectomy, or 
hysterectomy) or male partner vasectomy; intrauterine device (IUD); combined (estrogen- 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; or total sexual abstinence.
Women are not considered to be of childbearing potential if they are either ≥1 year 
post-menopausal (where menopause is defined as at least 12 months of amenorrhea), or have a 
serum follicle stimulating hormone (FSH) measurement consistent with post-menopausal status 
according to local laboratory thresholds. An FSH measurement at Screening is to be obtained for 
post-menopausal females aged < 50 years, or for those aged ≥50 years who have been post-
menopausal for < 2 years.
19. Use of an investigational drug in a Phase 1 study within the 30 days prior to the start of study 
treatment.
Note: Use of investigational drugs in Phase 2 or Phase 3 studies within the 30 days prior to the 
start of study drug treatment is allowed.
STUDY DRUG
Patients will be randomized to double-blind, double-dummy study treatment with ceftobiprole 
medocaril or daptomycin in a 1:1 allocation ratio, based on a computer-generated randomization 
schedule. Within the 6 h prior to the scheduled first dose of study drug, the investigator/designee 
will contact the Interactive Web Response System (IWRS) to obtain the study treatment assignment. 
The IWRS will allocate the patient to the appropriate randomization stratum. Randomization will be 
stratified by study site, dialysis status, and prior antibacterial treatment use (i.e., use of any systemic 
antibacterial treatment potentially effective against S. aureus within 7 days of randomization).
The treatment duration will be 21–42 days, with the treatment duration within this window to be 
defined by the study investigator.
Ceftobiprole medocaril powder for solution for infusion will be administered as 2-h intravenous 
infusion according to the following schedule:
Study Day
Normal renal function to 
mild renal impairment
(CLCr ≥ 50 mL/min)
Renal impairment 
(non-dialysis)
Intermittent 
hemodialysis or 
peritoneal dialysis
Day 1 to Day 8
500 mg q6h
CLCr 30–< 50 mL/min: 500 mg q8h
CLCr <30 mL/min: 250 mg q8h
250 mg q24h
Day 9 onwards
500 mg q8h
CLCr 30–< 50 mL/min: 500 mg q12h
CLCr < 30 mL/min: 250 mg q12h
250 mg q24h
CLCr=Creatinine clearance based on the Cockcroft-Gault formula.


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CONCURRENT CONTROL
Daptomycin lyophilized powder for solution for infusion will be administered as 0.5-h intravenous 
infusion according to the following schedule:
Normal renal function to 
moderate renal impairment
(CLCr ≥ 30 mL/min)
Renal impairment 
(non-dialysis)
(CLCr < 30 mL/min)
Intermittent 
hemodialysis or 
peritoneal dialysis
Daptomycin 
(0.5-h infusion)
6 mg/kg q24h
6 mg/kg q48h
6 mg/kg q48h
CLCr=Creatinine clearance based on the Cockcroft-Gault formula.
In accordance with institutional standards, an increase in the dose of daptomycin administered (up to 
10 mg/kg) may be implemented.
To maintain the blinding of study treatments, patients in the ceftobiprole group will receive dummy 
infusions with placebo (physiological saline, 0.9% NaCl) matching daptomycin, and patients in the 
daptomycin group will receive dummy infusions with placebo (physiological saline, 0.9% NaCl) 
matching ceftobiprole.
No switches to other systemic antibacterial treatments are permitted for any of the study drugs prior 
to the PTE visit. There is no intravenous-to-oral switch for any of the treatments in this study.
CONCOMITANT ANTIBACTERIAL TREATMENTS
Concomitant systemic antibacterials (other than study drugs) that provide activity against S. aureus
are prohibited from randomization up to the PTE visit.
Aztreonam may be used in the daptomycin group for coverage of Gram-negative infections (i.e., for 
polymicrobial bloodstream infections or for Gram-negative non-bloodstream infections). Patients 
randomized to the ceftobiprole group who are considered to require coverage against Gram-negative 
infections will receive dummy treatment with placebo so that blinding is maintained during the 
active treatment phase.
Open-label metronidazole may be used in both treatment groups for coverage of anaerobic 
infections.
Open-label nitrofurantoin may be used in both treatment groups for urinary tract infections.
Oral vancomycin is considered a non-systemic antibiotic and may be used at any time during the 
study.
Antibacterial treatment against Gram-negative pathogens and/or anaerobic pathogens for 
polymicrobial bloodstream infections or for non-bloodstream infections:
Known or suspected infections
Treatment arm(s)
Recommended treatment approach
Infections caused by Gram-negative 
pathogens susceptible to ceftobiprole 
and aztreonam
Daptomycin 
Aztreonam using a standard-dose regimen at the 
respective institution. 
Urinary tract infections caused by 
pathogens susceptible to 
nitrofurantoin 
Ceftobiprole 
Daptomycin
Nitrofurantoin using a standard-dose regimen at 
the respective institution
Infections caused by anaerobic 
pathogens
Ceftobiprole 
Daptomycin 
Metronidazole using a standard-dose regimen at 
the respective institution.


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STUDY-DRUG ADMINISTRATION
Ceftobiprole and daptomycin will be given intravenously for 21 to 42 days.
MAIN STUDY ENDPOINTS
Primary endpoint
Overall success at the PTE visit (Day 70±5 days post-randomization) in the mITT analysis set, as 
assessed by the DRC (see Appendix 4). The DRC will be a group of independent clinical experts, 
blinded to treatment allocation and not associated with the study conduct, who will review patient 
profiles, including signs and symptoms of infection, and relevant microbiological and imaging 
findings, and will assess the patients’ clinical and microbiological outcomes.
The primary endpoint will be tested for the non-inferiority of ceftobiprole versus daptomycin using a 
non-inferiority margin of 15%.
Overall success is defined as all of the following criteria being met:
1. Patient alive at Day 70 (±5 days) post-randomization.
2. No new metastatic foci or complications of the SAB infection.
3. Resolution or improvement of SAB-related clinical signs and symptoms.
4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for 
S. aureus):

at least one while the patient is on active study treatment; AND

confirmed by at least one subsequent negative blood culture for S. aureus
- either in the period between 7 days after the EOT visit and the PTE visit
- or at the PTE visit
Treatment failure is deﬁned as any of the following:
1. Premature discontinuation of study treatment due to DRC-assessed lack of efficacy (as assessed 
by the DRC) or for adverse events (AEs) that represent manifestation of disease progression or 
relapse, at any time between first dose of study drug and the PTE visit.
2. Development of new metastatic or other complications related to SAB (see Section 5.4.5.3.2) 
between Day 8 and the PTE visit. Development of new metastatic or other complications of SAB 
prior to Day 8 will be assessed by the DRC on a case-by-case basis to assess whether these 
constitute a delayed manifestation of the baseline disease or new complications.
3. SAB relapse or reinfection based on evidence from a blood culture positive for S. aureus (after 
documented clearance of S. aureus from the bloodstream and clinical improvement) between the 
EOT and PTE visits.
4. Receipt of systemic non-study antibacterial treatment, other than those permitted under the 
protocol, for the treatment of SAB. This includes patients who are prematurely discontinued from 
study therapy due to an AE, but who require continuation of antibacterial treatment for SAB.
5. Treatment of infections other than SAB with systemic non-study antibacterial treatment which is 
potentially effective against S. aureus (see Appendix 5), and which is considered by the DRC to 
have a relevant impact on the primary endpoint in accordance with the guidelines provided in 
Appendix 6.


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6. Death for any reason between first administration of study drug and the PTE visit.
7. Indeterminate outcome, defined as any data needed to determine whether the outcome is success 
or failure missing at the PTE visit, including but not limited to:
a) missing PTE visit, or missing key data to evaluate the primary endpoint
b) lost-to-follow-up, or patients who withdrew consent prior to the PTE visit
c) patients not meeting the criteria for Success or Failure, or patients not meeting all criteria for
overall success
8. Requirement for systemic antibacterial treatment for SAB beyond EOT.
Secondary endpoints
1.
All-cause mortality (mITT population) at Day 70 (PTE visit)
All-cause mortality will also be assessed at Day 28, and in the ITT population, and will be assessed 
descriptively.
2.
Microbiological eradication (mITT population) at Day 70 (PTE visit)
Microbiological eradication will also be assessed in the CE population, and at Day 4, Day 8, and the 
EOT visit, and will be assessed descriptively.
Eradication: No growth of the baseline pathogen(s), secondary to an adequate clinical response,
based on a negative blood culture while the patient is on active study treatment which is confirmed 
by at least one subsequent negative blood culture for S. aureus, either in the period between 7 days 
after EOT and the PTE visit, or at the PTE visit.
Failure: Persistence, relapse, or reinfection of S. aureus infection, defined as one or more of:

Ongoing positive blood cultures leading to discontinuation of the study drug

Subsequent isolation of S. aureus from a blood culture after clearance of bacteremia and clinical 
improvement
–
Relapse: bloodstream infection with the same pathogen isolated at baseline based on 
genotyping
–
Reinfection: bloodstream infection with a different S. aureus strain to that isolated at 
baseline based on genotyping

Absence of at least two negative blood cultures (at least one negative blood culture on active 
study treatment, and at least one post-treatment) to confirm eradication
Relapse or reinfection between EOT and PTE that is reported to the investigator from a healthcare 
provider not involved in the study (e.g., from another hospital), needs to be thoroughly documented 
and will be reviewed by the investigator and the DRC for determination.
3.
Overall success rate at PTE (CE population)
The overall success rate will also be assessed at the EOT visit in the mITT, ITT and CE populations, 
and in the ITT population at the PTE visit, and will be assessed descriptively.
See definitions for the primary endpoint above.


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4.
Development of new metastatic foci or other complications of SAB after Day 7 (mITT 
population)
Development of new metastatic foci or other complications of SAB after Day 7 will also be assessed 
in the CE population, and will be assessed descriptively.
Timepoints: Day 8–EOT, and PTE
Newly diagnosed IE or complicated SAB with metastatic foci or other complications of S. aureus
infection, including metastatic foci in the vertebral column (vertebral abscess, osteomyelitis, discitis 
or epidural abscess), cerebral abscess/infarction, splenic abscess/infarction, renal abscess/infarction, 
psoas abscess or other deep-tissue abscess, other metastatic infection of native tissue, septic arthritis
(or bacterial joint infection/empyema), septic or suppurative thrombophlebitis and septic pulmonary 
emboli/infarction.
5.
Time to S. aureus bloodstream clearance (mITT and CE populations)
Timepoints: Day 3–EOT
Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-culture-negative for 
S. aureus obtained at least 24 h after the first negative blood-culture.
6.
Safety/Tolerability (Safety population)
Timepoints: First dose of study drug–PTE
Incidence, type, severity, and relationship to study medication of AEs; and changes in laboratory 
tests (hematology, biochemistry including haptoglobin, urinalysis, and Coombs-test).
7.
Pharmacokinetics of ceftobiprole (PK population)
Plasma levels of ceftobiprole and the -lactam ring-open product BAL1029
Sparse PK sampling (all patients)

Day 3: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h

Day 12: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
Rich PK sampling (selected sites, N=40 ceftobiprole-treated patients [i.e., approximately 80 patients 
overall])

Day 3: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 3 h, 4 h, 6 h

Day 12: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
Plasma-concentration data will be analyzed at each time point and will be presented as individual 
concentrations with descriptive statistics (mean, SD, CV%, min, median, max).
STATISTICAL ANALYSIS
Analysis populations
The following analysis populations are defined for this study:
Intent-to-treat population (ITT)
The ITT population consists of all randomized patients. Patients will be analyzed according to the 
study medication assigned at randomization.


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Modified intent-to-treat population (mITT)
The mITT population consists of the subset of patients in the ITT population who have received any 
amount/dose of study medication, and who have a blood culture positive for S. aureus at baseline
based on a central microbiology laboratory assessment.*
Clinically evaluable population (CE)
The CE population consists of the subset of patients in the mITT population who have complied 
with important aspects of the study, e.g., no major protocol violations, with a completed primary
outcome assessment.
Safety population
The safety population consists of all randomized patients who received any amount/dose of study 
medication. Patients in the safety population will be analyzed according to the first medication 
actually received.
Pharmacokinetic population (PK)
All patients who receive at least one dose of ceftobiprole and have at least one plasma-concentration 
measurement obtained by the appropriate methodology.
Analysis of primary endpoint
The primary analysis will be based on the mITT population.
The study is designed to determine whether ceftobiprole is non-inferior to daptomycin for the 
outcome measure of overall success at the PTE visit at Day 70 (±5 days) after randomization, in the 
mITT population.
The observed difference in percentage of responders at PTE (ceftobiprole group minus the 
daptomycin group) will be determined and a two-sided 95% confidence interval (CI) for the 
observed difference will be computed, with adjustment for geographical region (North America, 
Europe, other regions), dialysis status and prior antibacterial treatment use. Cochran-Mantel-
Haenszel weights will be used for the stratum weight in the calculation of the CI. The non-inferiority 
hypothesis test is a one-sided hypothesis test performed at the 2.5% level of significance. If the 
lower limit of the two-sided 95% CI for the difference in response rates in the mITT population is 
greater than −15%, the non-inferiority of ceftobiprole to daptomycin therapy will be concluded.
The primary analysis will classify as failures all patients with missing data relevant to appropriate 
assessment of the primary endpoint at the PTE visit.
A sensitivity analysis will be performed to exclude those patients with missing data completely, and 
this assumes missing at random (MAR). Additional analyses will explore the robustness of the 
conclusion of the non-inferiority of ceftobiprole to further missingness not at random (MNAR)
assumptions. In particular, various proportions of the patients with missing data (10%, 20%, 30% 
and 40%) in the daptomycin group will be considered successes, while only half of the respective 
proportions of patients in the ceftobiprole group will be considered successes (5%, 10%, 15%, 20%),
and the analysis of non-inferiority repeated for each of the assumed proportions.
                                                
* Patients who are missing a central microbiological assessment may be included in the mITT population if there is 
documented unequivocal evidence of a baseline blood culture positive for S. aureus at the local laboratory


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Analysis of secondary efficacy endpoints
Two-sided 95% CIs will be constructed for the observed difference between ceftobiprole and 
daptomycin therapy for the endpoints of all-cause mortality, microbiological eradication, overall 
success, and development of new metastatic foci, using the same approach as for the primary 
endpoint.
In addition, a time-to-event analysis will be performed for all-cause mortality and for time-to-blood-
cultures-negative for S. aureus.
Safety analyses
Safety will be assessed through summaries of AEs, safety laboratory evaluations, physical 
examinations, and vital signs. All safety analyses will be based on the safety population.
Sample size justification
The sample size estimate is based on:

A point estimate for overall success of 40% in each treatment group in the mITT population.

One-sided alpha level of 0.025.

Power of > 80%.

Non-inferiority margin of 15% for the between-group difference in the primary endpoint.
With these assumptions, enrollment of 175 patients per treatment group (total of 350 patients) is 
required in the mITT population. Assuming that approximately 90% of patients in the ITT 
population will have confirmed SAB and will therefore be included in the mITT population, 
195 patients per group (total of 390 patients) will need to be randomized and receive study 
treatment.
Interim safety analysis
As animal studies have indicated the potential of an increased risk of convulsions with prolonged 
ceftobiprole therapy (> 4 weeks treatment duration), an initial cohort of patients was enrolled for a 
maximum treatment duration of 28 days (Cohort 1). An interim safety analysis was performed by an 
independent DSMB after 80 patients (approximately 40 patients per treatment group) have 
completed 21–28 days of treatment and safety follow-up. Based on this analysis the treatment 
duration was extended up to 42 days (Cohort 2)after discussion with the United States Food and 
Drug Administration (FDA).
The decision rules for the DSMB interim safety assessment of Cohort 1 are provided in Appendix 7.
Further interim safety assessments will be performed by the DSMB after enrollment of 200 and 
300 patients; details are provided in the DSMB Charter.
PROCEDURES
Overview
The total duration of the study, including follow-up, is up to 10 weeks (70±5 days) for each patient. 
Baseline assessments are defined as all relevant pre-randomization assessments that may be used for 
the study (see Section 5.2). Screening is defined as the period after informed consent has been 
obtained, i.e., a period up to 72 h prior to randomization.
Results from vital sign measurements, local safety laboratory tests, blood cultures, echocardiography 
or investigations to verify deep-seated infections or complications of SAB, may be used for the 
study if obtained prior to informed consent (i.e., outside the screening period) but within a 72-h 


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window prior to randomization (10 days for an echocardiography that was confirmatory for 
definitive right-sided endocarditis) (see Section 5.2).
Study assessments are shown in Table 6 of the protocol and summarized below.
The study comprises three phases:

Screening of up to 72 h prior to randomization.

Randomization and subsequent active-treatment phase with intravenous study drug (ceftobiprole 
or daptomycin therapy).

Post-treatment, comprising an EOT visit (within 72 h of last study-drug administration), Day 35 
(±3 days), Day 42 (±3 days), and a PTE visit on Day 70 (±5 days) post-randomization.
Patients with suspected or confirmed complicated SAB must sign informed consent within the 72 h 
prior to randomization. Baseline assessments must be completed according to the following 
timelines.
Blood cultures
Two sets of peripheral blood cultures (including aerobic and anaerobic) will be obtained from each 
patient at baseline. Blood cultures will be drawn at least 5 min apart, and samples for each of the two 
sets of blood cultures should be obtained from different anatomical locations.  Blood cultures that 
were positive for S. aureus and were conducted in the context of routine clinical diagnostic work-up 
practice prior to obtaining informed consent, but were drawn within the 72 h prior to randomization, 
may be used for the study to determine patient eligibility, and do not need to be repeated.
Post-randomization blood cultures (at least one, but preferably two blood cultures) will be obtained 
on Days 1, 2 and 3. Thereafter, blood cultures will be obtained approximately every 48–72 h if 
clearance of bacteremia has not yet been confirmed, i.e., until negative test results for S. aureus are 
obtained for two cultures (or negative test result for one culture if only one culture was obtained) at 
two time points taken at least 24 h apart. At least one blood culture must be obtained at the PTE 
visit, or in the period between 7 days after the EOT visit and the PTE visit.
Specimens will be cultured by the local laboratory. The microbiological work-up of the blood 
culture may:

Occur prior to informed consent to participation in the study (see Section 5.2.1 and Table 7).

Be undertaken either on-site or in an external microbiology laboratory specifically appointed for 
the purposes of this study.

Use a diagnostic test:
–
routinely performed locally for the detection of S. aureus from blood cultures
or
–
provided to the laboratory for the purpose of this study, if the test has regulatory approval in 
the country where the test is being performed
Regardless of diagnostic method, every effort should be made to isolate and send all unique 
organisms from blood to the Central Microbiology Laboratory; this applies particularly to the 
S. aureus isolated from blood at the Screening visit. The Central Microbiology Laboratory will re-
identify all isolates, with the results to be used to determine whether the patient meets the study 
inclusion criteria.


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Nevertheless, patients without a Central Microbiology Laboratory assessment may be included in 
the mITT population if there is unequivocal documented evidence of a baseline blood culture 
positive for S. aureus at the local laboratory.
The central microbiology laboratory will also perform susceptibility testing with both study drugs. 
For patients with persistent SAB (see Inclusion criterion 7), the susceptibility to ceftobiprole and 
daptomycin may be assessed at the local microbiology laboratory, but must be confirmed by the 
central laboratory. If a patient is randomized based on susceptibility results from the local 
laboratory, and a conflicting result is obtained from the central laboratory, then the central 
laboratory result will be considered valid. If local susceptibility testing is performed after a patient 
has been randomized, and the local results show non-susceptibility to either study drug, then the 
continuation of the patient in the study will be at the discretion of the investigator, based on clinical 
assessment.
Echocardiography
Echocardiography assessments obtained within 72 h prior to randomization (or up to 10 days if 
definite RIE has been confirmed) may be used for patient eligibility assessment, even if the 
echocardiography has been performed in the context of clinical practice prior to obtaining informed 
consent for this study.
Transthoracic echocardiography
A transthoracic echocardiography (TTE) must be performed within the 72 h prior to randomization 
for all patients with the following exceptions:

A transesophageal echocardiography (TEE) has been performed within this time window

A diagnosis of definite RIE (according to Modified Duke’s Criteria) is confirmed. For these 
patients, a TTE (or TEE) performed within the 10 days prior to randomization may be used to 
confirm patient eligibility. A TTE or TEE must be repeated within the 72 h before, or within the 
7 days after, randomization, for documentation purposes.
Transesophageal echocardiography
A TEE must be performed within 72 h prior to randomization or within 7 days after randomization 
in all patients with the following exceptions:

A diagnosis of definite RIE (according to Modified Duke’s Criteria) is confirmed. For these 
patients a TEE (or TTE) performed within 10 days prior to randomization may be used to 
confirm patient eligibility. A TTE or TEE must be repeated within 72 h before, or within 7 days 
after, randomization, for documentation purposes. If the diagnosis of a definite RIE can be based 
on a TTE, then a TEE is not required.

A condition associated with an increased risk of complications from TEE, including:
– altered mental status or an uncooperative patient
– unstable cardiorespiratory status 
– esophageal stricture or malignancy (identify esophageal location prior to TEE) or esophageal 
varices with recent/active bleeding
– surgical interposition of the esophagus
– Zenker's diverticulum (identify esophageal location prior to TEE)
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– cervical spine arthritis with reduced range of motion
– severe thrombocytopenia (< 50 × 109/L), elevated international normalized ratio (˃ 4), or 
prolonged partial thromboplastin time (> 150 seconds)
– obstructive sleep apnea/airway compromise (consider sedation by anesthesia)
Diagnostic assessments for metastatic or other complications related to SAB 
Diagnostic assessments for metastatic or other complications related to SAB (i.e., related to 
Inclusion criterion 8) that were conducted in the context of routine clinical diagnostic work-up 
practice prior to obtaining informed consent, but within the 72 h prior to randomization, may be 
used for the study to determine patient eligibility.
Furthermore, diagnostic assessments for metastatic or other complications related to SAB 
(i.e., related to Inclusion criterion 8) that are obtained within the 7 days after randomization may be 
used to determine the patient’s baseline condition of complicated SAB.
Other screening assessments
Vital sign measurements and local safety laboratory tests that were conducted in the context of 
routine clinical diagnostic work-up practice prior to obtaining informed consent, but within the 72 h 
prior to randomization, may be used for the study to determine patient eligibility and do not need to 
be repeated. This includes the assessment of signs and symptoms of bacteremia for the purposes of 
Inclusion criterion 4.
All other screening assessments except a pregnancy test (physical examination, 12-lead 
electrocardiogram, central laboratory safety tests, Modified Duke’s Criteria, creatinine clearance)
must be performed after informed consent has been obtained, and within the 72 h prior to 
randomization.
A pregnancy test must be assessed within 24 h prior to randomization. Clinical signs of deep-seated 
infections and metastatic or other complications of SAB must be assessed within the 12 h prior to 
randomization.
Clinical signs of metastatic complications (assessed by the investigator) include bone or back pain, 
back pain elicited on percussion of spine (suggestive of vertebral osteomyelitis, discitis, or epidural 
abscess); joint swelling, joint pain, pain elicited on external rotation of femoral head (suggestive of 
septic arthritis); protracted fever and/or sweats, new regurgitant murmurs or heart failure and further 
clinical stigmata suggestive of IE; abdominal pain, left upper quadrant pain (suggestive of splenic 
infarction); costovertebral angle tenderness (suggestive of renal infarction or psoas abscess); 
headache, focal neurologic impairment (suggestive of central nervous septic emboli) or other 
findings which could reasonably be regarded as clinical signs of metastatic infection. Careful 
examinations regarding in-dwelling prosthetic devices and orthopedic hardware should be 
undertaken.
Metastatic or other complications of SAB must be supported by imaging studies (including 
ultrasound, computed tomography [CT], magnetic resonance imaging [MRI], and positron emission 
tomography/computed tomography [PET/CT]), biopsies or cultures. The minimum requirements for 
baseline or post-baseline diagnosis of metastatic complications of SAB are provided in Appendix 2
and Appendix 3, respectively.
For clinical signs of bacteremia see Inclusion criterion 4.
Details of the time windows for baseline screening assessments are outlined in Section 5.2.


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TABLE OF CONTENTS
TABLE OF CONTENTS ......................................................................................................18
LIST OF TABLES ................................................................................................................22
LIST OF APPENDICES .......................................................................................................23
LIST OF ABBREVIATIONS ...............................................................................................24
1
BACKGROUND AND RATIONALE...........................................................................27
1.1
Disease characteristics and treatment ........................................................................27
1.2
Investigational medicinal products ............................................................................27
1.2.1
Test product………………....................................................................................27
1.2.2
Comparator regimen...............................................................................................27
1.3
Nonclinical studies with ceftobiprole ........................................................................27
1.3.1
Microbiology………………..................................................................................27
1.3.2
Pharmacokinetics and product metabolism in animals ..........................................29
1.3.3
Toxicology……………… .....................................................................................29
1.4
Clinical studies with ceftobiprole ..............................................................................30
1.4.1
Pharmacokinetics, product metabolism, and tissue distribution in humans...........30
1.4.2
Pharmacodynamics.................................................................................................31
1.4.3
Susceptibility testing breakpoints...........................................................................31
1.4.4
Efficacy in ABSSSIs/cSSTIs .................................................................................31
1.4.5
Efficacy in community-acquired pneumonia .........................................................32
1.4.6
Efficacy in hospital-acquired pneumonia...............................................................32
1.4.7
Safety………….…….............................................................................................33
1.5
Rationale for study BPR-CS-009...............................................................................33
1.5.1
Summary of study design.......................................................................................34
1.5.2
Study design rationale............................................................................................34
1.5.3
Dosing rationale for ceftobiprole and daptomycin.................................................38
1.6
Benefit–risk assessment .............................................................................................39
2
OBJECTIVES OF THE STUDY....................................................................................40
2.1
Primary objective .......................................................................................................40
2.2
Secondary objectives..................................................................................................40
3
STUDY DESIGN ...........................................................................................................41
3.1
Overview of study design and dosing regimen..........................................................41
3.2
Endpoints ...................................................................................................................42
3.2.1
Primary endpoint………………............................................................................42


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3.2.2
Secondary endpoints ..............................................................................................44
3.3
Treatment plan ...........................................................................................................46
3.3.1
Duration of treatment .............................................................................................46
3.3.2
Missed-dose management ......................................................................................47
3.3.3
Overdose……………….........................................................................................47
3.4
Definition of End of Study.........................................................................................47
4
STUDY POPULATION.................................................................................................47
4.1
Target population.......................................................................................................47
4.2
Inclusion criteria ........................................................................................................47
4.3
Exclusion criteria .......................................................................................................50
4.4
Patient withdrawal......................................................................................................52
4.5
Criteria for discontinuation of treatment....................................................................52
4.6
Replacement of patients.............................................................................................53
4.7
Patients with left-sided infective endocarditis ...........................................................53
5
STUDY ASSESSMENTS AND PROCEDURES..........................................................53
5.1
Summary of schedule of assessments ........................................................................53
5.2
Time windows for baseline/screening assessments ...................................................57
5.2.1
Blood cultures……………… ................................................................................57
5.2.2
Echocardiography...................................................................................................58
5.2.3
Diagnostic assessments for deep-seated infections and metastatic or other 
complications related to SAB.................................................................................60
5.2.4
Other screening assessments ..................................................................................60
5.3
Study visits.................................................................................................................64
Screening (Day −1; within the 72 h prior to randomization) ............................................64
Active-treatment Day 1 .....................................................................................................65
Active-treatment Day 2 .....................................................................................................65
Active-treatment Day 3 .....................................................................................................66
Active-treatment Days 4–12..............................................................................................66
Active-treatment Days 14, 21, and if applicable, Days 28, 35, and 42 .............................67
Post-treatment EOT visit ...................................................................................................67
Post-treatment Days 35 and 42..........................................................................................68
Post-treatment PTE visit....................................................................................................68
5.4
Study procedures........................................................................................................69
5.4.1
Informed consent………………............................................................................69


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5.4.2
Medical history, demographics and prior/ongoing therapies.................................69
5.4.3
Patient registration and IWRS................................................................................69
5.4.4
Safety assessments .................................................................................................70
5.4.5
Assessments of disease status ................................................................................74
5.4.6
Assessments of treatment success..........................................................................76
5.4.7
PK blood-sample collection ...................................................................................76
5.5
Prior and concomitant medication .............................................................................77
5.5.1
Prior medication……………….............................................................................77
5.5.2
Prohibited concomitant medication........................................................................77
5.5.3
Permitted concomitant medication.........................................................................77
5.6
Restrictions.................................................................................................................78
5.7
Health economic outcome measures..........................................................................78
6
STUDY DRUGS.............................................................................................................79
6.1
Blinding......................................................................................................................79
6.2
Randomization ...........................................................................................................79
6.3
Dose regimens and administration schedules ............................................................79
6.4
Study drug administration..........................................................................................80
6.4.1
Ceftobiprole………….……...................................................................................81
6.4.2
Daptomycin………………....................................................................................81
6.4.3
Study drug dosing volumes and sequence..............................................................81
6.5
Blinding......................................................................................................................83
6.5.1
Methods for ensuring blinding ...............................................................................83
6.5.2
Unblinding methods ...............................................................................................83
6.6
Drug accountability and compliance checks..............................................................84
6.7
Packaging and labelling .............................................................................................84
6.8
Shipping and storage conditions ................................................................................84
6.9
Drug supply................................................................................................................85
6.10 Drug disposal .............................................................................................................85
7
SAFETY .........................................................................................................................86
7.1
Definitions..................................................................................................................86
7.1.1
Adverse occurrence................................................................................................86
7.1.2
Adverse event……………….................................................................................86
7.1.3
Serious adverse event.............................................................................................86
7.1.4
Adverse events of special interest ..........................................................................87


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7.2
Evaluation of adverse events......................................................................................87
7.2.1
Severity………………...........................................................................................87
7.2.2
Relationship………………....................................................................................88
7.3
Handling of safety information and collection periods..............................................88
7.3.1
Handling of safety data during the pre-treatment period .......................................88
7.3.2
Handling of safety data during the treatment period and up to the last 
scheduled follow-up ...............................................................................................88
7.3.3
Handling of post-study safety data.........................................................................90
7.3.4
Reporting of SAEs to regulatory authorities..........................................................90
7.4
Pregnancy...................................................................................................................91
7.4.1
Contraception for women of childbearing potential ..............................................91
7.4.2
Reporting and handling of pregnancies..................................................................92
8
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN............................93
8.1
Sample size justification ............................................................................................93
8.2
Analysis populations..................................................................................................94
8.3
Statistical considerations............................................................................................94
8.4
Demographic and baseline characteristics .................................................................94
8.5
Prior and concomitant medication .............................................................................95
8.6
Baseline categories of complicated Staphylococcus aureus bacteremia ...................95
8.7
Analysis of the primary endpoint...............................................................................95
8.8
Analysis of secondary endpoints................................................................................97
8.8.1
Secondary endpoints ..............................................................................................98
8.9
Safety analyses...........................................................................................................99
8.10 Pharmacokinetics .......................................................................................................100
8.11 Interim safety analysis ...............................................................................................100
9
STUDY ADMINISTRATION AND REGULATORY ASPECTS ...............................101
9.1
Study records..............................................................................................................101
9.1.1
Investigator site file................................................................................................101
9.1.2
Case report forms ...................................................................................................101
9.1.3
Patient source documents.......................................................................................101
9.1.4
Document retention and archiving .........................................................................101
9.1.5
Sample retention……………….............................................................................102
9.2
Clinical monitoring ....................................................................................................102
9.3
Audits and inspections ...............................................................................................102


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9.4
Protocol amendments.................................................................................................103
9.5
Premature termination of the study............................................................................103
9.6
Publication policy ......................................................................................................103
10 ETHICS AND GOOD CLINICAL PRACTICE ............................................................104
10.1 Good Clinical Practice ...............................................................................................104
10.2 Informed consent........................................................................................................104
10.3 Patient confidentiality and data protection.................................................................105
10.4 Independent Ethics Committees / Institutional Review Boards.................................105
11 PROTOCOL VERSION HISTORY...............................................................................106
12 REFERENCES ...............................................................................................................107
13 APPENDICES ................................................................................................................112
LIST OF TABLES
Table 1
Ceftobiprole MICs established by EUCAST............................................... 31
Table 2
Comparison 
of 
overall 
success 
rates 
with 
daptomycin 
vs 
standard-of-care comparators in subgroups of complicated SAB............... 37
Table 3
Summary of treatment and follow-up schedule........................................... 42
Table 4
Ceftobiprole administration......................................................................... 46
Table 5
Daptomycin administration ......................................................................... 46
Table 6
Schedule of Assessments............................................................................. 54
Table 7
Time windows for baseline blood cultures.................................................. 61
Table 8
Time windows for baseline echocardiography............................................ 61
Table 9
Time windows for baseline assessments for confirmation of 
deep-seated infections and metastatic or other forms of complicated 
bacteremia (Inclusion criterion 8)................................................................ 62
Table 10
Time windows for other screening assessments.......................................... 63
Table 11
Local laboratory safety parameters mandatory (for patient eligibility) 
at Screening ................................................................................................. 71
Table 12
Central laboratory safety parameters........................................................... 72
Table 13
Schedule of ceftobiprole administration...................................................... 79
Table 14
Schedule of daptomycin administration ...................................................... 80
Table 15
Study drug dosing schedule: Day 1 to Day 8 .............................................. 82
Table 16
Study drug dosing schedule: Day 9 to Day 42 ............................................ 82


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LIST OF APPENDICES
Appendix 1 Modified Duke’s Criteria for the diagnosis of infective endocarditis....... 112
Appendix 2 Minimum diagnostic requirements for the assessment of deep-seated 
infections and metastatic or other complications related to S. aureus
bacteremia (related to Inclusion criterion 8) at baseline............................ 114
Appendix 3 Minimum diagnostic requirements for the assessment of deep-seated 
infections and metastatic or other complications related to S. aureus
bacteremia post-baseline............................................................................ 115
Appendix 4 DRC process.............................................................................................. 116
Appendix 5 Systemic antibacterial treatments considered to be potentially effective 
against S. aureus........................................................................................ 121
Appendix 6 DRC assessment of potentially-effective antibacterial treatment.............. 122
Appendix 7 DSMB Process and decision criteria for DSMB interim safety 
assessment of Cohort 1 and at subsequent DSMB meetings..................... 124
Appendix 8 Justification of the non-inferiority margin................................................. 131
Appendix 9 Criteria for evaluating relationship between adverse events and study 
treatment .................................................................................................... 137
Appendix 10 Investigator’s protocol signature page....................................................... 139


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LIST OF ABBREVIATIONS
ABSSSI
Acute bacterial skin and skin structure infection
ACM
All-cause mortality
AE
Adverse event
ALT
Alanine transaminase
AP
Alkaline phosphatase
aPPT
Activated partial thromboplastin time
AST
Aspartate transaminase
BPR
Ceftobiprole medocaril
CAP
Community-acquired pneumonia
CE
Clinically evaluable
CI
Confidence interval
CLCR
Creatinine clearance
CMV
Cytomegalovirus
CPK
Creatine phosphokinase
CRF
Case report form
CRP
C-reactive protein
cSSTI
complicated skin and soft tissue infection
CT
Computed tomography
DAP
Daptomycin
DRC
Data Review Committee
DSG
DSMB Statistics Group
DSMB
Data and Safety Monitoring Board
EOT
End-of-treatment
ESRD
End-stage renal disease
FDA
United States Food and Drug Administration 
FSH
Serum follicle stimulating hormone 
FISH
Fluorescent in situ hybridization
GGT
Gamma-glutamyl transferase
GISA
Glycopeptide-intermediate Staphylococcus aureus
HAP
Hospital-acquired pneumonia


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HCT
Hematocrit
HGB
Hemoglobin
ICH
International Council for Harmonisation
IE
Infective endocarditis
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
ISF
Investigator Site File
ITT
Intent-to-treat
IUD
Intrauterine device 
IWRS
Interactive Web Response System
LDH
Lactate dehydrogenase
LIE
Left-sided infective endocarditis
LPLV
Last Patient Last Visit
MIC
Minimum inhibitory concentration
mITT
Modified intent-to-treat
MRI
Magnetic resonance imaging
MRSA
Methicillin-resistant Staphylococcus aureus
MSSA
Methicillin-susceptible Staphylococcus aureus
NOEL
No-observed-effect-level
NSAID
Nonsteroidal anti-inflammatory drug
PBO
Placebo
PCR
Polymerase chain reaction
PET/CT
Positron emission tomography/computed tomography
PK
Pharmacokinetic (population)
PORT
Pneumonia Outcomes Research Team
PSI
Pneumonia Severity Index
PT
Preferred Term
PT
Prothombrin time
PTE
Post-treatment evaluation
RBC
Red blood cell
RIE
Right-sided infective endocarditis


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RSI
Reference Safety Information
SAB
Staphylococcus aureus bacteremia
SAE
Serious adverse event
SOC
System Organ Class
SPA
Special protocol assessment
SUSAR
Suspected unexpected serious adverse reaction
T>MIC
Time drug concentration is above the MIC
t1/2
Elimination half-life
TEE
Transesophageal echocardiography
TOC
Test-of-cure
TTE
Transthoracic echocardiography
UTI
Urinary tract infection
VAP
Ventilator-associated pneumonia 
VISA
Vancomycin-intermediate Staphylococcus aureus
VRSA
Vancomycin-resistant Staphylococcus aureus
WBC
White blood cell


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1
BACKGROUND AND RATIONALE
1.1
Disease characteristics and treatment
Staphylococcus aureus bacteremia (SAB) is a leading cause of bloodstream infections, 
responsible for a broad variety of complications and has been associated with significant 
morbidity and a mortality of 20 to 40% (Jensen 2002, Wang 2008).
Standard-of-care antibacterial treatments for SAB including infective endocarditis include 
vancomycin or daptomycin (active against MSSA and MRSA) or oxacillin and cefazolin 
(active against MSSA only) (Yaw 2014). Several studies have demonstrated that 
MRSA bacteremia is associated with a significantly higher mortality rate compared with 
methicillin-susceptible S. aureus (MSSA) bacteremia (Blot 2002, Cosgrove 2003). However, 
MSSA bacteraemia is more frequent than MRSA bacteraemia. This underlines the 
importance of antibacterial treatments that are rapidly bactericidal against both MRSA and 
MSSA. Daptomycin (a lipopeptide antibacterial), and ceftobiprole (a β-lactam antibacterial), 
provide such rapid bactericidal activity against both MSSA and MRSA while vancomycin 
(a glycopetide) shows a slower bactericidal effect, is less effective for treatment of SAB than 
β-lactam agents and is therefore not considered as an antibacterial treatment of first choice 
for MSSA infections by many experts (Cosgrove 2003, Murthy 2008).
1.2
Investigational medicinal products
1.2.1
Test product………………
Ceftobiprole medocaril powder for solution for infusion 500 mg four times daily (q6h) for 
study Days 1 through 8, three times daily (q8h) from study Day 9 onwards, with dose 
adjustments for renal impairment.
1.2.2
Comparator regimen
Daptomycin lyophilized powder for solution for infusion 6 mg/kg once daily (q24h), with 
dose adjustments for renal impairment.
1.3
Nonclinical studies with ceftobiprole
1.3.1
Microbiology………………
1.3.1.1 In vitro studies
Ceftobiprole has a strong affinity for several penicillin-binding proteins (PBPs), including 
PBP2a and PBP2x, which mediate resistance to other β-lactams in staphylococci and 
pneumococci, respectively (Davies 2010, Davies 2007, Entenza 2002, Hebeisen 2001, 
Henry 2013, Lovering 2012). 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 strong binding affinity to PBP2a under both 
neutral and acidic pH conditions (Lemaire 2009). Ceftobiprole also binds to, and saturates, 


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several other essential PBPs (Davies 2010, Henry 2013), distinguishing it from other 
available β-lactams, and is stable to hydrolysis by the S. aureus PC1 Class A β-lactamase, 
conserving its activity against staphylococci (Queenan 2007).
Ceftobiprole is also relatively stable against AmpC cephalosporinases and common class A 
β-lactamases produced by Gram-negative bacteria, but not to extended-spectrum 
β-lactamases (ESBLs), carbapenemases, or OXA β-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 (Bogdanovich 2005, Bogdanovich 2006, Kosowska 2005, Queenan 
2005, Queenan 2007, 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 MIC shifts were seen in surveillance studies.
In vitro, ceftobiprole has shown a bactericidal mode of action against MSSA, MRSA and 
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, Deshpande 2013, Leonard 2008, Rouse 2007).
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).
1.3.1.2 Animal models of infection
The in vivo potency of ceftobiprole against MRSA has been demonstrated in animal models 
of pneumonia (Laohavaleeson 2008), S. aureus-mediated IE (Chambers 2005, Entenza 2011, 
Fernandez 2012, Tattevin 2010) and osteomyelitis (Saleh-Mghir 2012, Yin 2008) using 
humanized doses. In a rat model of endocarditis, ceftobiprole was superior to vancomycin in 
reducing the bacterial load of cardiac vegetations in animals infected with MRSA, GISA, or 
VISA (Entenza 2011, Fernandez 2012). In addition, depending on the strain, 47–93% of 
vegetations were sterilized following ceftobiprole treatment, compared to none for 
vancomycin. Similar results were seen using rabbit models of aortic-valve endocarditis
(Chambers 2005, Tattevin 2010) and tibial osteomyelitis (Saleh-Mghir 2012, Yin 2008). 
One endocarditis study found ceftobiprole to be superior to vancomycin against VISA
(Chambers 2005), and in another, the activity of ceftobiprole was superior to that of 
vancomycin, daptomycin and linezolid for the treatment of MRSA-induced endocarditis
(Tattevin 2010). In this model, ceftobiprole also sterilized more vegetations than daptomycin 
or vancomycin.


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1.3.2
Pharmacokinetics and product metabolism in animals
In animals after single intravenous dose pharmacokinetic studies, ceftobiprole medocaril was 
rapidly metabolized 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 and 
in vivo metabolic patterns of ceftobiprole in rats, dogs, mice, marmosets, and humans were 
similar, with the microbiologically inactive 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 with no 
relevant accumulation, differences related to sex, or time-dependent pharmacokinetics.
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 intravenous administration of the prodrug.
Based on in vitro cytochrome P450 inhibition and induction data, the lack of a specific 
enzyme involved in the 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.
Further details on the nonclinical pharmacology, pharmacokinetics and pharmacodynamics 
of ceftobiprole medocaril are provided in the ceftobiprole Investigator’s Brochure.
1.3.3
Toxicology………………
The primary targets of toxicity after intravenous 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 over 4–8 h into the vena cava at concentrations up to 
62 mg/mL.
In a local tolerability study in rabbits, repeated intravenous administration of ceftobiprole 
into the auricular vein (8 consecutive days with a 3-minute endothelial contact period per 
day) caused no irritation at 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 medocaril was neither teratogenic nor embryotoxic in rats and cynomolgus 
monkeys, and had no effects on fertility and early embryonic development in rats. No effects 
on behavioral or developmental parameters were noted in pups. No signs of skin 
sensitization, irritation, or phototoxicity were seen. The antigenic potential of ceftobiprole 
medocaril is low.
The convulsive potential after intracerebroventricular administration to mice was comparable 
to that of imipenem. Animal studies in rats have indicated the potential of an increased 
risk of convulsions with prolonged ceftobiprole therapy (> 4 weeks treatment duration). 
In the 13-week studies, convulsions were only observed in male rats at high doses 
(no-observed-effect-level [NOEL] 250 mg/kg; mean Cmax 84 µg/mL), and the convulsions in 
rats may have been confounded by nephrotoxicity. There were no convulsions in the 
13-week dog study.
Further details on the nonclinical toxicology of ceftobiprole medocaril are provided in the 
Investigator’s Brochure.
1.4
Clinical studies with ceftobiprole
1.4.1
Pharmacokinetics, product metabolism, and tissue distribution in humans
The pharmacokinetics of ceftobiprole in adult subjects are predictable, linear and 
time-independent across the dose range of 125–1000 mg, and variability is low (< 30%). 
Steady-state drug concentrations are attained on the first day of dosing, and no appreciable 
accumulation is observed in subjects 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 3–4 h.
Ceftobiprole is eliminated primarily unchanged by renal excretion, with minimal metabolism 
to an (inactive) open-ring metabolite, which accounts for approximately 4% of total 
exposure. The predominant mechanism responsible for elimination is glomerular filtration. 
As the systemic clearance of ceftobiprole correlates with creatinine clearance (CLCR), 
dose regimen adjustments are recommended in subjects with moderate or severe renal 
impairment, in end-stage renal disease (ESRD) subjects, and in subjects with 
CLCR > 150 mL/min. Given no underlying renal impairment, the primary PK/PD driver of 
ceftobiprole (time that drug concentration exceeds MIC, 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.


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1.4.2
Pharmacodynamics
In animal models, for efficacy (bacteriostasis) the plasma concentrations of ceftobiprole must 
remain above the target MIC (T>MIC) of 4 g/mL for > 30% of the dosing interval for 
susceptible Gram-positive pathogens, and > 50% for susceptible Gram-negative pathogens. 
For 1 log-kill in CFU (bactericidal effect) in animal pneumonia and thigh models, the target 
T>MIC of 4 g/mL remains > 30% of the dosing interval for susceptible Gram-positive 
pathogens, and is > 60% for susceptible Gram-negative pathogens.
A retrospective population pharmacokinetic analysis of subjects in the Phase 3 HAP study 
demonstrated the probability of target attainment for a dosing regimen of 500 mg q8h 
(administered as 2-hour [h] infusions) for a 60% T>MIC of 4 g/mL to be 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 PK/PD target for Gram-negative organisms.
1.4.4
Efficacy in ABSSSIs/cSSTIs
Two Phase 3 studies have previously been completed with ceftobiprole in acute bacterial 
skin and skin structure infection (ABSSSIs) / complicated skin and soft tissue infection
(cSSTIs). Study BAP00414 compared ceftobiprole 500 mg q8h (N=547) with vancomycin 1 
g q12h plus ceftazidime 1 g q8h (N=281) in patients with Gram-positive or Gram-negative 
ABSSSIs/cSSTIs including patients with diabetic foot infections (Noel 2008b). Study 
BAP00154 compared ceftobiprole 500 mg q12h (N=397) with vancomycin 1 g q12h 
(N=387) in patients with Gram-positive ABSSSIs/cSSTIs (Noel 2008a).


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Clinical cure at the test-of-cure (TOC) visit was primary endpoint in both studies. 
Clinical cure 
rates in 
study 
BAP00414 
were 
81.9% 
(ceftobiprole) 
vs 
80.8% 
(vancomycin/ceftazidime) in the Intent-to-Treat (ITT) analysis set (95% CI of the 
between-group difference ceftobiprole minus comparator: −4.5 to 6.7), and 90.5% 
(ceftobiprole) vs 90.2% (vancomycin/ceftazidime) in the Clinically Evaluable (CE) analysis 
set (95% CI of between-group difference: −4.2 to 4.9).
Clinical cure rates in study BAP00154 were 77.8% (ceftobiprole) vs 77.5% (vancomycin) in 
the ITT analysis set (95% CI of between-group difference: −5.5 to 6.1), and 93.3% 
(ceftobiprole) vs 93.5% (vancomycin) in the CE analysis set (95% CI of between-group 
difference: −4.4 to 3.9).
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 q8h to treatment with ceftriaxone 2 g q24h with or without 
linezolid 600 mg q12h, for subjects hospitalized with CAP, within a pre-specified margin of 
10% for the primary efficacy endpoint of clinical cure rate at the TOC visit. The ITT analysis 
set included 314 ceftobiprole patients and 324 patients in the comparator group.
The clinical cure rates at the TOC visit were 86.6% and 87.4% in the ceftobiprole 
and ceftriaxone with or without linezolid groups, respectively, in the CE analysis set, and 
76.4% and 79.3% in the ITT analysis set. The respective clinical cure rates in patients in 
Pneumonia Outcomes Research Team (PORT) Risk Classes ≥III (Pneumonia Severity Index
[PSI] score ≥ 71) were 86.5% and 86.3% (ITT), and 79.1% and 78.5% (CE).
1.4.6
Efficacy in hospital-acquired pneumonia
In the Phase 3 HAP study BAP248/307 (Awad 2014), the non-inferiority of ceftobiprole 
500 mg q8h to ceftazidime 2 g q8h plus linezolid 600 mg q12h was demonstrated within the 
pre-specified 15% margin for the primary efficacy endpoint of clinical cure rate at the TOC 
visit for all subjects in the CE and 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/ceftazidime groups, respectively.
Non-inferiority of ceftobiprole to linezolid/ceftazidime was also demonstrated in the 
prespecified subgroup of subjects with HAP (excluding ventilator-associated pneumonia 
[VAP]) subjects (N=571). Non-inferiority of ceftobiprole was not demonstrated in the 
smaller subset of VAP subjects (N=210).


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1.4.7
Safety………….…….
The current safety experience from clinical studies of ceftobiprole comprises 3,037 subjects 
(1,404 from Phase 3 pneumonia studies, 1,633 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.
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 include thrombocytopenia, 
agranulocytosis, anaphylaxis, Clostridium difficile colitis, convulsion, agitation (including 
anxiety, panic attacks and nightmares), and renal failure.
1.5
Rationale for study BPR-CS-009
Favorable pharmacological properties and a rapid bactericidal effect compared to other drug 
classes, make -lactam antibacterials a mainstay treatment of SAB. However, none of the 
current -lactams licensed for the treatment of SAB provide coverage against MRSA. 
Ceftobiprole has bactericidal activity against both MSSA and MRSA, and therefore 
addresses shortcomings of the alternative -lactam antibacterials for this indication. In 
addition, animal studies of IE indicate that ceftobiprole may provide superior efficacy in the 
clearance of vegetations from heart valves (see Section 1.3.1.2).
Daptomycin, a cyclic lipopeptide, is the only antibacterial treatment licensed for SAB 
including infective endocarditis that provides similar bactericidal activity against both MSSA 
and MRSA (see Section 1.5.2.9).
The proposed study is designed to compare ceftobiprole versus daptomycin in a randomized, 
double-blind study. The study will include a broad spectrum of patients with complicated 
SAB, which is expected to enhance its applicability to clinical practice compared to existing 
studies. This includes subgroups such as patients on chronic hemodialysis, a population that 
has not been studied in other completed (daptomycin NCT00093067 [Fowler 2006]) or 
ongoing (telavancin NCT02208063) Phase 3 studies in SAB, based on the available 
published information.
As animal studies have indicated the potential of an increased risk of convulsions 
(see Section 1.3.3) with prolonged ceftobiprole therapy (> 4 weeks treatment duration), an 
initial cohort was enrolled with a maximum treatment duration of 28 days (Cohort 1). After 
completion of 80 patients (approximately 40 patients per treatment group) who received 
study medication for 21–28 days, an interim safety assessment was performed by an 
independent Data and Safety Monitoring Board (DSMB) (see Appendix 7). Based on this
analysis, the treatment duration was extended to 42 days (Cohort 2), after discussion with 
the United States Food and Drug Administration (FDA).


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As a consequence of the treatment duration restriction in the initial cohort to a maximum of 
28 days, some forms of SAB, such as patients with osteomyelitis or brain abscesses, or right-
sided infective endocarditis in patients with additional complications that necessitate more 
than 28 days of study treatment, were excluded from the initial phase of the study.
1.5.1
Summary of study design
This is a randomized, double-blind, multi-center study to assess the efficacy and safety of 
ceftobiprole medocaril (500 mg q6h, administered as an intravenous 2-h infusion from study 
Day 1 to Day 8, and 500 mg q8h from study Day 9 onwards, with renal function-dependent 
dose adjustment) compared to daptomycin (6 mg/kg, up to 10 mg/kg q24 h with renal 
function-dependent dose adjustment) in the treatment of complicated bacteremia, including 
IE caused by S. aureus.
In the first part of the study, the maximum duration of study antibacterial treatment was 
limited to 28 days. Following an interim safety analysis, this treatment duration is extended 
up to 42 days (i.e., 21–42 days). 
1.5.2
Study design rationale
1.5.2.1 Randomization and blinding
A randomized (1:1 ratio), double-blind study with patients, investigators, and clinical staff 
fully blinded is considered the most robust study design. Randomization minimizes
differences between treatment groups at the outset of the study (or distributes these 
differences at random), and blinding supports the objective assessment of efficacy and 
safety, and prevents potential biases due to differential treatment or differential assessment 
of outcomes when the treatment allocation is known by investigators.
A blinded study also minimizes potential issues with the post-randomization ascertainment 
of different types of complicated SAB. The determination of a final diagnosis of underlying
conditions or complications of SAB frequently takes several days, during which patients are 
already on active antibacterial treatment. Allowance of a post-randomization ascertainment 
window takes this clinical reality into account, and permits enrollment of patients whose 
diagnostic work-up is ongoing at the time of randomization, which represent a large 
proportion of patients with complicated SAB. In a blinded study, this post-randomization 
ascertainment window is not affected by potential biases that could be introduced when 
investigators are unblinded and may make subjective determinations post-randomization as 
to which patients have confirmed SAB, and are thereby to be included in the primary 
analysis population.


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Selected pharmacy staff will be unblinded to treatment allocation, as the conduct of the study 
would otherwise not be feasible. However, implementation of, and strict adherence to, site-
specific blinding plans has been shown to be effective in maintaining the blind of the 
investigator and clinical staff in other recent Phase 3 antibacterial studies, e.g., in ABSSSI.
1.5.2.2 Randomization stratification factors
Randomization stratification factors in this study are study site, dialysis status, and prior 
antibacterial treatment use (i.e., use of any systemic antibacterial treatment potentially 
effective against S. aureus within 7 days of randomization). In the analysis, study sites will 
be pooled according to geographic region, and the primary analysis will be adjusted by 
geographic region, hemodialysis status, and prior antibacterial treatment use. The rationales
for these factors are respectively to balance the treatment arms with respect to regional 
standards of medical care; to allow for the fact that hemodialysis patients may be considered 
a specific patient group with underlying chronic diseases, with prognoses which may differ 
from non-hemodialysis SAB patients, and with a presumed high prevalence of catheter- or 
shunt-related SAB; and to account for the potential confounding effect of prior antibacterial 
treatment on study outcomes. The introduction of additional stratification factors at 
randomization, e.g., based on different types of SAB or infective endocarditis, would be 
unreliable, because the final ascertainment of these conditions may not yet be available at the 
time of randomization.
1.5.2.3 Primary endpoint
The primary endpoint of overall success comprises several components, including survival, 
absence of endocarditis and SAB-related metastatic infections, resolution of SAB-related 
symptoms, and microbiological eradication. This is considered to be a clinically meaningful 
endpoint, similar to that utilized in other Phase 3 studies in SAB (daptomycin NCT00093067
[Fowler 2006], or telavancin NCT02208063).
1.5.2.4 Primary endpoint assessment
A post-therapy assessment time point 70 days after randomization provides insurance that 
observed favorable treatment effects are durable, and that long-lasting cure from SAB and its 
complications is achieved. Furthermore, the assessment by an independent blinded Data 
Review Committee (DRC, see Appendix 4) optimizes uniformity and homogeneity through 
the application of standardized assessment criteria, and supports the robustness of the 
primary outcome assessment in a non-inferiority study setting. The independent DRC will 
review detailed patient profiles, including imaging, microbiological, and laboratory results, 
of all patients in the ITT population, to verify the baseline condition of SAB, its 
complications, and the response outcome for the primary endpoint in the modified intent-to-
treat (mITT) population, and for the secondary endpoints. The results of the DRC review, 
rather than the investigator’s assessment, will form the basis for an assessment of the non-
inferiority of ceftobiprole versus daptomycin.


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1.5.2.5 Primary analysis population
The primary analysis population is the mITT population, defined as the subset of patients in 
the ITT population who receive any amount/dose of study medication, and who have a blood 
culture positive for S. aureus at baseline based on a central microbiology laboratory 
assessment (or unequivocal evidence of a baseline blood culture positive for S. aureus at the 
local laboratory). The double-blind nature of the study, together with a short time frame 
(no more than 6 h) between randomization and start of study treatment, is considered 
sufficient justification for the exclusion of patients from the mITT population who were 
randomized but did not receive any study treatment.
In this context, the blinding prevents a potential differential bias between treatment groups if
investigators could withhold study treatment from randomized patients based on knowledge 
of the treatment group allocation.
1.5.2.6 Secondary endpoints
Secondary endpoints have been selected based on clinical relevance, and include individual 
components of the primary endpoint such as all-cause mortality, microbiological eradication, 
and development of new metastatic lesions, as well as an assessment of the primary endpoint
in additional analysis populations.
1.5.2.7 Patient population
The study selection criteria allow the inclusion of a broad spectrum of patients with 
complicated SAB, including those on hemodialysis, a subgroup which has not been studied 
in other Phase 3 SAB clinical studies.
While the inclusion of a broad spectrum of patients improves the external validity of the 
study and its applicability to clinical practice, it also increases the heterogeneity of the study 
population. To limit this heterogeneity, the study has been designed to focus on patients with 
complicated SAB, and to exclude patients from enrollment who present with uncomplicated 
forms of SAB, e.g., by excluding catheter-related infections in non-hemodialysis patients or 
in patients without local or metastatic complications or infective endocarditis, or by 
excluding patients with negative follow-up blood cultures who have no signs of metastatic 
complications or IE. In addition, randomization is stratified by dialysis status, as patients on 
hemodialysis are considered a distinct group who may often present with catheter- or 
shunt-related complications rather than metastatic complications or IE.
An attempt to balance subgroups of various types of complicated SAB by introducing 
additional randomization strata would be problematic, because a final ascertainment of the 
type of complicated SAB may not be available at the time of randomization, especially in 
patients with endocarditis or osteoarticular infections.
In the pivotal Phase 3 study with daptomycin, the overall success rates were comparable for 
different types of complicated SAB, except for patients with left-sided endocarditis, whose 
success rates were very low (Table 2).


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Table 2
Comparison of overall success rates with daptomycin vs standard-of-care 
comparators in subgroups of complicated SAB
Group (mITT)
Overall success at PTE
Reference
Daptomycin
% (n/N)
Comparator
% (n/N)
Pooled groups
% (n/N)
Complicated SAB 
excluding endocarditis
43% (26/60)
38% (23/61)
40% (49/121)
Fowler 2006
Complicated SAB 
or right-sided endocarditis
43% (34/79)
39% (30/77)
41% (64/156)
Fowler 2006
Right-sided endocarditis
42% (8/19)
44% (7/16)
43% (15/35)
Fowler 2006
Kanafani 2010
Left-sided endocarditis
11% (1/9)
22% (2/9)
17% (3/18)
Fowler 2006
Osteoarticular infections
67% (14/21)
55% (6/11)
63% (20/32)
Lalani 2008
Uncomplicated SAB
56% (18/32)
55% (16/29)
56% (34/61)
Fowler 2006
SAB=Staphylococcus aureus bacteremia; PTE=Post-treatment evaluation; mITT=modified intent-to-treat.
Patients with left-sided endocarditis are therefore excluded from the study. Many of these
patients are candidates for surgery, and those who are not represent a very unfavourable 
prognostic subgroup.
1.5.2.8 Prior and concomitant antibacterial treatments
As prior and concomitant antibacterial treatments that provide activity against S. aureus may 
confound the study outcomes, the permitted duration of prior antibacterial treatment has been 
restricted to 48 h or less within the 7 days prior to randomization.
With some exceptions (see Section 5.5.3), the use of concomitant antibacterial treatments is 
prohibited from the start of study medication up to the PTE visit. If it occurs, its significance 
is to be assessed by the blinded DRC in accordance with guidelines provided in Appendix 6, 
to determine whether the treatment had an impact on the primary endpoint.
1.5.2.9 Active comparator and non-inferiority margin
A non-inferiority study versus an active comparator design has been chosen due to the severe 
and often life-threatening nature of complicated SAB, for which a placebo-controlled study 
would be unethical. Daptomycin is considered the most efficacious comparator, with potent 
activity against both MSSA and MRSA; it is approved for the treatment of SAB, including 
right-sided infective endocarditis (RIE), in the US and many countries worldwide, which 
allows the conduct of a global study in the treatment of SAB.
The use of vancomycin as a comparator would not be clinically acceptable for a substantial 
proportion of study investigators, due to concerns about its weaker bactericidal activity 
against MSSA. This is not a concern with daptomycin, which has shown similar clinical 


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efficacy in a Phase 3 study to standard-of-care semi-synthetic penicillins (nafcillin, oxacillin) 
in patients with MSSA bacteremia (44.6% vs 46.7% overall success rate for daptomycin and 
semi-synthetic penicillins, respectively) (Fowler 2006). Daptomycin has also shown similar 
in vitro activity against MSSA to cloxacillin and nafcillin (Cantoni 1990, Huang 2008, 
LaPlante 2004).
The use of multiple comparators, or a switch between different antibacterial treatments in the 
control group, would preclude the conduct of a blinded study for practical reasons.
The justification for the non-inferiority margin is described in Appendix 8.
1.5.3
Dosing rationale for ceftobiprole and daptomycin
The recommended ceftobiprole dosing regimen for licensed indications is 500 mg, 
administered as a 2-h intravenous infusion every 8 h. The ceftobiprole dosing regimen for 
this study aims to achieve rapid, early killing of S. aureus and to optimize the ability to 
achieve effective bloodstream clearance in the initial treatment period. The median time to 
S. aureus bloodstream clearance, as reported in the Phase 3 study with daptomycin
(Fowler 2006), is 8 to 9 days. Therefore, for the first 8 days of study treatment ceftobiprole 
500 mg will be administered as 2-h infusions every 6 h instead of every 8 h. This will 
achieve a sustained coverage for S. aureus well above the ceftobiprole MIC90 of 2 mg/L for 
MRSA (Farrell 2014). Based on the need for prolonged therapy with an acceptable number 
of infusions per day as well as adequate coverage, from Day 9 onwards the frequency of 
2-h infusions will be reduced to the standard q8h.
Daptomycin will be used in this protocol as the active control comparator antibacterial agent.
Adjustments of the recommended dose of 6 mg/kg to higher doses (up to 10 mg/kg) may be 
implemented, according to institutional standards, to reflect the clinical-practice situation 
(see Section 3.1).
The duration of study treatment is up to 42 days. Within this time frame, the study 
investigator will determine the study treatment duration for each patient.
The minimum target treatment duration in this study is 21 days. Some guideline 
recommendations permit shorter durations (e.g., 14 days treatment from the first negative 
blood-culture) for conditions such as uncomplicated SAB or uncomplicated right-sided 
endocarditis caused by S. aureus (characterized by the absence of renal failure, 
extrapulmonary metastatic infections, aortic or mitral valve involvement, meningitis, or 
infection by MRSA); however an extended treatment duration of at least 21 days appears 
justified in view of the degree of uncertainty both in the literature and among practising 
clinicians, of whether SAB is truly uncomplicated. In this context it is important to note that 
recent studies have suggested that among patients identified with SAB, the majority of 
patients present with complicated SAB (Kaasch 2014, Incani 2013).


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1.6
Benefit–risk assessment
SAB is a leading cause of bloodstream infections and is associated with significant morbidity 
and mortality. Currently there are only a limited number of antibiotics available for the 
treatment of SAB, and the resistance to these antibiotics is increasing. Therefore, there is a 
need to augment the existing choice of antibacterial treatment options against SAB.
Both study drugs, ceftobiprole and daptomycin, have bactericidal activity against MSSA and 
MRSA, and are expected to have a beneficial therapeutic impact for participating patients. 
Daptomycin is already approved for the treatment of SAB, including RIE, in many countries 
worldwide. The current study may help to develop further understanding of SAB, and may 
potentially result in the addition of a new treatment (ceftobiprole) for patients with SAB.
All study drugs are marketed in many countries globally. There are relatively large safety 
databases for both ceftobiprole and daptomycin based on previous randomized clinical 
studies and on post-marketing real-world experience. Both antibiotics have generally been 
shown to be well tolerated and to have a good safety profile. The safety risks of the 
investigational drug, ceftobiprole, are consistent with the cephalosporin class of antibiotics 
that have been used in clinical practice for decades. Current experience with ceftobiprole is 
described in more detail in Sections 1.2 through 1.4, including the most common adverse 
reactions associated with its use. Moreover, it is not anticipated that either ceftobiprole or 
daptomycin will interfere with other treatments the patients may receive while enrolled in 
this study. Patients in the study will undergo tests and procedures that represent clinical 
standard-of-care for the diagnosis and management of complicated SAB.
The study sites are experienced in the management of SAB and in the conduct of clinical 
studies. They have available procedures to provide the best possible care for the study 
patients, including the ability to manage possible side effects. All patients are closely 
monitored during the entire treatment duration and thereafter. The protocol eligibility criteria 
have been selected to exclude patients who may not benefit from the study drugs, are 
unstable, or may be at an increased risk of adverse effects from the study drugs.
Considering the potential utility of ceftobiprole as a novel broad-spectrum antibacterial 
treatment, the expected benefits of the current study outweigh potential risks.


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2
OBJECTIVES OF THE STUDY
2.1
Primary objective
To demonstrate the non-inferiority of ceftobiprole to daptomycin for overall success as 
assessed by an independent DRC in the treatment of S. aureus bacteremia, including 
infective endocarditis, at the post-treatment evaluation (PTE) visit* in the modified intent-to-
treat (mITT) population.
2.2
Secondary objectives

To compare ceftobiprole with daptomycin with respect to:
1. All-cause mortality through Day 70 (PTE visit) and Day 28 in the ITT and mITT 
populations.
2. Microbiological eradication rates (negative blood culture for S. aureus) at Day 4, Day 
8, and the end-of-treatment (EOT) and PTE visits.
3. Overall success rates in the mITT, ITT, and clinically evaluable (CE) populations:
a) at the EOT and PTE visits (ITT and CE populations only)
b) at the EOT and PTE visits, for IE vs non-IE SAB
c) at the EOT and PTE visits, by renal-function status
4. Development of new metastatic foci, or other complications of SAB, after Day 7.
5. Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-
culture-negative for S. aureus, obtained at least 24 h after the first negative blood-
culture.
6. Safety and tolerability (Safety population).

To assess the pharmacokinetics (PK) of ceftobiprole.
                                                
* The PTE visit will be performed 70 days (± 5 days) after randomization.


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3
STUDY DESIGN
3.1
Overview of study design and dosing regimen
This is a randomized, double-blind, double-dummy, active-controlled, parallel-group, 
multi-center study in adult hospitalized* patients with SAB, including IE,  conducted in two 
parts.
In Part 1 of the study (Cohort 1), the administration of the study drug was restricted to 
28 days. Exceptional cases of patients in Cohort 1 who turned out to require more than 28 
days of treatment were discontinued from the study, with treatment allocation remaining 
blinded. These patients were switched to open-label non-study treatment according to 
institutional practice, and considered failures in the mITT and ITT analyses irrespective of 
treatment groups.
Part 2 (Cohort 2): Following a protocol pre-defined DSMB interim safety assessment after 
treatment of 80 patients (approximately 40 patients per treatment group) who received study 
medication for 21–28 days, a decision was made to extend the maximum treatment period to 
42 days, and the protocol was amended accordingly. 
The decision rules for the DSMB interim safety assessment of Cohort 1 are provided in 
Appendix 7.
The study comprises three phases (see Table 3): 
1. Screening assessments of up to 72 h prior to randomization (with the possibility of
utilizing existing echocardiography assessments [TTE or TEE] that demonstrated 
definitive RIE within 10 days of randomization) (see Section 5.2.2).
2. Randomization and subsequent active-treatment with intravenous
study drug 
(ceftobiprole or daptomycin).
3. Post-treatment, comprising an EOT visit (within 72 h of last study-drug administration),
Day 35 (±3 days), Day 42 (±3 days), and a PTE visit on Day 70 (±5 days) 
post-randomization.
                                                
* In a hospital or equivalent medical confinement or clinical research unit.


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Table 3
Summary of treatment and follow-up schedule
Study phase
1
2
3
Pre-treatment
Active-treatment
Post-treatment
Screening assessments
Randomization and study-
drug treatment
End-of-treatment visit 
(EOT)
Post-treatment 
evaluation visit (PTE)
Up to 72 h prior to 
randomization
Day 1 up to Day 42  
Within the 72 h after 
the last treatment 
administration
Day 70 (±5 days) post-
randomization
3.1.1
After randomization and during active treatment, patients will receive 
ceftobiprole medocaril powder for solution for infusion (administered as 2-h 
intravenous infusion) according to the schedule outlined in Table 4Duration of 
treatment
The target treatment duration is 21 to 42 days of study drug, with the treatment duration 
within this window to be defined by the study investigator.
Exceptional cases of patients who turn out to require more than 42 days of treatment will be 
discontinued from the study, with treatment allocation remaining blinded. These patients are 
to be switched to open-label non-study treatment according to institutional practice, and 
considered failures in the mITT and ITT analyses irrespective of treatment groups.
Ceftobiprole medocaril powder for solution for infusion will be administered as a 2-h 
intravenous infusion according to the schedule in Table 4.
Table 4, or daptomycin lyophilized powder for solution for infusion (administered as 0.5-h 
intravenous infusion) according to the schedule outlined in Table 5.
Study assessments are shown in Table 6 and outlined in more detail in Section 5.
3.2
Endpoints
3.2.1
Primary endpoint………………
The primary endpoint is overall success at the PTE visit (Day 70±5 days post-randomization) 
in the mITT analysis set, as assessed by the DRC. The DRC will be a group of independent 
clinical experts, blinded to treatment allocation and not associated with the study conduct, 
who will review patient profiles, including signs and symptoms of infection, and relevant 
microbiological and imaging findings, and will assess the patients’ clinical and 
microbiological outcomes (see Appendix 4).
The primary endpoint will be tested for the non-inferiority of ceftobiprole versus daptomycin 
using a non-inferiority margin of 15%.
Overall success is defined as all of the following criteria being met:
1. Patient alive at Day 70 (±5 days) post-randomization.


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2. No new metastatic foci or complications of the SAB infection.
3. Resolution or improvement of SAB-related clinical signs and symptoms.
4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture 
for S. aureus):

at least one while the patient is on active study treatment; AND

confirmed by at least one subsequent negative blood culture for S. aureus
- either in the period between 7 days after the EOT visit and the PTE visit
- or at the PTE visit


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Treatment failure is deﬁned as any of the following:
1. Premature discontinuation of study treatment due to DRC-assessed lack of efficacy (as 
assessed by the DRC) or for adverse events (AEs) that represent manifestation of disease 
progression or relapse, at any time between first dose of study drug and the PTE visit.
2. Development of new metastatic or other complications related to SAB (see Section 
5.4.5.3.2) between Day 8 and the PTE visit. Development of new metastatic or other 
complications of SAB prior to Day 8 will be assessed by the DRC on a case-by-case 
basis to assess whether these constitute a delayed manifestation of the baseline disease or 
new complications.
3. SAB relapse or reinfection based on evidence from a blood culture positive for S. aureus
(after documented clearance of S. aureus
from the bloodstream
and clinical 
improvement) between the EOT and PTE visits.
4. Receipt of systemic non-study antibacterial treatment, other than those permitted under 
the protocol, for the treatment of SAB. This includes patients who are prematurely 
discontinued from study therapy due to an AE, but who require continuation of 
antibacterial treatment for SAB.
5. Treatment of infections other than SAB with systemic non-study antibacterial treatment 
which is potentially effective against S. aureus (see Appendix 5), and which 
is considered by the DRC to have a relevant impact on the primary endpoint in 
accordance with the guidelines provided in Appendix 6.
6. Death for any reason between first administration of study drug and the PTE visit.
7. Indeterminate outcome, defined as any data needed to determine whether the outcome is 
success or failure missing at the PTE visit, including but not limited to:
a) missing PTE visit, or missing key data to evaluate the primary endpoint
b) lost-to-follow-up, or patients who withdrew consent prior to the PTE visit
c) patients not meeting the criteria for Success or Failure, or patients not meeting all
criteria for overall success
8. Requirement for systemic antibacterial treatment for SAB beyond EOT.


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3.2.2
Secondary endpoints
1. All-cause mortality (mITT population) at Day 70 (PTE visit)
All-cause mortality will also be assessed at Day 28, and in the ITT population, and will be 
assessed descriptively.
2. Microbiological eradication (mITT population) at Day 70 (PTE visit)
Microbiological eradication will also be assessed in the CE population, and at Day 4, Day 8, 
and the EOT visit, and will be assessed descriptively.
Eradication: No growth of the baseline pathogen(s), secondary to an adequate clinical 
response, based on a negative blood culture while the patient is on active study treatment 
which is confirmed by at least one subsequent negative blood culture for S. aureus, either in 
the period between 7 days after EOT and the PTE visit, or at the PTE visit.
Failure: Persistence, relapse, or reinfection of S. aureus infection, defined as one or more of:

Ongoing positive blood cultures leading to discontinuation of the study drug

Subsequent isolation of S. aureus from a blood culture after clearance of bacteremia and 
clinical improvement
–
Relapse: bloodstream infection with the same pathogen isolated at baseline based on 
genotyping
–
Reinfection: bloodstream infection with a different S. aureus strain to that isolated at 
baseline based on genotyping

Absence of at least two negative blood cultures (at least one negative blood culture on 
active study treatment, and at least one post-treatment) to confirm eradication
Relapse or reinfection between EOT and PTE that is reported to the investigator from a 
healthcare provider not involved in the study (e.g., from another hospital), needs to be 
thoroughly documented and will be reviewed by the investigator and the DRC for 
determination.
3. Overall success rate at PTE (CE population)
The overall success rate will also be assessed at the EOT visit in the mITT, ITT and CE 
populations, and in the ITT population at the PTE visit, and will be assessed descriptively.
See definitions for the primary endpoint above.


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4. Development of new metastatic foci or other complications of SAB after Day 7 (mITT 
population)
Development of new metastatic foci or other complications of SAB after Day 7 will also be 
assessed in the CE population, and will be assessed descriptively.
Timepoints: Day 8–EOT, and PTE
Newly diagnosed IE or complicated SAB with metastatic foci or other complications of 
S. aureus infection, including metastatic foci in the vertebral column (vertebral abscess, 
osteomyelitis, 
discitis 
or 
epidural 
abscess), 
cerebral 
abscess/infarction, 
splenic 
abscess/infarction, renal abscess/infarction, psoas abscess or other deep-tissue abscess, other 
metastatic infection of native tissue, septic arthritis (or bacterial joint infection/empyema), 
septic or suppurative thrombophlebitis, and septic pulmonary emboli/infarction.
5. Time to S. aureus bloodstream clearance (mITT and CE populations)
Timepoints: Day 3–EOT
Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-
culture-negative for S. aureus obtained at least 24 h after the first negative blood-culture.
6. Safety/Tolerability (Safety population)
Timepoints: First dose of study drug–PTE
Incidence, type, severity, and relationship to study medication of AEs; and changes in 
laboratory tests (hematology, biochemistry including haptoglobin, urinalysis, and Coombs-
test).
7. Pharmacokinetics of ceftobiprole (PK population)
Plasma levels of ceftobiprole and the -lactam ring open product BAL1029
Sparse PK sampling (all patients)

Day 3: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h

Day 12: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
Rich PK sampling (selected sites, N=40 ceftobiprole-treated patients [i.e., approximately 80 
patients overall])

Day 3: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 3 h, 4 h, 6 h

Day 12: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
Plasma-concentration data will be analyzed at each time point and will be presented as 
individual concentrations with descriptive statistics (mean, SD, CV%, min, median, max).


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3.3
Treatment plan
3.3.1
Duration of treatment
The target treatment duration is 21 to 42 days of study drug, with the treatment duration 
within this window to be defined by the study investigator.
Exceptional cases of patients who turn out to require more than 42 days of treatment will be 
discontinued from the study, with treatment allocation remaining blinded. These patients are 
to be switched to open-label non-study treatment according to institutional practice, and 
considered failures in the mITT and ITT analyses irrespective of treatment groups.
Ceftobiprole medocaril powder for solution for infusion will be administered as a 2-h 
intravenous infusion according to the schedule in Table 4.
Table 4
Ceftobiprole administration
Study day
Normal renal function to 
mild renal impairment
CLCr ≥50 mL/min
Renal impairment 
(non-dialysis)
Intermittent 
hemodialysis or 
peritoneal dialysis
Day 1 to Day 8
500 mg q6h
CLCr 30–< 50 mL/min: 500 mg q8h
CLCr < 30 mL/min: 250 mg q8h
250 mg q24h
Day 9 onwards
500 mg q8h
CLCr 30–< 50 mL/min: 500 mg q12h
CLCr < 30 mL/min: 250 mg q12h
250 mg q24h
CLCr=Creatinine clearance based on the Cockcroft-Gault formula.
Daptomycin lyophilized powder for solution for infusion will be administered as a 0.5-h 
intravenous infusion according to the schedule in Table 5.
Table 5
Daptomycin administration
Normal renal function to 
moderate renal impairment
Renal impairment 
(non-dialysis)
Intermittent hemodialysis or 
peritoneal dialysis
Daptomycin
(0.5-h infusion)
CLCr ≥ 30 mL/min
6 mg/kg q24h
CLCr < 30 mL/min 
6 mg/kg q48h
6 mg/kg q48h
CLCr=Creatinine clearance based on the Cockcroft-Gault formula.
In accordance with institutional standards, an increase in the dose of daptomycin 
administered (up to 10 mg/kg) may be implemented.
To maintain the blinding of study treatments, patients in the ceftobiprole group will receive 
dummy infusions with placebo (physiological saline, 0.9% NaCl) matching daptomycin, and 
patients in the daptomycin group will receive dummy infusions with placebo (physiological 
saline, 0.9% NaCl) matching ceftobiprole.


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No switches to other systemic antibacterial treatments are permitted for any of the study 
drugs prior to the PTE visit. There is no intravenous-to-oral switch for any of the treatments 
in this study.
Details of treatment with active study drug and dummies, and dose adjustment of study drugs 
according to renal function, are provided in Section 6.4.
3.3.2
Missed-dose management
Doses are to be administered in accordance with the schedules in Table 4 and Table 5. If one 
or more doses are missed for administrative reasons, the investigator may consider 
discontinuing the patient from the study after discussion with the sponsor’s medical monitor.
3.3.3
Overdose………………
Ceftobiprole: There is no available information on overdoses with ceftobiprole in humans. 
The highest daily dose administered in Phase 1 clinical studies was 3 g (1 g q8h). If an 
overdose occurs, it should be treated symptomatically. Ceftobiprole plasma concentrations 
can be reduced by hemodialysis. In a study in which six subjects with ESRD on 
hemodialysis received a single 250 mg dose of ceftobiprole by intravenous infusion, 
ceftobiprole was demonstrated to be hemodialysable, with an extraction ratio of 0.7.
Daptomycin: In the event of overdosage, supportive care is advised with maintenance of 
glomerular filtration. Daptomycin is cleared slowly from the body by hemodialysis 
(approximately 15% of the administered dose is removed over 4 h) and by peritoneal dialysis 
(approximately 11% of the administered dose is removed over 48 h). The use of high-flux 
dialysis membranes during 4 h of hemodialysis may increase the percentage of dose removed 
compared with that removed by low-flux membranes.
3.4
Definition of End of Study
The End of Study is defined as the completion of the last study-related contact with any 
patient, referred to as the date of ‘Last Patient, Last Visit’ (LPLV).
4
STUDY POPULATION
4.1
Target population
Adult male or female patients with SAB, including IE, meeting all of inclusion criteria
1–5, at least one of inclusion criteria 6–11, and none of the exclusion criteria, are eligible for 
enrollment in this study.
4.2
Inclusion criteria
Patients meeting all of inclusion criteria 1–5 and at least one of inclusion criteria 6–11 will 
be eligible for enrollment.
1. Male or female ≥ 18 years of age.


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2. Informed consent signed by the patient (or by their legally acceptable representative, if 
appropriate) indicating that they understand the purpose of, and procedures required for, 
the study and are willing to participate in the study.
3. SAB, based on at least one positive blood culture obtained within the 72 h prior to 
randomization:
(a) identified by culture laboratory report, or
(b) positive diagnostic test for S. aureus (e.g., polymerase chain reaction [PCR], tube 
coagulase test and fluorescent in situ hybridization [FISH]) obtained from a blood 
culture.
Note: The microbiological work-up of the blood culture may:

Occur prior to informed consent to participation in the study (see Section 5.2.1 and 
Table 7).

Be undertaken either on-site or in an external microbiology laboratory specifically 
appointed for the purposes of this study.

Use a diagnostic test:
–
routinely performed locally for the detection of S. aureus from blood cultures
or
–
provided to the laboratory for the purpose of this study, if the test has regulatory 
approval in the country where the test is being performed
Regardless of diagnostic method, every effort should be made to isolate and send all unique 
organisms from blood to the Central Microbiology Laboratory; this applies particularly to the 
S. aureus isolated from blood at the Screening visit. The Central Microbiology Laboratory 
will re-identify all isolates, with the results to be used to determine whether the patient meets 
the study inclusion criteria. 
Nevertheless, patients without a Central Microbiology Laboratory assessment may be 
included in the mITT population if there is unequivocal documented evidence of a baseline 
blood culture positive for S. aureus at the local laboratory. 
4. At least one of the following signs or symptoms of bacteremia within the 72 h prior to 
randomization (may be based on measurements obtained before or after informed consent 
but within the 72 h prior to randomization):
(a) fever > 38 °C / 100.4 °F measured orally, > 38.5 °C / 101.3 °F measured 
tympanically, > 37.5 °C / 99.5 °F measured by axillary method, or > 39 °C / 102.2 °F 
measured rectally
(b) white blood cell (WBC) count ˃ 10.0 × 109/L or < 4.0 × 109/L, or > 10% immature 
neutrophils (bands)
(c) tachycardia (heart rate > 90 bpm)
(d) hypotension (systolic blood pressure < 90 mmHg)
5. Required duration of study antibacterial treatment ≤ 42 days.
6. SAB in patients undergoing chronic intermittent hemodialysis or peritoneal dialysis.


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7. Persistent SAB: documented failure of bloodstream clearance, defined as a positive blood 
culture for S. aureus within the 72 h prior to randomization, after prior appropriate anti-
staphylococcal treatment (except failure under daptomycin therapy) of at least 3 complete 
days.
8. Other forms of complicated SAB, including the following:
(a) ABSSSIs
(b) Metastatic infection of native tissue. Examples include but are not limited to:

Septic arthritis or bacterial joint infection/empyema

Septic or suppurative thrombophlebitis

Visceral soft-tissue abscesses requiring ≤ 42 days of study antibacterial treatment

Septic pulmonary emboli/infarction
Note: The diagnosis of a septic pulmonary embolism will be made by the investigator 
based on clinical symptoms of fever, cough, sputum/hemoptysis in the presence of an 
extrapulmonary infection, sepsis, or risk factors for septic emboli (e.g., intravenous drug 
use) and will be based on the following radiological signs:
Contrast-enhanced CT (preferred):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of cavitation) 
or wedge-shaped infiltrates 
–
with/without a feeding vessel sign (vessel leading to the nodule)
–
with/without pleural effusion or features suggestive of pleural empyema
Non-contrast enhanced CT (e.g., in patients with a contraindication for contrast 
administration):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of cavitation) 
or wedge-shaped infiltrates 
–
with/without pleural effusion or features suggestive of pleural empyema
Plain X-ray (e.g., in patients unable to undergo a CT):
Multifocal nodular densities or wedge-shaped infiltrates in varying stages of cavitation 
with or without pleural effusion or features suggestive of pleural empyema
9. Definite native-valve right-sided IE (RIE) by Modified Duke's Criteria (see 
Appendix 1).
Note: Patients with left-sided infective endocarditis (LIE) are excluded from the study. If LIE 
is diagnosed after onset of study therapy, patients may be maintained in the study. In the event 
that the investigator decides to discontinue the study therapy, the patient will be included in the 
mITT population and considered a failure (see Section 4.7).
The minimum requirements for a diagnosis of RIE and LIE (Modified Duke’s Criteria) are 
provided in Appendix 1. The minimum requirements for baseline diagnosis of other forms of 
complicated SAB are provided in Appendix 2.
10. Osteomyelitis (including vertebral, sternal, or long-bone osteomyelitis).
11. Epidural or cerebral abscess.


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Inclusion criteria 1–7 must be ascertained based on assessments within the 72-h screening 
window. For inclusion criteria 8–11, assessments performed up to 7 days after randomization 
may be used to confirm the diagnosis of complicated SAB.
Patients randomized with suspected complicated SAB who turn out not to meet at least 
one of inclusion criteria 6–11 (i.e., who do not have confirmed complicated SAB), will be 
considered to have uncomplicated bacteremia. These patients will continue in the study, with 
a target treatment duration of 21 days. The maximum treatment duration in this study is 
42 days.
4.3
Exclusion criteria
Patients meeting any of the following exclusion criteria at Screening will be excluded from 
the study:
1. Treatment with potentially effective (anti-staphylococcal) systemic antibacterial 
treatment (see Appendix 5) for more than 48 h within the 7 days prior to randomization.
Exception: Documented failure of bloodstream clearance with prior antistaphylococcal 
treatment (except failure under daptomycin therapy) administered for at least 3 complete 
days.
2. Bloodstream or non-bloodstream concomitant infections with Gram-negative bacteria 
that are known (at Screening) to be non-susceptible to either ceftobiprole or aztreonam.
3. Confirmed uncomplicated SAB (e.g., catheter-related non-persistent SAB without signs 
of SAB complications, unless the patient has end-stage renal disease and is on 
intermittent hemodialysis or peritoneal dialysis).
4. Left sided infective endocarditis.
Note: If LIE is diagnosed after onset of study therapy, patients may be maintained in the study. In 
the event that the investigator decides to discontinue the study therapy, the patient will be 
included in the mITT population and considered a failure. 
5. Prosthetic cardiac valves or valve support rings, cardiac pacemakers, automatic
implantable cardioverter-defibrillator, or left-ventricular assist devices.
6. Complicated SAB in patients with other foreign body material that cannot be removed 
within the 7 days after randomization.
Exceptions: 

Patients with non-infected coronary stents may be included regardless of the time of 
stent implantation.

Patients with non-infected (no signs or symptoms of clinical involvement at the time 
of randomization) prosthetic joints, plates, spinal hardware, or other extravascular 
material may be included if implantation of the foreign material was performed at 
least 60 days before randomization.


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
Patients with non-infected (no signs or symptoms of clinical involvement at the time 
of randomization) intravascular prosthetic material or vena cava filters may be 
included if implantation of the foreign material was performed at least 90 days before 
randomization.
7. Cardiac native-valve surgery planned within 3 days after randomization.
8. Community- or hospital-acquired pneumonia.
Note: The diagnosis of pneumonia will be made by the investigator based on respiratory 
complaints (e.g., cough, dyspnea, purulent secretions, and chest pain) and new or worsening 
infiltrates suggestive of bacterial pneumonia on a chest radiograph or a high-resolution CT. 
Equivocal findings on a chest radiograph should be further assessed by the conduct of a high-
resolution chest CT (if feasible) and/or the conduct of lung ultrasound to support the presence or 
absence of a diagnosis of pneumonia.
9. High probability of death within 7 days due to the underlying SAB or SAB-associated 
disease, or high probability of death within 28 days from an unrelated underlying disease.
10. Clinically-relevant hypersensitivity to -lactam antibacterials or daptomycin. 
11. Known infection due to Staphylococcus aureus that exhibits reduced susceptibility to 
daptomycin (minimum inhibitory concentration [MIC] > 1 mg/L), or ceftobiprole 
(MIC > 2 mg/L).
12. Absolute neutrophil count < 0.5 × 109/L.
13. Either: a) a history of opportunistic infections (e.g., invasive fungal infections or 
cytomegalovirus [CMV]) within 30 days prior to randomization, where the underlying 
cause of these infections is still active (e.g., leukemia, transplant, acquired 
immunodeficiency syndrome [AIDS]); or b) CD4 count < 100 cells/mm3 in patients with 
AIDS; or c) patients treated with cotrimoxazole as prophylaxis for pneumocystis 
pneumonia.
14. Requirement or expected requirement between randomization and the PTE visit for 
potentially effective (anti-staphylococcal) systemic antibacterial treatment that is 
unrelated to the treatment of SAB, e.g., in the context of planned surgery, gynecological 
or other procedures requiring antibacterial prophylaxis or other anticipated uses of 
antibacterials such as treatment for acne vulgaris.
15. Requirement for continuous renal-replacement therapy at the time of randomization, or 
high likelihood of requirement for continuous renal-replacement therapy during the study 
period. 
Note: Patients undergoing chronic intermittent hemodialysis or peritoneal dialysis are permitted 
to participate in the study.
16. Alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 8 × the upper 
limit of normal, or severe hepatic disease with Child-Pugh class C.
17. Women who are pregnant or nursing.


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18. Women who are of childbearing potential and unwilling to use an acceptable method of 
birth control during the study: female sterilization (bilateral tubal occlusion or 
oophorectomy, or hysterectomy) or male partner vasectomy; intrauterine device (IUD); 
combined (estrogen- 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; or total sexual abstinence.
Women are not considered to be of childbearing potential if they are either ≥1 year 
post-menopausal (where menopause is defined as at least 12 months of amenorrhea), or 
have a serum follicle stimulating hormone (FSH) measurement consistent with post-
menopausal status according to local laboratory thresholds. An FSH measurement at 
Screening is to be obtained for post-menopausal females aged < 50 years, or for those aged 
≥50 years who have been post-menopausal for < 2 years.
19. Use of an investigational drug in a Phase 1 study within the 30 days prior to the start of 
study treatment.
Note: Use of investigational drugs in Phase 2 or Phase 3 studies within the 30 days prior to the 
start of study drug treatment is allowed.
4.4
Patient withdrawal
Patients may voluntarily withdraw from the study at any time for any reason. The 
investigator may also withdraw a patient from the study.
The investigator should discuss all study withdrawals with the medical monitor.
4.5
Criteria for discontinuation of treatment
Reasons for discontinuation of treatment must be recorded and may include:

AE

abnormal laboratory value

abnormal test procedure result

intercurrent illness that prevents further administration of treatment

protocol violation

protocol non-compliance

lost to follow-up

administrative/logistical reasons

need for the use of systemic non-study antibacterials to treat complicated SAB (e.g., due 
to lack of efficacy)

confirmation of reduced susceptibility of S. aureus to either ceftobiprole or daptomycin, 
when a susceptibility test result is received after start of study treatment

pregnancy

death

diagnosis with a condition that requires more than 42 days of antibacterial treatment for 
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All ITT patients should be followed until complete capture of main study outcomes, 
including those who did not receive study treatment or had no confirmed SAB by a S. aureus
blood culture using a standard diagnostic test, or who discontinue the study prematurely.
For all patients who discontinue the study, AE monitoring must be continued until the PTE 
visit at Day 70 (±5 days) after randomization (see Section 7.3.2).
If a patient who has been randomized, discontinues from the study at any time, every effort 
must be made to obtain the patient’s consent to the use of the data generated as a result of 
participation up to that point, and to have the patient complete the EOT and PTE visits.
The investigator must make every effort to contact (by telephone or mail correspondence)
patients who fail to return for the EOT or PTE visits. The outcome of this contact must be 
documented by the investigator and filed in the Investigator Site File (ISF), and the reasons 
for the failure to attend the visit must be recorded in the case report form (CRF).
4.6
Replacement of patients 
Patients failing screening procedures are to be replaced.
Patients who for any reason discontinue participation in the study after randomization but 
prior to receiving the first dose of study drug, are to be replaced.
Patients who for any reason discontinue participation in the study after receiving the first 
dose of study drug are not to be replaced.
4.7
Patients with left-sided infective endocarditis
Patients with LIE are excluded from the study. 
In Part 1 of the study (Cohort 1), if LIE was diagnosed after the commencement of study 
therapy, the patient must have been discontinued from the study and switched to open-label 
non-study standard-of-care antibacterial treatment. These patients are included in the mITT 
population and considered failures.
In Part 2 of the study (Cohort 2), if LIE is diagnosed after the commencement of study 
therapy, the patient may be maintained in the study. In the event that the investigator decides 
to discontinue study therapy, the patient will be included in the mITT population and 
considered a failure.
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Summary of schedule of assessments
Table 6 presents a summary of the schedule of assessments.
Study days, as outlined in the schedule of assessments and study visits, are calendar days.
Day 1 is defined as the day on which first study drug administration occurs. However, some 
study procedures that belong to the Day 1 visit may occur on the previous calendar day, 
e.g., if randomization occurs on the calendar day prior to first study drug administration,
randomization will nevertheless be considered to belong to the Day 1 visit.


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Table 6
Schedule of Assessments
Baseline/
Screening
Active treatment
Post-treatment
Time
≤ 72 h prior to 
randomization
Day 1
Day 2
Day 3
Days 
4–12
Days 
14, 21, 28, 
35, 42*
EOT
Days 
35 (±3), 
42 (±3)*
PTE (Day 70±5 
days post-
randomization)
Study procedures
Informed consent1
X
Inclusion/exclusion criteria2
X
Medical history/demographics/prior and ongoing therapy3
X
Documentation of surgical procedures anticipated during the course of 
the study and planned at baseline
X
Complete physical examination4
X
Brief physical examination4
X
X
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
Body temperature6
X
X
X
X
X
X
X
X
X
Transthoracic echocardiography7
<------------------------------------X--------------> Day 7
Transesophageal echocardiography7
<------------------------------------X--------------> Day 7
12-lead electrocardiogram8
X
X
Pregnancy test9
X
X
X
Safety laboratory (local lab)10
X
Safety laboratory (central lab)10
X
X
Day 7
X
X
X
X
Reticulocytes, haptoglobin and Coombs test (central lab)11
X
X
X
WBC count, CRP and procalcitonin (central lab)12
X
X
X
Day 7
Day 14
X
Blood culture13, 14
X
X
X
X
<------------------------------X13----------------------------->
Investigator-assessed clinical signs and symptoms of SAB15
X
X
X
X
X
X
X
X
Assessment of deep-seated infections and metastatic or other 
complications of SAB16
X
<----------------------> Day 7
X
X
X
X
Modified Duke’s Criteria17
X
X
X
X
X
X
X
X
Randomization18
X
PK blood-sample collection19
X
Day 12
Study drug administration20
X
X
X
X
To Day 42
Drug accountability21
X
X
X
X
To Day 42
Investigator assessment of overall success22
X
X
X
X
X
X
Concomitant antimicrobial and other therapies23
X
X
X
X
X
X
X
X
Concomitant non-drug procedures23
X
X
X
X
X
X
X
X
Creatinine clearance24
X
X
X
Day 5, 7
X
Adverse events25
X
X
X
X
X
X
X
X
Health economics outcome measures26
X


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* Note: Day 35 and Day 42 may be active treatment visits for patients in Cohort 2, if treatment for longer than 28 days is required. Day 35 and Day 42 are post-treatment visits for all 
patients in Cohort 1, and for patients in Cohort 2 who are treated for longer than 28 days, but have not completed treatment by the Day 35 or Day 42 visits.
1. Written Informed Consent (IC) must be obtained within the 72 h prior to randomization (Section 5.4.1). No study-specific assessments will be performed prior to IC; however, blood 
cultures, transthoracic echocardiography (TTE), or transesophageal echocardiography (TEE) procedures performed in the context of routine clinical diagnostic practice prior to IC may 
be used for the study if they were conducted within the 72 h prior to randomization (or up to 10 days prior to randomization if RIE has been confirmed, see Section 5.4.4.10).
2. Inclusion and exclusion criteria (Sections 4.2 and 4.3) will be assessed at Screening.
3. At Screening the investigator must obtain the patient’s medical history, demographics, and prior (within 30 days) antibacterial, other drug, and non-drug therapies (Section 5.4.2)
4. Complete physical examination (Section 5.4.4) will be performed at Screening. Thereafter, a brief physical examination (Section 5.4.4) focusing on changes from baseline will be 
performed at each scheduled study visit from Day 2, up to the PTE visit.
5. Vital signs (Section 5.4.4.2) will be taken once during each scheduled study visit. Baseline vital signs will be obtained at Screening. The patient’s weight is to be assessed at Screening, 
and at a minimum on study Days 2, 3, 5, 7, 14, 21, if applicable 28/35,  at the EOT visit, and at the PTE visit.
6. Body temperature (Section 5.4.4.3) will be measured every 8 h for the first 96 h after start of treatment, and every 8 h thereafter, until a 24 h period is achieved during which no 
measurement is greater than 38 °C / 100.4 °F measured orally, 38.5 °C / 101.3 °F measured tympanically, 37.5° C / 99.5 °F measured by axillary method, or 39 °C / 102.2 °F measured
rectally. Temperature measurements will then be taken once at each scheduled study visit.
7. TTE or TEE (Section 5.4.4.10) must be performed in accordance with the description in Table 8.
8. A standard 12-lead ECG will be performed at Screening and at the EOT visit (Section 5.4.4.4).
9. Pregnancy testing is to be performed for women of childbearing potential; at Screening a serum pregnancy test is to be obtained; at the EOT and PTE visits it is at the discretion of the 
investigator whether a serum or urine pregnancy test is obtained, and subject to local regulations. The investigator may conduct additional (serum or urine) pregnancy tests to confirm 
the absence of pregnancy at any time during the study (Section 5.4.4.5). If a pregnancy test result is positive, study drug must be discontinued, and the patient followed for safety, and 
assessment of the pregnancy outcome (Section 7.4.2).
10. Central and local safety laboratory tests (Section 5.4.4.6) will be performed at Screening, and additional local laboratory tests may be performed at any time during the study, as 
clinically indicated. Safety laboratory tests will be performed on Days 3, 7, 14, 21, 28, 35, and 42, at the EOT visit, and at the PTE visit, and analyzed by the central laboratory.
11. Reticulocyte counts, haptoglobin levels and Coombs tests will be measured at Screening, and at the EOT and PTE visits.
12. White blood cell (WBC) counts, C-reactive protein (CRP) levels, and procalcitonin levels will be assessed at Screening, on Days 2, 3, 7, 14, and at the EOT visit.
13. Two sets of peripheral blood cultures (including aerobic and anaerobic) (Section 5.2.1) will be obtained at baseline. Blood cultures will be drawn at least 5 minutes apart, and samples 
for each of the two sets of blood cultures should be obtained from different anatomical locations. Post-randomization repeat blood cultures (at least one, but preferably two blood 
cultures), will be obtained on Days 1, 2 and 3. Thereafter blood cultures will be obtained approximately every 48–72 h if clearance of bacteremia has not yet been confirmed, i.e., until 
negative-S. aureus test results are obtained for two blood cultures (or negative test result for one culture if only one culture was obtained) at two time points at least 24 h apart. At least 
one blood culture must be obtained at the PTE visit, or in the period between 7 days after EOT and the PTE visit. Performance of a Gram-stain from each positive blood culture is 
recommended but not mandatory.
14. Blood cultures positive for S. aureus that were obtained in the context of routine clinical diagnostic work-up prior to obtaining informed consent, but were drawn within the 72 h prior 
to randomization, may be used for the study to determine patient eligibility, and do not need to be repeated. 
15. Clinical assessments of the signs and symptoms of complicated SAB (Section 5.4.5.2) will be made at Screening and at each scheduled study visit from Day 2, up until PTE.
16. Clinical signs of deep-seated infections and metastatic or other complications of SAB (Section 5.4.5.3) will be assessed at Screening and at each scheduled study visit from Day 2, up 
until the PTE visit. The diagnosis of deep-seated infections, metastatic or other complications of SAB must be supported by imaging studies (including ultrasound, computed 
tomography [CT], magnetic resonance imaging [MRI], and positron emission tomography/computed tomography [PET/CT]), biopsies or cultures within 72 h prior to randomization or 
within 7 days after randomization (see Table 9). The minimum requirements for baseline diagnosis of other forms of complicated SAB are provided in Appendix 2.
17. Modified Duke’s Criteria (see Appendix 1) will be assessed at Screening. In patients without definite IE, Modified Duke’s Criteria will be assessed at every scheduled visit from Day 2 
until the PTE visit. Modified Duke’s Criteria will be assessed in all patients (including those with definite IE) at Screening, EOT and PTE.
18. Patients are to be randomized (Section 5.4.3) to a study treatment within the 6 h prior to the planned time of first study-drug administration.
19. Sparse PK sampling (all patients): Days 3 and 12, pre-dose before the first BPR/PBO infusion, 2 h [end of infusion], and 4 to 6 h post-dose. Rich PK sampling (selected sites, N=40 
ceftobiprole-treated patients [i.e, approximately 80 patients overall]): Day 3: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 3 h, 4 h, 6 h post-dose; Day 12: pre-dose
before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h post-dose (Section 5.4.7).


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20. Intravenous study drug will be administered for up to 42 days (see Sections 3.1 and 6.4). Study drug treatment must be initiated within the 6 h after randomization. On each treatment 
day, study drug administration should occur within ±1 h for ≤q6h dose regimens, and ±2 h for > q6h dose regimens, of the scheduled time point.
21. Drug accountability will be performed for each study-drug administration (Section 6.5).
22. Overall success (Section 5.4.6) will be assessed at each scheduled study visit from Day 3 to the PTE visit.
23. Concomitant antimicrobial therapies, other drug-therapies, and non-drug procedures will be assessed at each scheduled study visit from Day 1 to the PTE visit.
24. Creatinine clearance: CLCR should be calculated for all patients except patients on dialysis, using the Cockcroft-Gault formula based on local laboratory results, and should be 
performed at Screening, and at a minimum on study Days 2, 3, 5, 7, 14, 21, and if applicable, 28/35. The actual age, weight and serum creatinine level on the day of CLCR calculation 
should be used. Additional CLCR calculations may be performed as clinically indicated. All CLCR results obtained during the active treatment period (i.e., when the patient is receiving 
study medication) need to be reviewed by the unblinded pharmacist (or delegate) on the day when local laboratory serum-creatinine results are obtained and the doses of ceftobiprole 
and daptomycin are adjusted in accordance with Table 13 and Table 14, respectively.
25. Adverse events and SAEs will be monitored throughout the study, from start of first dose of study treatment up to and including the PTE visit (see Sections 7.3.1 and 7.3.2).
26. Information on health economics outcome measures from baseline to the PTE visit will be collected at the PTE visit, including total length of stay in hospital, location of treatment 
within the healthcare system (e.g., Emergency Department), post-study drug procedures and interventions including AEs and any treatment required by these events, re-admission rates, 
outpatient healthcare encounters, Emergency Department visits, and surgical and non-surgical procedures, e.g., debridement, grafts, amputation, prostheses.


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5.2
Time windows for baseline/screening assessments
Baseline assessments are defined as all relevant pre-randomization assessments that may be 
used for the study.
Screening is defined as the period after informed consent has been obtained, i.e., a period up 
to 72 h prior to randomization.
Results from vital sign measurements (see Table 10), local safety laboratory tests
(see Table 10), blood cultures (see
Table 7), echocardiography (see Table 8) or 
investigations to verify deep-seated infections or complications of SAB (see Table 9), may 
be used for the study if obtained prior to informed consent (i.e., outside the screening period) 
but within a 72 h window prior to randomization (10 days for an echocardiography that was 
confirmatory of definitive right-sided endocarditis).
The study comprises three phases:

Screening of up to 72 h prior to randomization.

Randomization and subsequent active-treatment phase with intravenous study drug 
(ceftobiprole or daptomycin).

Post-treatment phase, comprising an EOT visit (within 72 h of last study-drug 
administration), Day 35 (±3 days), Day 42 (±3 days), and a PTE visit on Day 70 (±5 days)
post-randomization.
Note: Day 35 and Day 42 may be active treatment visits for patients in Cohort 2, if treatment for longer 
than 28 days is required. Day 35 and Day 42 are post-treatment visits for all patients in Cohort 1, and for 
patients in Cohort 2 who are treated for longer than 28 days, but have not completed treatment by the Day 
35 or Day 42 visits.
Patients with suspected or confirmed complicated SAB must sign informed consent within 
72 h prior to randomization. Baseline assessments must be completed according to the 
following timelines.
5.2.1
Blood cultures………………
Two sets of peripheral blood cultures (including aerobic and anaerobic) will be obtained 
from each patient at baseline. Blood cultures will be drawn at least 5 minutes apart, and 
samples for each of the two sets of blood cultures should be obtained from different 
anatomical locations. Blood cultures that were positive for S. aureus and were conducted in 
the context of routine clinical diagnostic work-up practice prior to obtaining informed 
consent, but were drawn within the 72 h prior to randomization, may be used for the study to 
determine patient eligibility, and do not need to be repeated.
Post-randomization repeat blood cultures (at least one, but preferably two blood cultures)
will be obtained on Days 1, 2 and 3. Thereafter, blood cultures will be obtained 
approximately every 48–72 h if clearance of bacteremia has not yet been confirmed, 
i.e., until negative test results for S. aureus are obtained for two cultures (or negative test 


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result for one culture if only one culture was obtained) at two time points taken at least 24 h 
apart. At least one blood culture must be obtained at the PTE visit, or in the period between 
7 days after EOT and the PTE visit.
Specimens will be cultured by the local laboratory. 
Note: The microbiological work-up of the blood culture may:

Occur prior to informed consent to participation in the study (see Section 5.2.1 and 
Table 7).

Be undertaken either on-site or in an external microbiology laboratory specifically 
appointed for the purposes of this study.

Use a diagnostic test:
–
routinely performed locally for the detection of S. aureus from blood cultures
or
–
provided to the laboratory for the purpose of this study, if the test has regulatory 
approval in the country where the test is being performed
Regardless of diagnostic method, every effort should be made to isolate and send all unique 
organisms from blood to the Central Microbiology Laboratory; this applies particularly to the 
S. aureus isolated from blood at the Screening visit. The Central Microbiology Laboratory 
will re-identify all isolates, with the results to be used to determine whether the patient meets 
the study inclusion criteria. 
Nevertheless, patients without a Central Microbiology Laboratory assessment may be 
included in the mITT population if there is unequivocal documented evidence of a baseline 
blood culture positive for S. aureus at the local laboratory. 
The central microbiology laboratory will also perform susceptibility testing with both study 
drugs. For patients with persistent SAB (see Inclusion criterion 7), the susceptibility to 
ceftobiprole and daptomycin may be assessed at the local microbiology laboratory, but must 
be confirmed by the central laboratory. If a patient is randomized based on susceptibility 
results from the local laboratory, and a conflicting result is obtained from the central 
laboratory, then the central laboratory result will be considered valid. If local susceptibility
testing is performed after a patient has been randomized, and the local results show non-
susceptibility to either study drug, then the continuation of the patient in the study will be at 
the discretion of the investigator, based on clinical assessment.
5.2.2
Echocardiography
Echocardiography assessments obtained within 72 h prior to randomization (or up to 10 days
if definite RIE has been confirmed) may be used for patient eligibility assessment, even if the 
echocardiography has been performed in the context of clinical practice prior to obtaining 
informed consent for this study.


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5.2.2.1 Transthoracic echocardiography
A transthoracic echocardiography (TTE) must be performed within the 72 h prior to
randomization in all patients, with the following exceptions:

A transesophageal echocardiography (TEE) has been performed within this time window

A diagnosis of definite RIE (according to Modified Duke’s Criteria, see Appendix 1) is 
confirmed. For these patients, a TTE (or TEE) performed within the 10 days prior to 
randomization may be used to confirm patient eligibility. A TTE or TEE must be 
repeated within the 72 h before, or within the 7 days after, randomization, for 
documentation purposes.
5.2.2.2 Transesophageal echocardiography
A TEE must be performed within 72 h prior to randomization or within 7 days after 
randomization in all patients with the following exceptions:

A diagnosis of definite RIE (according to Modified Duke’s Criteria, see Appendix 1) is 
confirmed. For these patients a TEE (or TTE) performed within 10 days prior to 
randomization may be used to confirm patient eligibility. A TTE or TEE must be 
repeated within 72 h before, or within 7 days after, randomization, for documentation 
purposes. If the diagnosis of a definite endocarditis can be based on a TTE, then a TEE is 
not required.

A condition associated with an increased risk of complications from TEE, including:
–
altered mental status or an uncooperative patient
–
unstable cardiorespiratory status 
–
esophageal stricture or malignancy (identify esophageal location prior to TEE) or 
esophageal varices with recent/active bleeding
–
surgical interposition of the esophagus
–
Zenker's diverticulum (identify esophageal location prior to TEE)
–
history of odynophagia or dysphagia
–
cervical spine arthritis with reduced range of motion
–
severe thrombocytopenia (< 50 × 109/L), elevated international normalized ratio
(˃ 4), or prolonged partial thromboplastin time (>150 seconds)
–
obstructive sleep apnea/airway compromise (consider sedation by anesthesia)


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5.2.3
Diagnostic assessments for deep-seated infections and metastatic or other 
complications related to SAB 
Diagnostic assessments for deep-seated infections and metastatic or other complications 
related to SAB (i.e., related to Inclusion criterion 8) that were conducted in the context of 
routine clinical diagnostic work-up practice prior to obtaining informed consent, but within 
the 72 h prior to randomization, may be used for the study to determine patient eligibility.
Furthermore, diagnostic assessments for deep-seated infections and metastatic or other 
complications related to SAB (i.e., related to Inclusion criterion 8) obtained within the 7 days 
after randomization may be used to determine the patient’s baseline condition of SAB.
5.2.4
Other screening assessments
Vital sign measurements and local safety laboratory tests that were conducted in the context 
of routine clinical diagnostic work-up practice prior to obtaining informed consent, but 
within the 72 h prior to randomization, may be used for the study to determine patient 
eligibility and do not need to be repeated. This includes the assessment of signs and 
symptoms of bacteremia for the purposes of Inclusion criterion 4.
All other screening assessments except a pregnancy test (physical examination, 12-lead
electrocardiogram, central laboratory safety tests, Modified Duke’s Criteria, creatinine 
clearance) must be performed after informed consent has been obtained, and within the 72 h 
prior to randomization.
A pregnancy test must be assessed within 24 h prior to randomization. Clinical signs of deep-
seated infections and metastatic or other complications of SAB must be assessed within the 
12 h prior to randomization. Clinical signs of metastatic complications (assessed by the 
investigator) include bone or back pain, back pain elicited on percussion of spine (suggestive 
of vertebral osteomyelitis, discitis, or epidural abscess); joint swelling, joint pain, pain 
elicited on external rotation of femoral head (suggestive of septic arthritis or bacterial joint 
infection/empyema); protracted fever and/or sweats, new regurgitant murmurs or heart 
failure and further clinical stigmata suggestive of endocarditis; abdominal pain, left upper 
quadrant pain (suggestive of splenic infarction); costovertebral angle tenderness (suggestive 
of renal infarction or psoas abscess); headache, focal neurologic impairment (suggestive of 
central nervous septic emboli) or other findings which could reasonably be regarded as 
clinical signs of metastatic infection. Careful examinations regarding in-dwelling prosthetic 
devices and orthopedic hardware should be undertaken.
Metastatic or other complications of SAB must be supported by imaging studies (including 
ultrasound, computed tomography [CT], magnetic resonance imaging [MRI], and positron 
emission tomography/computed tomography [PET/CT]), biopsies or cultures. The minimum 
requirements for baseline or post-baseline diagnosis of metastatic complications of SAB are 
provided in Appendix 2 and Appendix 3, respectively.


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Details on the time windows for baseline screening assessments are outlined in Section 5.2.
The respective time windows for baseline screening assessments are shown in Table 7, 
Table 8, Table 9, and Table 10.
Table 7
Time windows for baseline blood cultures
Assessment Patient 
description
Time window to randomization
Time relative to 
informed consent
Blood 
culture
Positive for 
S. aureus
Blood cultures positive for S. aureus drawn within the 72 h prior 
to randomization may be used for patient eligibility, regardless 
of whether informed consent had been obtained at the time of 
the blood draw.
Before or after
Table 8
Time windows for baseline echocardiography
Assessment
Patient 
description
Time window to randomization
Time relative to 
informed consent
TTE 
and/or 
TEE
Definite
endocarditis
TEE or TTE within the 10 days prior to randomization may 
be used for patient eligibility.
Before or after
A TTE or TEE must be repeated within the 72 h before, or 
the 7 days after randomization, for documentation purposes.
After
No definite 
endocarditis
A TEE or TTE must be performed within the 72 h prior to 
randomization for patient eligibility.
Before or after 
If only a TTE is performed within the 72 h prior to 
randomization, a TEE must either also be performed within 
the 72 h prior to randomization, or be performed within 
7 days after randomization (see Section 5.4.4.10 for 
exceptions).
After
If only a TEE is performed within the 72 h prior to 
randomization, a TTE is not required.
After
TTE=transthoracic echocardiography; TEE=transesophageal echocardiography.


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Table 9
Time windows for baseline assessments for confirmation of deep-seated 
infections and metastatic or other forms of complicated bacteremia 
(Inclusion criterion 8)
Assessment
Patient description/condition
Time window to 
randomization
Time relative to 
informed 
consent
Local findings, biopsy or 
drainage
ABSSSI
Within the 72 h before or 
7 days after randomization
Before or after
Arthrocentesis
Septic arthritis or bacterial joint 
infections/empyema
Within the 72 h before or 
7 days after randomization
Before or after
Synovial biopsy
MRI
Local findings
Septic or suppurative 
thrombophlebitis
(including peripheral, pelvic, portal 
veins; superior or inferior vena 
cava, internal jugular veins, or other 
veins
Within the 72 h before or 
7 days after randomization
Before or after
Duplex ultrasound
CT*
MRI
Chest X-ray and/or chest 
CT
Septic pulmonary emboli/infarcts
Within the 72 h before or 
7 days after randomization
Before or after
Ultrasound, CT*, MRI, 
biopsy or drainage as per 
institutional standard
Visceral soft-tissue abscesses 
requiring ≤ 42 days of study 
antibacterial treatment
Within the 72 h before or 
7 days after randomization
Before or after
* Radioisotope studies (e.g., PET or PET-CT) may be conducted as adjunct to diagnosis, as primary diagnostic approach, or 
when radiographic changes on MRI or CT scans are absent or equivocal.
CT=computed tomography; PET/CT=positron emission tomography/computed tomography; MRI=magnetic resonance 
imaging.


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Table 10 Time windows for other screening assessments
Assessment
Patient 
description
Time window to 
randomization
Time relative to 
informed consent
Demographics and medical history
All patients
Within 72 h prior 
to randomization
After
Concomitant medication (within the previous 
30 days)
Inclusion and exclusion criteria
Vital signs*
Body temperature*
Local laboratory safety tests*
All patients
Within 72 h prior 
to randomization
Before or after
Complete physical examination
12-lead electrocardiogram
Creatinine clearance**
Central laboratory tests 
Safety laboratory tests
WBC count, CRP 
and procalcitonin
Reticulocytes, haptoglobin and Coombs test
Modified Duke’s Criteria
All patients
Within 72 h prior 
to randomization
After
Pregnancy test
Women of 
childbearing 
potential
Within 24 h prior 
to randomization
After
Clinical signs of deep-seated infections and 
metastatic or other complications related to SAB
All patients
Within 12 h prior 
to randomization
After
* Vital signs measurement and local laboratory safety tests that were conducted in the context of routine clinical diagnostic 
work-up practice prior to obtaining informed consent, but within the 72 h prior to randomization, may be used for the 
study to determine patient eligibility and do not need to be repeated. This includes the assessment of signs and symptoms 
of bacteremia for the purposes of Inclusion criterion 4. 
** Assessment of creatinine clearance is not required for patients on dialysis.
Patients will be classified as having uncomplicated SAB if they are not diagnosed with a 
complication meeting one of the following criteria, up to 7 days after randomization:

being on intermittent hemodialysis or peritoneal dialysis within the 72 h prior to 
randomization (during screening)

persistent SAB

confirmation of SAB with metastatic or other complications; or

RIE


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5.3
Study visits
The following assessments and procedures are to be performed at the respective visits.
Screening (Day −1; within the 72 h prior to randomization)
Informed consent
Assign patient number
Inclusion/exclusion criteria
Medical history/demographics/prior (within 30 days) antibacterial and other pre-study
drug/non-drug therapies (including those ongoing at the time of screening, prior to 
randomization)
Documentation of surgical procedures anticipated during the course of the study and 
planned at baseline
Complete physical examination
Vital signs 
Body temperature
TTE and/or TEE – see Table 8
12-lead electrocardiogram
Pregnancy test (serum; within 24 h prior to randomization)
Safety laboratory (local and central laboratories), both blood and urine
Reticulocytes, haptoglobin and Coombs test (central lab)
WBC count, CRP and procalcitonin (central lab)
Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)
Blood culture including standard microbiological investigation indicating S. aureus 
infection (either by standard laboratory tests or by non-standard diagnostic tests 
subsequently confirmed by standard diagnostic tests for S. aureus)
Note: Blood cultures positive for S. aureus that were obtained in the context of routine clinical 
diagnostic work-up prior to obtaining informed consent, but were drawn within the 72 h prior to 
randomization, may be used for the study to determine patient eligibility, and do not need to be 
repeated.
Investigator-assessed clinical signs and symptoms of SAB
Clinical signs of deep-seated infections and metastatic or other complications related to 
SAB (see Section 5.4.5.3), diagnosis of which must be supported by imaging studies 
(including ultrasound, CT, MRI, and PET/CT), biopsies or cultures at baseline, or within 
7 days after randomization. The minimum requirements for baseline diagnosis of or forms 
of complicated SAB are provided in Appendix 2.
Modified Duke’s Criteria (see Appendix 1) for the diagnosis of IE.


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Baseline assessments (except for a TEE) must be completed within the 72 h prior to 
randomization. Patients with suspected or confirmed SAB must sign informed consent prior 
to randomization. Blood cultures, TTE, or TEE conducted in the context of routine clinical 
diagnostic practice prior to obtaining informed consent, but within the 72-h window before 
randomization, may be used for the study and do not need to be repeated. The respective 
time windows for baseline screening assessments are outlined in Table 7–Table 10.
Once all screening procedures have been completed and a patient is assessed as being 
eligible for the study, they will randomly be assigned to treatment with ceftobiprole or 
daptomycin in a 1:1 ratio. Study drug treatment must be initiated within the 6 h after 
randomization.
Active-treatment Day 1
Randomization: IWRS registration
Vital signs
Body temperature
Blood culture, including standard microbiological investigation
TTE and/or TEE to be performed by Day 7 – see Table 8
Study drug administration
Drug accountability
Concomitant antimicrobial and other therapies
Concomitant non-drug procedures
Adverse events
Active-treatment Day 2
Brief physical examination
Vital signs
Body temperature
WBC count, CRP and procalcitonin (central lab)
Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)
Blood culture, including standard microbiological investigation
TTE and/or TEE to be performed by Day 7 – see Table 8
Study drug administration
Drug accountability
Investigator-assessed clinical signs and symptoms of SAB
Clinical signs of metastatic or other complications of SAB
Modified Duke’s Criteria (see Appendix 1) in patients without definite IE
Concomitant antimicrobial and other therapies
Concomitant non-drug procedures
Adverse events


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Active-treatment Day 3
Brief physical examination
Vital signs
Body temperature 
Safety laboratory (central lab)
WBC count, CRP and procalcitonin (central lab)
Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)
Blood culture including standard microbiological investigation
PK blood-sample collection
– Sparse PK sampling: pre-dose before the first BPR/PBO infusion, 2 h post-dose, and 4 to 
6 h post-dose
– Rich PK sampling: pre-dose before the first BPR/PBO infusion, and 2, 3, 4 and 6 h 
post-dose
TTE and/or TEE to be performed by Day 7 – see Table 8
Study drug administration
Drug accountability
Investigator-assessed clinical signs and symptoms of SAB
Clinical signs of metastatic or other complications of SAB
Modified Duke’s Criteria (see Appendix 1) in patients without definite IE
Investigator assessment of overall success
Concomitant antimicrobial and other therapies
Concomitant non-drug procedures
Adverse events
Active-treatment Days 4–12
Brief physical examination
Vital signs
Body temperature
Safety laboratory (central lab) (Day 7 only)
WBC count, CRP and procalcitonin (central lab) (Day 7 only)
Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)  (Days 5 and 7 only)
Blood culture including standard microbiological investigation unless negative test results 
have already been confirmed
PK blood-sample collection (Day 12 only)
– All patients: pre-dose before the first BPR/PBO infusion, 2 h post-dose, 4 to 6 h post-dose
TTE and/or TEE to be performed by Day 7 – see Table 8
Study drug administration
Drug accountability
Investigator-assessed clinical signs and symptoms of SAB


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Clinical signs of metastatic or other complications of SAB 
Modified Duke’s Criteria (see Appendix 1) in patients without definite IE
Investigator assessment of overall success
Concomitant antimicrobial and other therapies
Concomitant non-drug procedures
Adverse events
Active-treatment Days 14, 21, and if applicable, Days 28, 35, and 42
Brief physical examination
Vital signs
Body temperature 
Safety laboratory (central lab)
WBC count, CRP and procalcitonin (central lab) (Day 14 only)
Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)
Blood culture including standard microbiological investigation unless negative test results 
have already been confirmed

Study drug administration
Drug accountability
Investigator-assessed clinical signs and symptoms of SAB
Clinical signs of metastatic or other complications of SAB
Modified Duke’s Criteria (see Appendix 1) in patients without definite IE
Investigator assessment of overall success
Concomitant antimicrobial and other therapies
Concomitant non-drug procedures
Adverse events
Post-treatment EOT visit
The EOT visit is to be performed within 72 h of last study-drug administration. For patients 
who prematurely discontinue study-drug treatment, the EOT visit should take place within 
the 72 h after discontinuation.
Brief physical examination
Vital signs
Body temperature
12-lead electrocardiogram
Pregnancy test (serum or urine)
Safety laboratory (central lab)
Reticulocytes, haptoglobin and Coombs test (central lab)
WBC count, CRP and procalcitonin (central lab)


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Blood culture including standard microbiological investigation, unless negative test 
results have already been confirmed (see Section 5.2.1).
Investigator-assessed clinical signs and symptoms of SAB
Clinical signs of metastatic or other complications of SAB
Modified Duke’s Criteria (see Appendix 1) in all patients
Investigator assessment of overall success 
Concomitant antimicrobial and other therapies
Concomitant non-drug procedures
Adverse events
Post-treatment Days 35 and 42
The following assessments and procedures are to be performed on Days 35 (±3 days) and 42
(±3 days):
Brief physical examination
Vital signs
Body temperature 
Safety laboratory (central lab)
Blood culture including standard microbiological investigation*
Investigator-assessed clinical signs and symptoms of SAB
Clinical signs of metastatic or other complications of SAB
Modified Duke’s Criteria (see Appendix 1) in patients without definite IE
Investigator assessment of overall success
Concomitant antimicrobial and other therapies
Concomitant non-drug procedures
Adverse events
Post-treatment PTE visit
The PTE visit should be performed 70 days (±5 days) after randomization and will constitute
the last patient follow-up, with the exception of AEs that require prolonged follow-up (see 
Section 7.3.2.1.2).
The following assessments and procedures are to be performed at the PTE visit:
Brief physical examination
Vital signs
Body temperature
Pregnancy test (serum or urine)
Safety laboratory (central lab)
Reticulocytes, haptoglobin and Coombs test (central lab)
                                                
* At least one blood culture must be obtained at the PTE visit, or in the period between 7 days after EOT and the 
PTE visit.


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Blood culture including standard microbiological investigation*
Investigator-assessed clinical signs and symptoms of SAB
Clinical signs of metastatic or other complications of SAB
Modified Duke’s Criteria (see Appendix 1) in all patients
Investigator assessment of overall success 
Concomitant antimicrobial and other therapies
Concomitant non-drug procedures
Adverse events
Health economic outcome measures
5.4
Study procedures
5.4.1
Informed consent………………
The investigator must obtain the patient’s informed consent to participation in the study 
before carrying out any study procedures during screening. Non-study blood cultures, TTEs, 
and TEEs conducted prior to informed consent, but within the 72 prior to randomization,
may be used for the study and do not need to be repeated.
The investigator is to assign a patient number once informed consent is obtained.
5.4.2
Medical history, demographics and prior/ongoing therapies
At 
the 
Screening
visit, 
the 
investigator
must 
obtain 
the 
patient’s 
medical 
history/demographics/prior (within 30 days) antibacterial and other pre-study drug/non-drug 
therapies (see Section 5.5), and review the inclusion/exclusion criteria (Section 4.2 and 
Section 4.3).
5.4.3
Patient registration and IWRS
Eligible patients will be randomized in a 1:1 ratio to ceftobiprole or daptomycin treatment, 
based on a computer-generated randomization schedule. An Interactive Web Response 
System (IWRS) will be used for this study.
Within the 6 h prior to the planned time of first study-drug administration, the 
investigator/designee will contact the IWRS to obtain the study treatment assignment and 
dispense double-blind therapy accordingly. The IWRS will associate that patient with the 
next available treatment in the appropriate stratum on the randomization.
Randomization will be stratified by study site, dialysis status, and prior antibacterial 
treatment use (i.e., use of any systemic antibacterial treatment potentially effective against 
S. aureus within 7 days of randomization).
                                                
* At least one blood culture must be obtained at the PTE visit, or in the period between 7 days after EOT and the 
PTE visit.


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Detailed handling instructions are provided in the IWRS User’s Guide.
5.4.4
Safety assessments
The investigator will evaluate patient safety by AE monitoring, physical examination, vital 
signs, safety laboratory tests and other assessments as indicated. Safety data will also be 
reviewed by the sponsor.
Safety assessments must be performed at the intervals indicated in the Schedule of 
Assessments (Table 6). More frequent assessments may be performed at the investigator’s 
discretion if medically indicated.
Detailed handling instructions are provided in the Medical Monitoring Plan.
5.4.4.1 Physical examination
A complete physical examination must be performed in accordance with the Schedule of 
Assessments (Table 6). Physical examination includes general appearance, skin, neck 
inclusive thyroids, eyes, nose, throat, cardiovascular system, musculoskeletal system (spine, 
joints, pelvis), thorax/lungs, abdomen, lymph nodes, extremities, nervous system, and mental 
status.
A brief physical examination must be performed in accordance with the Schedule of 
Assessments (see Table 6). Brief physical examination is to be focused on any changes from 
baseline.
5.4.4.2 Vital signs
Vital signs must be assessed in accordance with the Schedule of Assessments (Table 6), at 
the same time as the temperature assessment is performed.
Vital signs include height, weight, respiratory rate, radial pulse rate, systolic blood pressure 
(SBP) and diastolic blood pressure (DPB). Pulse rates and BPs must be obtained in the same 
position throughout a visit, i.e., either sitting or supine as appropriate, after the patient has 
been at rest for at least 5 min.
The patient’s height is only to be assessed during the Screening visit.
The patient’s weight is to be assessed at Screening, and at a minimum on study Days 2, 3, 5, 
7, 14, 21, and if applicable, 28/35, at the EOT visit, and at the PTE visit.
5.4.4.3 Body temperature measurement
Body temperature must be assessed in accordance with the Schedule of Assessments 
(Table 6), at the same time as the vital signs are taken. For all patients enrolled at the same 
site, the same method of temperature measurement should be used during the course of the 
study.
5.4.4.4 Electrocardiograms
Standard 12-lead ECGs will be obtained and assessed locally, in accordance with the 
Schedule of Assessments (Table 6).


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5.4.4.5 Pregnancy testing
Women of childbearing potential must have a negative serum pregnancy test result during 
the 24 h prior to randomization.
At the EOT and PTE visits it is at the discretion of the investigator whether a serum or urine 
pregnancy test is obtained, and subject to local regulations.
The investigator may conduct additional pregnancy tests (serum or urine) to confirm the 
absence of pregnancy at any time during the study. If a pregnancy test result is positive, 
study drug must be discontinued, the patient followed for safety, and the outcomes of the 
pregnancy assessed.
Further details regarding pregnancy are provided in Section 7.4.
5.4.4.6 Safety laboratory parameters
5.4.4.6.1
Local laboratory safety assessments
Local laboratory safety parameters include hematology, biochemistry, coagulation, blood 
glucose, and urinalysis.
Creatinine clearance for dose determination is to be calculated using the Cockcroft-Gault 
formula.
Local laboratory safety tests will be used to assess patient eligibility, and additional local 
laboratory tests may be performed at any time during the study, as clinically indicated. The 
results of such additional tests should not be entered in the laboratory results page of the 
CRF; if the results constitute an AE they should be entered in the AE page of the CRF.
The local laboratory safety parameters are provided in Table 11.
Table 11 Local laboratory safety parameters mandatory (for patient eligibility) at 
Screening
Hematology
Clinical chemistry
Coagulation
Urine (dipstick analysis)
HGB
HCT
RBC count
WBC count
Platelets
(Abs. neutrophils
and % immature 
neutrophils [bands] are to 
be obtained if required for 
patient eligibility)
Albumin
ALT
AST
Bilirubin (total)
Potassium
Sodium
Creatinine
Urea or BUN
Glucose 
Serum-pregnancy test
FSH*
PT
Blood
Glucose
Ketones
Leukocytes
Nitrite
pH
Protein
Specific gravity
Bilirubin
Urobilinogen
ALT=alanine transaminase; AST=aspartate transaminase; FSH=serum follicle stimulating hormone; HCT=hematocrit; 
HGB=hemoglobin; PT=prothrombin time; RBC=red blood cell; WBC=white blood cell.
* For post menopausal females aged < 50 years, or for those aged ≥ 50 years who have been post-menopausal for < 2 years.


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5.4.4.6.2
Central laboratory safety assessments
The central laboratory safety parameters are provided in Table 12.
Table 12 Central laboratory safety parameters 
Hematology
Clinical chemistry
Coagulation
HGB
HCT
RBC count
WBC count
Platelets
% Basophils
% Eosinophils
% Lymphocytes
Monocytes
Neutrophils
Abs. basophils
Abs. eosinophils
Abs. lymphocytes
Abs. monocytes
Abs. neutrophils
Albumin
Total Protein
AP
ALT
AST
CPK
GGT
LDH
Bilirubin (direct & indirect)
Potassium
Sodium
Chloride
Creatinine
Urea
Uric acid
Glucose 
CRP
PCT
PT
INR
aPTT
Fibrinogen
Central laboratory safety testing will be conducted in accordance with the Schedule of 
Assessments (Table 6). Additional central testing may be performed at the discretion of the 
investigator when clinically indicated. All samples for a given study site must be analyzed by 
the same central laboratory throughout the study, as designated by the sponsor. The results 
are to be printed, signed and dated by the investigator/designee.
In the event of unexplained abnormal laboratory test values, the tests might be repeated 
immediately and followed-up until the results return to the normal range, stabilization, and/or 
until an adequate explanation of the abnormality has been determined. If 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.
Detailed handling instructions are provided in the Laboratory Manual.
5.4.4.7 Reticulocytes, haptoglobin and Coombs test
Reticulocyte counts, haptoglobin measurements, and Coombs tests will be assessed by the 
central laboratory at baseline, and at the EOT and PTE visits.
5.4.4.8 WBC count and CRP and procalcitonin testing
WBC counts, CRP levels, and procalcitonin levels will be assessed by the central laboratory, 
according to the schedule shown in Table 6.


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5.4.4.9 Creatinine clearance
Creatinine clearance (CLCR): CLCR should be calculated for all patients except patients on 
dialysis, using the Cockcroft-Gault formula based on local laboratory results, and should be 
performed at Screening, and at a minimum on study Days 2, 3, 5, 7, 14, 21, and if applicable, 
28/35. The actual age, weight, and serum creatinine level on the day of CLCR calculation 
should be used. Additional CLCR calculations may be performed as clinically indicated. All 
CLCR results obtained during the active treatment period (i.e., when the patient is receiving 
study medication) need to be reviewed by the unblinded pharmacist (or delegate) on the day 
when local laboratory serum-creatinine results are obtained and the doses of ceftobiprole and 
daptomycin are adjusted in accordance with Table 13 and Table 14, respectively.
5.4.4.10 Transthoracic and transesophageal echocardiography
Standard two-dimensional or three-dimensional TTE and/or TEE will be performed, 
depending on whether a definite diagnosis of IE has been made at the time of screening
(see Table 8).
For patients with definite IE according to Modified Duke’s Criteria (see Appendix 1), a TTE 
or TEE performed within 10 days prior to randomization may be used to confirm patient 
eligibility. In these cases, a TTE or TEE must be repeated within 72 h before, or 7 days after, 
randomization, for documentation purposes. If the diagnosis of a definite endocarditis can be 
based on a TTE, then a TEE is not required.
For patients without definite endocarditis, a TTE or TEE must be performed within 72 h 
prior to randomization. A TTE or TEE performed in this time window but prior to obtaining 
informed consent may be used for patient eligibility assessment. If a TTE is performed 
within 72 h prior to randomization, then a TEE must be performed within 72 h prior to 
randomization, or within 7 days after randomization, unless the patient has one or more of 
the following conditions associated with an increased risk of complications from a TEE:

altered mental status or an uncooperative patient

unstable cardiorespiratory status

esophageal stricture or malignancy (identify esophageal location prior to TEE) 
or esophageal varices with recent/active bleeding

surgical interposition of the esophagus

Zenker's diverticulum (identify esophageal location prior to TEE)

history of odynophagia or dysphagia

cervical spine arthritis with reduced range of motion

severe thrombocytopenia (< 50 × 109/L), elevated international normalized ratio (˃ 4), 
or prolonged partial thromboplastin time (>150 seconds)

obstructive sleep apnea/airway compromise (consider sedation by anesthesia)
If a TEE is performed within 72 h prior to randomization, a TTE is not required.


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5.4.5
Assessments of disease status
5.4.5.1 Microbiological assessments
Two peripheral blood cultures must be obtained at least 5 minutes apart from separate 
peripheral-venous sites from each patient at baseline. Blood cultures that were positive for 
S. aureus and were conducted in the context of routine clinical diagnostic work-up practice
prior to obtaining informed consent, but were drawn within the 72 h prior to randomization, 
may be used for the study to determine patient eligibility, and do not need to be repeated.
Post-randomization repeat blood cultures (at least one, but preferably two blood cultures)
will be obtained on Days 1, 2 and 3. Thereafter, blood cultures will be obtained 
approximately every 48–72 h if clearance of bacteremia has not yet been confirmed, 
i.e., until negative test results for S. aureus are obtained for two successive cultures taken at 
least 24 h apart. At least one blood culture is to be taken at the PTE visit, or in the period 
between 7 days after the EOT visit and the PTE visit.
Specimens will be cultured by the local laboratory using standard microbiological 
procedures. All unique organisms from blood will be sent to the central microbiology 
laboratory for identification, and for susceptibility testing with both study drugs. For patients 
with persistent SAB (see Inclusion criterion 7), the susceptibility to ceftobiprole and 
daptomycin may be assessed at the local microbiology laboratory, but must be confirmed by 
the central laboratory. If a patient is randomized based on susceptibility results from the local 
laboratory, and a conflicting result is obtained from the central laboratory, then the central 
laboratory result will be considered valid. If local susceptibility testing is performed after a 
patient has been randomized, and the local results show non-susceptibility to either study 
drug, then the continuation of the patient in the study will be at the discretion of the 
investigator, based on clinical assessment.
5.4.5.2 Investigator-assessed clinical signs and symptoms of SAB
The investigator is to include body temperature, WBC count, heart rate, respiratory rate, 
systolic blood pressure, and signs or symptoms of localized catheter-related infection in the 
assessment of SAB.
5.4.5.3 Clinical signs of deep-seated infections and metastatic or other complications
of SAB
Clinical signs of metastatic complications to be assessed by the study investigator include:

Bone or back pain, back pain elicited on percussion of spine (suggestive of vertebral 
osteomyelitis, discitis, or epidural abscess)

Joint swelling, joint pain, pain elicited on external rotation of femoral head (suggestive of 
septic arthritis or bacterial joint infection/empyema) 

Protracted fever and/or sweats, new regurgitant murmurs or heart failure and further 
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
Abdominal pain, left upper quadrant pain (suggestive of splenic abscess or infarction) 

costovertebral angle tenderness (suggestive of renal abscess or infarction or psoas 
abscess)

headache, focal neurologic impairment (suggestive of central nervous septic emboli or 
other CNS complications)
Careful examinations should also be made by the investigator regarding indwelling 
prosthetic devices and orthopedic hardware.
The diagnosis of deep-seated infections and metastatic or other complications related to SAB 
must be supported by imaging studies (including ultrasound, CT, MRI, and PET/CT), 
biopsies or cultures. The minimum requirements for baseline or post-baseline diagnosis of 
deep-seated infections and metastatic or other complications related to SAB are provided in 
Appendix 2 and Appendix 3, respectively.
5.4.5.3.1
Assessment of deep-seated infections and metastatic or other complications of 
SAB at baseline
Diagnostic assessments for deep-seated infections and metastatic or other complications 
related to SAB that were conducted in the context of routine clinical diagnostic work-up 
practice prior to obtaining informed consent, but within 7 days prior to randomization may 
be used for the study to determine patient eligibility.
Furthermore, diagnostic assessments for deep-seated infections and metastatic or other 
complications related to SAB (see Inclusion criterion 8) that are obtained within 72 h after 
randomization may be used to determine the patient`s baseline condition of SAB.
Baseline deep-seated infections and metastatic or other complications of SAB will be 
categorized as (see Appendix 2):

ABSSSI

Septic arthritis or bacterial joint infection/empyema

Septic or suppurative thrombophlebitis

Visceral soft-tissue abscesses requiring ≤ 42 days of study treatment

Septic pulmonary emboli/infarction (as assessed by the investigator based on clinical 
symptoms of fever, cough, sputum/hemoptysis in the presence of an extrapulmonary 
infection, sepsis, or risk factors for septic emboli, and based on radiological signs as
outlined in Appendix 2)


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5.4.5.3.2
Assessment of new occurrences of deep-seated infections and metastatic or other 
complications of SAB
New occurrences of deep-seated infections and metastatic or other complications of SAB 
will be categorized in the same way as at baseline, and must be supported by imaging studies 
(including ultrasound, CT, MRI, and PET/CT), biopsies, or cultures. The minimum 
requirements for baseline or post-baseline diagnosis of deep-seated infections and metastatic 
or other complications of SAB are provided in Appendix 2 and Appendix 3, respectively.
5.4.5.4 Modified Dukes criteria
Modified Duke’s Criteria (see Appendix 1) will be assessed in all patients at Screening, EOT 
and PTE.
For patients without definite IE, Modified Duke’s Criteria will be assessed at every 
scheduled visit from Day 2 until the PTE visit.
5.4.6
Assessments of treatment success
5.4.6.1 Investigator-assessed overall success
Overall success requires clinical success, deﬁned as the improvement or resolution of clinical 
signs and symptoms, plus confirmed negative blood culture for S. aureus (microbiological
success) and no requirement for further systemic antibacterial treatment for SAB or its 
complications.
5.4.6.2 DRC-assessed overall success
Independent clinical experts, blinded to treatment allocation and not associated with the 
study conduct, will review all patient profiles, including signs and symptoms of infection and 
relevant microbiological, laboratory, and imaging findings, and will assess baseline 
condition of SAB, its complications, and outcomes for primary and secondary endpoints (see 
Appendix 4). The results of the DRC review will form the basis for assessing the non-
inferiority of ceftobiprole versus daptomycin.
The definition of overall success is provided in Section 3.2.1.
5.4.7
PK blood-sample collection
Rich and sparse PK sampling will be performed to determine the secondary endpoint of 
plasma levels of ceftobiprole and the -lactam ring-open product BAL1029.
Sparse PK sampling
Sparse PK sampling will be performed for all patients in the study, comprising three blood 
samples of approximately 2 mL, collected on Days 3 and 12 at the following timepoints:

Day 3: pre-dose before the first BPR/PBO infusion, 2 h post-dose (end of infusion), 4 to 6 
h post-dose

Day 12: pre-dose before the first BPR/PBO infusion, 2 h post-dose (end of infusion), 4 to 
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Rich PK sampling
Rich PK sampling will be performed for a total of 40 ceftobiprole-treated patients (i.e., 
approximately 80 patients overall) at selected sites, comprising two additional samples of 
approximately 2 mL each on Day 3, in addition to those collected for the sparse PK 
sampling. In total, patients who undergo rich PK sampling will have five blood samples 
collected on Day 3 and three on Day 12, at the following timepoints:

Day 3: pre-dose before the first BPR/PBO infusion, 2 h post-dose (end of infusion), and 
at 3, 4, and 6 h post-dose

Day 12: pre-dose before the first BPR/PBO infusion, 2 h post-dose (end of infusion), 4 to
6 h post-dose
5.5
Prior and concomitant medication
5.5.1
Prior medication………………
All prior medication taken within the 30 days prior to the Screening visit must be 
documented for each patient in the CRF, including the route of administration, therapeutic 
indication, and start/stop dates of use.
5.5.2
Prohibited concomitant medication
Concomitant systemic antibacterials (other than study drugs) that provide activity against 
S. aureus are prohibited from randomization up to the PTE visit.
The use of non-study antibacterial treatment during the study (if it occurs) is not necessarily 
to be considered an outcome of ‘failure’. The significance of concomitant potentially 
effective non-study antibacterial treatment (except aztreonam, metronidazole, nitrofurantoin, 
and oral vancomycin, see Section 5.5.3) is to be assessed by the blinded DRC in accordance 
with the guidelines provided in Appendix 6, to determine whether the treatment had an 
impact on the primary endpoint.
5.5.3
Permitted concomitant medication
5.5.3.1 Permitted non-antibacterial treatments
The following concomitant medication is permitted during the study:

Non-antibacterial standard-of-care medication.

Acetaminophen or paracetamol, when an antipyretic medication is indicated.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and systemic steroids.

Low-dose aspirin (≤ 200 mg per day) for cardiovascular prophylaxis.
Any concomitant medication (including herbal medicines) received by the patient during the 
study must be recorded in the CRF, including the route of administration, therapeutic 
indication, and start/stop dates of use.


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5.5.3.2 Permitted antibacterial treatments
The following concomitant antibacterial medication is permitted during the study:

In the daptomycin treatment group, aztreonam using a standard-dose regimen at the site 
for coverage of Gram-negative infections (i.e., for polymicrobial bloodstream infections,
or Gram-negative non-bloodstream infections). Patients randomized to the ceftobiprole 
group who are considered to require coverage against Gram-negative infections will 
receive dummy treatment with placebo so that blinding is maintained during the active 
treatment phase.

In both treatment groups,
–
nitrofurantoin for urinary tract infections
–
metronidazole using a standard-dose regimen at the site for coverage of anaerobic 
infections
–
oral vancomycin is considered a non-systemic antibiotic and may be used at any time 
during the study
5.6
Restrictions
Patients will be encouraged to continue their usual diet, as dictated by their clinical 
condition. Activities that would impact clinical outcome should be avoided.
Participation in any other interventional clinical study or medical device investigation is 
prohibited from 30 days prior to enrollment up to and including the PTE visit.
5.7
Health economic outcome measures
Resource requirements and health economic data will be derived from study-specific data or 
collected ancillary to study conduct to perform a health economic analysis (ITT and CE 
populations). These analyses will aim to enable economic comparisons of ceftobiprole versus 
daptomycin.
Health economic outcome measures may include:

Study treatment duration

Total length of stay in hospital

Location of treatment within the healthcare system (e.g., Emergency Department)

Concomitant medication

Post-study drug procedures and interventions

Adverse events and any treatment required by these events

Incidence of re-hospitalization

Outpatient healthcare encounters

Emergency Department visits

Antibacterial treatment utilization

Surgical and non-surgical procedures, e.g. debridement, grafts, amputation, prostheses, 
and others


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6
STUDY DRUGS
6.1
Blinding
This is a randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-
center study in adult hospitalized* patients with SAB, including IE.
6.2
Randomization
Patients will be randomized to double-blind, double-dummy study treatment with 
ceftobiprole or daptomycin in a 1:1 allocation ratio, based on a computer-generated 
randomization schedule.
Within the 6 h prior to the scheduled first dose of study drug, the investigator/designee will 
contact the IWRS to obtain the study treatment assignment and will dispense blinded 
treatment accordingly. The IWRS will allocate that patient to the appropriate randomization 
stratum. Randomization will be stratified by study site, dialysis status, and prior antibacterial 
treatment use (i.e., use of any systemic antibacterial treatment potentially effective against 
S. aureus within 7 days of randomization).
Detailed randomization instructions are provided in the IWRS User’s Guide.
6.3
Dose regimens and administration schedules
After randomization and during active treatment, patients will receive either ceftobiprole 
as 2-h intravenous infusions (Table 13), or daptomycin as 0.5-h intravenous infusions
(Table 14).
Table 13 Schedule of ceftobiprole administration 
Study day
Normal renal function to 
mild renal impairment 
(CLCr ≥ 50 mL/min)
Renal impairment 
(non-dialysis)
Intermittent 
hemodialysis or 
peritoneal dialysis
Day 1 to Day 8
500 mg q6h
CLCr 30 – < 50 mL/min: 500 mg q8h
CLCr <30 mL/min: 250 mg q8h
250 mg q24h
Day 9 onwards
500 mg q8h
CLCr 30–< 50 mL/min: 500 mg q12h
CLCr < 30 mL/min: 250 mg q12h
250 mg q24h
CLCr=Creatinine clearance based on the Cockcroft-Gault formula.
                                                
* In a hospital or equivalent medical confinement or clinical research unit.


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Table 14 Schedule of daptomycin administration
Normal renal function to 
moderate renal impairment
(CLCr ≥ 30 mL/min)
Renal impairment 
(non-dialysis)
(CLCr < 30 mL/min)
Intermittent 
hemodialysis or 
peritoneal dialysis
Day 1 onwards
6 mg/kg q24h
6 mg/kg q48h
6 mg/kg q48h
CLCr=Creatinine clearance based on the Cockcroft-Gault formula.
In accordance with institutional standards, an increase in the dose of daptomycin 
administered (up to 10 mg/kg) may be implemented.
To maintain the blinding of study treatments, patients in the ceftobiprole group will receive 
dummy infusions with placebo (physiological saline, 0.9% NaCl) matching daptomycin, and 
patients in the daptomycin group will receive dummy infusions with placebo (physiological 
saline, 0.9% NaCl) matching ceftobiprole.
No switches to other systemic antibacterial treatments are permitted for any of the study 
drugs prior to the PTE visit. There is no intravenous-to-oral switch for any of the treatments 
in this study.
The minimum treatment duration is 21 days of study medication, and the maximum 
treatment duration is 42 days of study medication.
Exceptional cases of patients who are considered to require further antibacterial treatment for 
SAB at the end of the 42-day study treatment period, and who do not meet any other failure 
criteria, will be switched to open-label non-study treatment according to institutional 
practice. These patients will be considered failures in the mITT and ITT analyses irrespective 
of treatment group.
6.4
Study drug administration
All study drugs will be administered intravenously. There is no option to switch to oral 
treatment in this study.
Hospitalization (in a hospital or equivalent medical confinement or clinical research unit) of 
study participants is required to initiate study treatment. Where individual patient 
requirements and circumstances allow for outpatient care after this time, homecare services 
or site nurse visits are permitted, provided that all data relevant to the study continue to be 
obtained.
For outpatients, the investigator must provide the required settings in order to ensure strict 
compliance with the protocol for all study-related treatments and assessments.
Study drug treatment must be initiated within the 6 h after randomization. On each treatment 
day, study-drug administration should occur within ±1 h for ≤ q6h dose regimens, and ±2 h 
for > q6h dose regimens, of the scheduled time point.


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6.4.1
Ceftobiprole………….…….

For patients with normal to mildly-impaired renal function (i.e., CLCr ≥50 mL/min), 
ceftobiprole 500 mg is to be administered as a 2-h intravenous infusion every 6 h, 
from study Day 1 up to and including study Day 8. From study Day 9 until the end 
of treatment, ceftobiprole 500 mg is to be administered as a 2-h intravenous infusion 
every 8 h.

For patients with renal impairment (i.e., CLCr < 50 mL/min) who do not require dialysis, 
the following dose adjustments will be made (see Table 13):
– CLCr 30 – < 50 mL/min: ceftobiprole 500 mg is to be administered as a 2-h intravenous 
infusion every 8 h from study Day 1 up to and including study Day 8. From study
Day 9 until the end of treatment, ceftobiprole 500 mg is to be administered as a 
2-h intravenous infusion every 12 h.
– CLCr < 30 mL/min: ceftobiprole 250 mg is to be administered as a 2-h intravenous 
infusion every 8 h from study Day 1 up to and including study Day 8. From study Day 
9 until the end of treatment, ceftobiprole 250 mg is to be administered as a 
2-h intravenous infusion every 12 h.

For patients with renal impairment who require hemodialysis or peritoneal dialysis, 
ceftobiprole 250 mg is to be administered as a 2-h intravenous infusion every 24 h, from 
study Day 1 up to the end of treatment. On the days of hemodialysis, ceftobiprole will be 
administered after the hemodialysis session has been completed.
6.4.2
Daptomycin………………

For patients with normal to moderately-impaired renal function (i.e., CLCr ≥30 mL/min), 
daptomycin 6 mg/kg is to be administered as a 0.5-h intravenous infusion every 24 h, 
from study Day 1 until the end of treatment (see Table 14).

For patients with renal impairment (i.e., CLCr < 30 mL/min) who do not require dialysis, 
daptomycin 6 mg/kg is to be administered as a 0.5-h intravenous infusion every 48 h, 
from study Day 1 until the end of treatment (see Table 14).

For patients with renal impairment who require hemodialysis or peritoneal dialysis, 
daptomycin 6 mg/kg is to be administered as a 0.5-h intravenous infusion every 48 h, 
from study Day 1 until the end of treatment (see Table 14).
Detailed guidelines for the dosing of ceftobiprole and daptomycin are provided in the
Pharmacy Manual.
6.4.3
Study drug dosing volumes and sequence
The total daily volume of study-drug infusions is shown in Table 15 (study Days 1 to 8) and 
Table 16 (study Days 9 to 42). The sequence of administration of study drug infusions at any 
time point should be maintained as per Table 15 and Table 16 whenever possible (i.e., at 0 h 
the DAP/PBO should be administered before BPR /PBO).


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Table 15 Study drug dosing schedule: Day 1 to Day 8
CLCr ≥ 50 mL/min
CLCr 30 – < 50 mL/min
CLCr < 30 mL/min*
Dialysis*
Time
BPR
DAP
BPR
DAP
BPR
DAP
BPR
DAP
0 h
50 mL PBO
(30 min)
50 mL DAP
(30 min)
50 mL PBO
(30 min)
50 mL DAP
(30 min)
50 mL PBO
(30 min)
(q48h)
50 mL DAP 
(30 min )
(q48h)
50 mL PBO
(30 min)
(q48h)
50 mL DAP 
(30 min )
(q48h)
250 mL BPR
(120 min)
250 mL PBO
(120 min)
250 mL BPR
(120 min)
250 mL PBO
(120 min)
125 mL BPR
(120 min)
125 mL PBO
(120 min)
125 mL BPR
(120 min)
125 mL PBO
(120 min)
6 h
250 mL BPR
(120 min)
250 mL PBO
(120 min)
8 h
250 mL BPR
(120 min)
250 mL PBO
(120 min)
125 mL BPR
(120 min)
125 mL PBO
(120 min)
12 h
250 mL BPR
(120 min)
250 mL PBO
(120 min)
16 h
250 mL BPR
(120 min)
250 mL PBO
(120 min)
125 mL BPR
(120 min)
125 mL PBO
(120 min)
18 h
250 mL BPR
(120 min)
250 mL PBO
(120 min)
Vol.
1050 mL per day
800 mL per day
425/375 mL per day
175/125 mL per day
CLCr= Creatinine clearance; BPR=ceftobiprole medocaril; DAP=daptomycin; PBO=placebo.
* To maintain blinding, it is particularly important that patients with CLCr < 30 mL/min or on dialysis receive both infusions (i.e., 50 mL 
DAP/PBO and 125 mL BPR/PBO) on Day 1 at time 0 h.
Table 16 Study drug dosing schedule: Day 9 to Day 42
CLCr ≥ 50 mL/min
CLCr 30 – < 50 mL/min
CLCr < 30 mL/min
Dialysis
Time
BPR
DAP
BPR
DAP
BPR
DAP
BPR
DAP
0 h
50 mL PBO
(30 min)
50 mL DAP
(30 min)
50 mL PBO
(30 min)
50 mL DAP
(30 min)
50 mL PBO
(30 min)
(q48h)
50 mL DAP 
(30 min )
(q48h)
50 mL PBO
(30 min)
(q48h)
50 mL DAP 
(30 min )
(q48h)
250 mL BPR
(120 min)
250 mL PBO
(120 min)
250 mL BPR
(120 min)
250 mL PBO
(120 min)
125 mL BPR
(120 min)
125 mL PBO
(120 min)
125 mL BPR
(120 min)
125 mL PBO
(120 min)
8 h
250 mL BPR
(120 min)
250 mL PBO
(120 min)
12 h
250 mL BPR
(120 min)
250 mL PBO
(120 min)
125 mL BPR
(120 min)
125 mL PBO
(120 min)
16 h
250 mL BPR
(120 min)
250 mL PBO
(120 min)
Vol.
800 mL per day
550 mL per day
300/250 mL per day
175/125 mL per day
CLCr= Creatinine clearance; BPR=ceftobiprole medocaril; DAP=daptomycin; PBO=placebo.


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6.5
Blinding
The unblinded site pharmacist/designee will provide blinded and properly-labeled study 
medication to investigational staff.
At the site, only the unblinded pharmacist/designee will have access to treatment codes via 
the IWRS.
Investigators, other site staff, sponsor employees, and others involved in the conduct of the 
study will remain blinded to the treatment codes until the database has been locked for final 
analysis.
6.5.1
Methods for ensuring blinding
This study will be double-blind with regard to the administration of study drugs. To ensure 
that the blinding is maintained, only the following personnel may have access to details of 
the treatment allocation:

those setting up the randomization scheme and IWRS

the unblinded pharmacist/designee responsible for blinded study-drug preparation, 
adjustments, and documentation

those required to break the blind for the purposes of expedited reporting to health 
authorities and other relevant institutions

those responsible for unblinded monitoring of study-drug preparation and accountability, 
and their supervisors

those performing PK analyses

the unblinded statistician, if required for safety reasons, or producing outputs for the 
DSMB.
These personnel must not disclose any details of the randomization scheme or treatment 
allocation.
6.5.2
Unblinding methods
Individual treatment codes from the IWRS for each randomized patient will be available to 
investigators; an investigator should only break the treatment code if this is necessary to 
respond to a medical emergency. It is advisable for the investigator to contact the Medical 
Monitor prior to breaking the blind.
If it is necessary to break the code, the investigator will record the reason for unblinding in 
the patient’s records/source documents. In order to maintain the blinded nature of the study, 
the patient’s treatment allocation must not be disclosed, unless required for the treatment 
and/or surveillance of the patient. Adverse events and SAEs must be reported as outlined in 
Section 7.


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The sponsor/designee may only break the blind, via the IWRS, if this is necessary for 
regulatory reporting purposes, and must ensure that this is fully documented, with only the 
minimum number of staff necessary having access to the unblinded information.
Detailed handling instructions in regard to blinding are provided in the IWRS User’s Guide.
Systematic unblinding of the clinical database will occur after database lock as described in 
the Data Management Plan and Statistical Analysis Plan.
6.6
Drug accountability and compliance checks
The investigator, and a pharmacist designated by the investigator, must maintain records of 
the delivery of study drug to the site, the inventory at the site, the use by each patient, and the 
return to the sponsor or alternative disposal of unused product.
These records must include dates, quantities, batch/serial numbers, expiration dates, and the 
unique code numbers assigned to the study drugs and study patients. These records must be 
available for monitoring by the sponsor’s unblinded Monitor.
Investigators must maintain records that document adequately that the study patients were 
provided the doses specified by the protocol, and must reconcile all study drug received from 
the sponsor.
6.7
Packaging and labelling
Study drugs will be packed and labeled in accordance with local regulations and the 
Annex 13 Good Manufacturing Practice rules. Labels will include the identity of the sponsor
and investigator, protocol number, drug identification, storage conditions, content of study 
drug, and expiry date.
Information on drug shipment, including temperature logger and acknowledgement of 
receipt form to be completed by the receiver, will also be included.
6.8
Shipping and storage conditions
Study drug for intravenous administration will be presented as follows:

vials of sterile lyophilized ceftobiprole medocaril containing the equivalent of 500 mg 
ceftobiprole. The dry powder must be stored in a refrigerator (2–8 °C/36–46°F).

vials of sterile daptomycin containing 350 mg or 500 mg. The dry powder must be stored 
in a refrigerator (2–8 °C/36–46°F).
All vials of study drug for intravenous administration must be shipped to the study sites and 
stored at the required temperature levels. All study drug must be kept under secure 
conditions, e.g., in the hospital pharmacy.
Further information on the handling and stability of study drug is provided in the Pharmacy 
Manual.


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6.9
Drug supply
A Drug Dispensing Log must be kept up to date, and must contain the following information:

Site ID, Subject ID, Random ID

Investigator’s name

Code of the drug to be dispensed

Date(s), quantity and batch number of the drug dispensed to the patient

Quantity of the drug remaining in stock
The inventory must be available for monitoring by the sponsor’s clinical monitor.
6.10 Drug disposal
Any remaining drug, including empty vials, may either be returned to the study supply 
packaging provider, or destroyed at the site at the request of the sponsor. If drug is destroyed 
at the study site, the investigator/designee must provide the sponsor with documentation of 
the destruction.
Detailed study drug handling instructions are provided in the Pharmacy Manual.


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7
SAFETY
7.1
Definitions
7.1.1
Adverse occurrence
An adverse occurrence is any untoward medical occurrence taking place after informed 
consent has been provided and before first study-drug administration (see Section 7.3.1).
7.1.2
Adverse event………………
An AE is any untoward medical occurrence from the start of first dosing up to and including 
the scheduled PTE visit 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 (see Section 7.3.2).
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 hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is classified as an important medical event or a medically significant event
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 hospitalization but may jeopardize 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 hospitalization, 
and development of drug dependency or drug abuse.
It should be noted that:

In this study, any convulsion event is an AE of special interest; a convulsion event is 
considered an ‘important medical event’, and is therefore an SAE for the purposes of the 
study.

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.


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
Inpatient hospitalization is defined as any inpatient admission, even if for less than 24 h. 
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 tuberculosis unit).
The following hospitalizations, whether planned before or during the study, should not be 
considered SAEs:
–
Routine treatment or monitoring of the SAB, not associated with any deterioration in 
condition (e.g., hospitalizations related to study procedures, such as study-drug 
administration, PK assessments, etc).
–
Elective or planned treatment, including surgical interventions, for SAB if the plan 
for the respective intervention has been documented prior to randomization.
–
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
SAB 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.
7.1.4
Adverse events of special interest
In addition to convulsions, which are to be considered SAEs (see Section 7.1.3), the 
following are considered AEs of special interest for the purposes of this study, based on the 
known safety profiles of ceftobiprole and daptomycin:

Hypersensitivity reactions

Clostridium difficile-associated diarrhea

Myopathy

Rhabdomyolysis

Eosinophilic pneumonia

Peripheral neuropathy
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


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7.2.2
Relationship………………
The relationship of AEs to the study treatment must be assessed by the investigator as one of 
the following:

not related

unlikely 

possible 

probable
Appendix 9 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.
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 informed 
consent has been provided but prior to the start of first study-drug administration, is to be 
recorded in the CRF as pre-dose medical history (see Section 5.4.2). 
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 PTE 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 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.


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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 SAB.
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 9).
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).
7. Outcome.
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 stabilized, or 
until the scheduled PTE visit.
In addition, an AE which remains unresolved after completion of the study (including the 
last scheduled follow-up contact) 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 leads to a patient’s withdrawal from the study

an SAE


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These cases will be followed-up on the CRF unless otherwise agreed with the sponsor.
7.3.2.2 Recording and reporting of serious adverse events and adverse events of 
special interest
In addition to being reported and followed-up as AEs (see Section 7.3.2.1 and 7.3.2.2), SAEs 
and AEs of special interest must be reported to the sponsor’s safety representative listed 
below, within 24 h of awareness of the event.
The investigator must complete the ‘Serious Adverse Event Report Form’ in English, and 
send the completed, signed form by fax or email to:
Such preliminary reports must be followed by detailed anonymized 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 site in the Investigator Site File (ISF).
7.3.3
Handling of post-study safety data
Any AE occurring after the PTE 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 9)
should be reported to the sponsor’s designated safety representative using the same forms 
and procedures as for an SAE (see Section 7.1.3).
Events first occurring after the PTE 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 will ensure the reporting of SUSARs and any expeditable 
SAEs to regulatory Authorities in accordance with applicable laws.
In the event of a SUSAR, the sponsor will ensure that investigators active in 
Basilea-sponsored interventional studies with ceftobiprole are informed.


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Expectedness of SAEs for regulatory expedited reporting will be assessed by the sponsor 
against the applicable Reference Safety Information (RSI).
For ceftobiprole, the RSI is Section 6 of the Investigator’s Brochure (‘Reference safety 
information for assessment of expectedness of serious adverse reactions’).
For daptomycin, expectedness for regulatory expedited reporting will be assessed against the 
‘Adverse reactions’ section of the US Prescribing Information for submission to the US 
FDA, and against section 4.8 ‘Undesirable effects’ of the EU Summary of Product 
Characteristics for submission to non-US regulatory authorities.
7.3.4.2 Investigator’s responsibilities
The 
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 law. 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 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).
Women of childbearing potential must have a negative serum pregnancy test result within 
the 24 h prior to randomization. If results of the pregnancy test are positive (see Section 
5.4.4.5), the patient will not be enrolled in the study.
Women of childbearing potential must agree to use one of the following methods of 
contraception until 7 days after the last dose of study drug:

Female sterilization (bilateral tubal occlusion or oophorectomy, or hysterectomy) or male 
partner vasectomy.

Intrauterine device (IUD).

Combined (estrogen- 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.


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Women are not considered to be of childbearing potential if they are either ≥1 year 
post-menopausal (where menopause is defined as at least 12 months of amenorrhea), or have 
an FSH measurement consistent with post-menopausal status according to local laboratory 
thresholds. An FSH measurement at Screening is to be obtained for post-menopausal females 
aged < 50 years, or for those aged ≥ 50 years who have been post-menopausal for < 2 years.
7.4.2
Reporting and handling of pregnancies
Female patients must inform the investigator within 24 h if they have experienced a ruptured 
condom, or any other concerns about possible reduction of contraceptive effectivity 
(i.e., forgotten pill or vomiting) during the study. In these cases the patients must return to 
the study site as soon as possible, but not later than 24 h, after the investigator is informed.
Female patients must inform the 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 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 Sections 7.3.2.1 and 7.3.2.2). Note that an induced abortion which is not required by an 
AE does not constitute an SAE.
The investigator must notify the local IEC/IRB about any pregnancies resulting in an adverse 
outcome, in accordance with applicable laws and regulations.


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8
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN
8.1
Sample size justification
The sample size estimate is based on:

A point estimate for overall success of 40% in each treatment group in the mITT 
population

One-sided alpha level of 0.025

Power of > 80%

Non-inferiority margin of 15% for the between-group difference in the primary endpoint
With these assumptions, enrollment of 175 patients per treatment group (total of 
350 patients) is required in the mITT population. Assuming that approximately 90% of 
patients in the ITT population will have confirmed SAB and will therefore be included in the 
mITT population, 195 patients per group (total of 390 patients) will need to be randomized 
and receive study treatment.
A sample size of 350 patients in the mITT population (175 per group) will provide at least 
80% power to reject the null hypothesis (H0) against the alternative hypothesis (HA) at the 
one-sided alpha level of 0.025 as follows, using a two-group large-sample normal 
approximation test of proportions:
H0: Pdaptomycin minus Pceftobiprole ≥ 0.15
versus
HA: Pdaptomycin minus Pceftobiprole < 0.15
A justification of the non-inferiority margin of 15% is provided in Appendix 8. The 
assumption of an overall success rate of 40% in each treatment group in the mITT population 
is based on the respective outcomes in patients with complicated bacteremia from a previous 
Phase 3 study (Fowler 2006), in which overall success across treatment groups in patients 
with complicated SAB was 40% (49/121). Using a conservative approach in the sample size 
calculation, a sample size of 350 patients (175 patients per group) in the mITT population 
would still provide 80% power for the assessment of the primary endpoint if the overall 
success rate is 50% instead of 40% (see Appendix 8, Table E3).
The assumption that approximately 90% of patients in the ITT population will have
confirmed SAB is based on the result from a previous Phase 3 study (Fowler 2006) in SAB, 
in which 96% of patients in the ITT population (235 out of 246 patients) were in the mITT 
population.


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8.2
Analysis populations
The following analysis populations are defined for this study:
Intent-to-treat population (ITT): The ITT population consists of all randomized patients. 
Patients will be analyzed according to the study medication assigned at randomization.
Modified intent-to-treat population (mITT): The mITT population consists of the subset of 
patients in the ITT population who have received any amount/dose of study medication, and 
who have a blood culture positive for S. aureus at baseline based on a central microbiology 
laboratory assessment.*
Clinically evaluable population (CE): The CE population consists of the subset of patients 
in the mITT population who have complied with important aspects of the study, e.g., no 
major protocol violations, with a completed primary outcome assessment.
Safety population: The safety population consists of all randomized patients who received 
any amount/dose of study medication. Patients in the safety population will be analyzed 
according to the first medication actually received.
Pharmacokinetic population (PK): all patients who receive at least one dose of ceftobiprole 
and have at least one plasma-concentration measurement obtained by the appropriate 
methodology.
All ITT patients should be followed until complete capture of main study outcomes, 
including those who did not receive study treatment or had no confirmed SAB by a S. aureus
blood culture using a standard diagnostic test, or who discontinue the study prematurely.
8.3
Statistical considerations
Descriptive statistics, including the numbers and percentages for categorical variables, and 
the numbers, means, standard deviations, medians, minimums, and maximums for 
continuous variables, will be provided. All comparisons will be performed for ceftobiprole 
versus daptomycin. Exploratory analyses may also be performed.
Unless otherwise specified, the latest evaluation prior to the initiation of study drug will be 
considered the ‘baseline’ evaluation for statistical analyses.
8.4
Demographic and baseline characteristics
Enrollment, protocol deviations, discontinuations from the study drug, and withdrawal from 
the study will be summarized by treatment group.
Demographics and baseline characteristics will be summarized by treatment group for all 
patient populations.
                                                
* Patients who are missing a central microbiological assessment may be included in the mITT population if there is 
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8.5
Prior and concomitant medication
Prior and concomitant medication will be summarized by treatment group. Additional 
summaries will be provided of prior and concomitant antibacterial treatment use, including 
those administered concomitantly for Gram-negative coverage.
8.6
Baseline categories of complicated Staphylococcus aureus bacteremia
Six categories of SAB will be summarized by treatment group based on the assessment of 
the DRC (see Appendix 4):
1. Uncomplicated SAB.
2. Any complicated SAB.
3. SAB in patients undergoing chronic intermittent hemodialysis or peritoneal dialysis.
4. Persistent SAB
5. Forms of complicated SAB with signs or symptoms of metastatic foci of S. aureus
infection, or other complications including the following (see Section 5.4.5.3.1):

ABSSSIs

Metastatic infection of native tissue requiring ≤ 42 days of study antibacterial
treatment. Examples include but are not limited to:
–
Septic arthritis or bacterial joint infection/empyema
–
Septic or suppurative thrombophlebitis
–
Visceral soft-tissue abscesses requiring ≤ 42 days of study antibacterial treatment
–
Septic pulmonary emboli/infarction

Osteomyelitis (including vertebral, sternal, or long-bone osteomyelitis)

Epidural or cerebral abscess
6. Definite native-valve RIE and/or LIE, by Modified Duke’s Criteria.
8.7
Analysis of the primary endpoint
The primary analysis will be based on the mITT population.
The primary endpoint is overall success at the PTE visit (Day 70±5 days post-randomization) 
in the mITT analysis set. The DRC will be a group of independent clinical experts, blinded to 
treatment allocation and not associated with the study conduct, who will review patient 
profiles, including signs and symptoms of infection, and relevant microbiological and 
imaging findings, and will assess the patients’ clinical and microbiological outcomes (see 
Appendix 4).
The primary endpoint will be tested for the non-inferiority of ceftobiprole versus daptomycin 
using a non-inferiority margin of 15%.


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Overall success is defined as all of the following criteria being met:
1. Patient alive at Day 70 (±5 days) post-randomization.
2. No new metastatic foci or complications of the SAB infection.
3. Resolution or improvement of SAB-related clinical signs and symptoms.
4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture 
for S. aureus):

at least one while the patient is on active study treatment; AND

confirmed by at least one subsequent negative blood culture for S. aureus
- either in the period between 7 days after the EOT visit and the PTE visit
- or at the PTE visit
Treatment failure is deﬁned as any of the following:
1. Premature discontinuation of study treatment due to DRC-assessed lack of efficacy (as 
assessed by the DRC) or for adverse events (AEs) that represent manifestation of disease 
progression or relapse, at any time between first dose of study drug and the PTE visit.
2. Development of new metastatic or other complications related to SAB (see Section 
5.4.5.3.2) between Day 8 and the PTE visit. Development of new metastatic or other 
complications of SAB prior to Day 8 will be assessed by the DRC on a case-by-case basis 
to assess whether these constitute a delayed manifestation of the baseline disease or new 
complications.
3. SAB relapse or reinfection based on evidence from a blood culture positive for S. aureus
(after documented clearance of S. aureus from the bloodstream and clinical improvement) 
between the EOT and PTE visits.
4. Receipt of systemic non-study antibacterial treatment, other than those permitted under 
the protocol, for the treatment of SAB. This includes patients who are prematurely 
discontinued from study therapy due to an AE, but who require continuation of 
antibacterial treatment for SAB.
5. Treatment of infections other than SAB with systemic non-study antibacterial treatment 
which is potentially effective against S. aureus (see Appendix 5), and which is considered 
by the DRC to have a relevant impact on the primary endpoint in accordance with the 
guidelines provided in Appendix 6.
6. Death for any reason between first administration of study drug and the PTE visit.
7. Indeterminate outcome, defined as any data needed to determine whether the outcome is 
success or failure missing at the PTE visit, including but not limited to:
a) missing PTE visit, or missing key data to evaluate the primary endpoint
b) lost-to-follow-up, or patients who withdrew consent prior to the PTE visit
c) patients not meeting the criteria for Success or Failure, or patients not meeting all 
criteria for overall success
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The numbers and percentages of patients with overall success versus overall failure will be 
determined in each treatment group. The observed difference in percentage of responders at 
PTE (ceftobiprole group minus the daptomycin group) will be determined and a two-sided 
95% confidence interval (CI) for the observed difference will be computed, with adjustment 
for geographical region (North America, Europe, other regions), dialysis status and prior 
antibacterial treatment use. Cochran-Mantel-Haenszel weights will be used for the stratum 
weight in the calculation of the CI.
The non-inferiority hypothesis test is a one-sided hypothesis test performed at the 2.5% level 
of significance. If the lower limit of the two-sided 95% CI for the difference in response 
rates in the mITT population is greater than −15%, the non-inferiority of ceftobiprole to 
daptomycin therapy will be concluded.
The primary efficacy analysis is based on the difference in the rates between the 
two treatment groups. Analyses using risk ratio and odds ratio will also be performed.
The primary analysis will classify as failures all patients with missing data relevant to 
appropriate assessment of the primary endpoint at the PTE visit.
A sensitivity analysis will be performed to exclude those patients with missing data
completely and this assumes missing at random (MAR). Additional analyses will explore the 
robustness of the conclusion of the non-inferiority of ceftobiprole to further missingness not 
at random (MNAR) assumptions. In particular, various proportions of the patients with 
missing data (10%, 20%, 30% and 40%) in the daptomycin group will be considered 
successes, while only half of the respective proportions of patients in the ceftobiprole group 
will be considered successes (5%, 10%, 15%, 20%), and the analysis of non-inferiority 
repeated for each of the assumed proportions.
Subgroup analyses will be conducted for the primary efficacy outcome in the mITT, ITT and 
CE populations. Subgroup analyses will include, but not be limited to, the following factors: 
demographic characteristics (age, sex, race), geographic region, baseline pathogen 
(e.g., MRSA vs MSSA), baseline SAB category (see Section 8.6), underlying medical 
conditions, baseline fever status, antibacterial medication prior to study drug, and 
concomitant antibacterial medication including a separate analysis in patients who received 
concomitant antibacterial treatment for Gram-negative coverage. Further details are provided 
in the Statistical Analysis Plan (SAP).
8.8
Analysis of secondary endpoints
Two-sided 95% CIs will be constructed for the observed difference between ceftobiprole and 
daptomycin therapy for the endpoints of all-cause mortality, microbiological eradication, 
overall success, and development of new metastatic foci, using the same approach as for the 
primary endpoint.
In addition, a time-to-event analysis will be performed for all-cause mortality and for time-
to-blood-cultures-negative for S. aureus.


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The following are the secondary endpoints.
8.8.1
Secondary endpoints
1. All-cause mortality (mITT population) at Day 70 (PTE visit)
All-cause mortality will also be assessed at Day 28, and in the ITT population, and will be 
assessed descriptively.
2. Microbiological eradication (mITT population) at Day 70 (PTE visit) 
Microbiological eradication will also be assessed in the CE population, and at Day 4, Day 8, 
and the EOT visit, and will be assessed descriptively.
Eradication: No growth of the baseline pathogen(s), secondary to an adequate clinical 
response, based on a negative blood culture while the patient is on active study treatment 
which is confirmed by at least one subsequent negative blood culture for S. aureus, either in 
the period between 7 days after EOT and the PTE visit, or at the PTE visit.
Failure: Persistence, relapse, or reinfection of S. aureus infection, defined as one or more of:

Ongoing positive blood cultures leading to discontinuation of the study drug

Subsequent isolation of S. aureus from a blood culture after clearance of bacteremia and 
clinical improvement
–
Relapse: bloodstream infection with the same pathogen isolated at baseline based on 
genotyping
–
Reinfection: bloodstream infection with a different S. aureus strain to that isolated at 
baseline based on genotyping

Absence of at least two negative blood cultures (at least one negative blood culture on 
active study treatment, and at least one post-treatment) to confirm eradication
Relapse or reinfection between EOT and PTE that is reported to the investigator from a
healthcare provider not involved in the study (e.g., from another hospital), needs to be 
thoroughly documented and will be reviewed by the investigator and the DRC for 
determination.
3. Overall success rate at PTE (CE population)
The overall success rate will also be assessed at the EOT visit in the mITT, ITT and CE 
populations, and in the ITT population at the PTE visit, and will be assessed descriptively.
See definitions for the primary endpoint above.
4. Development of new metastatic foci or other complications of SAB after Day 7
(mITT population)
Development of new metastatic foci or other complications of SAB after Day 7 will also be 
assessed in the CE population, and will be assessed descriptively.
Timepoints: Day 8–EOT, and PTE
Newly diagnosed IE or complicated SAB with metastatic foci or other complications of 
S. aureus infection, including metastatic foci in the vertebral column (vertebral abscess, 


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osteomyelitis, discitis or epidural abscess), cerebral abscess/infarction, splenic abscess/
infarction, renal abscess/infarction, psoas abscess or other deep-tissue abscess, other 
metastatic infection of native tissue, septic arthritis (or bacterial joint infection/empyema), 
septic or suppurative thrombophlebitis, and septic pulmonary emboli/infarction.
5. Time to S. aureus bloodstream clearance (mITT and CE populations)
Timepoints: Day 3–EOT
Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-
culture-negative for S. aureus obtained at least 24 h after the first negative blood-culture.
6. Safety/Tolerability (Safety population)
Timepoints: First dose of study drug–PTE
Incidence, type, severity, and relationship to study medication of AEs; and changes in 
laboratory tests (hematology, biochemistry including haptoglobin, urinalysis, and Coombs-
test).
7. Pharmacokinetics of ceftobiprole (PK population)
Plasma levels of ceftobiprole and the -lactam ring open product BAL1029
Sparse PK sampling (all patients)

Day 3: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h

Day 12: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
Rich PK sampling (selected sites, N=40 ceftobiprole-treated patients [i.e., approximately 80 
patients overall])

Day 3: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 3 h, 4 h, 6 h

Day 12: pre-dose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
Plasma-concentration data will be analyzed at each time point and will be presented as 
individual concentrations with descriptive statistics (mean, SD, CV%, min, median, max).
8.9
Safety analyses 
Safety will be assessed through summaries of AEs, safety laboratory evaluations, physical 
examinations, and vital signs. All safety analyses will be based on the Safety population. 
Analyses will be presented by treatment group.
Patients who receive the wrong dose of study drug will be analyzed in the group based on the 
first drug actually received.
An AE is defined in Section 7.1.2 as an event which occurs from the start of first study-drug 
administration up to and including the scheduled PTE visit (see also Section 7.3.2). 
Summary tables of AEs will be provided. (An adverse occurrence after informed consent has 
been provided but prior to the start of first study-drug administration is to be recorded in the 
CRF as pre-dose medical history; see Sections 7.1.1 and 7.3.1).


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The incidence of AEs and SAEs will be tabulated by System Organ Class (SOC) and 
Preferred Term (PT) for each treatment group, and by severity, relationship to treatment, and 
outcome. Tables of AEs leading to study drug discontinuation and withdrawal from the study 
will also be provided. Adverse occurrences (as defined in Section 7.1.1) will be provided in a 
listing.
Descriptive statistics summarizing central laboratory data will be presented by study visit. 
The change from baseline to each post-baseline visit and to the overall worst post-baseline 
value will also be summarized by treatment group.
Descriptive statistics of vital signs will be presented by treatment group and study visit, as 
well as the change from baseline at each study visit. The percentage of abnormalities in the 
physical examination will be presented by treatment group and study visit.
8.10 Pharmacokinetics
Pharmacokinetic analyses will be based on the PK population. Blood-concentration data will 
be analyzed at each time point and will be presented as individual concentrations and with 
descriptive statistics (mean, SD, CV%, min, median, max). A retrospective population-PK 
model will be developed as a separate study. Pharmacokinetic analyses will be based on the 
population-PK model and the effects of demographic and baseline factors such as age, 
weight, sex, race, and renal function on the PK parameters will be examined. The 
population-PK analysis will derive the ƒT>MIC and target attainment rate, and will analyze 
the relationship between exposure and efficacy/safety.
8.11 Interim safety analysis
As animal studies have indicated the potential of an increased risk of convulsions with 
prolonged ceftobiprole therapy (> 4 weeks treatment duration), an initial cohort of patients 
was enrolled for a maximum treatment duration of 28 days (Cohort 1). An interim 
safety analysis was performed by an independent DSMB after 80 patients (approximately 
40 patients per treatment group) had completed 21–28 days of treatment and safety 
follow-up. Based on this analysis the treatment duration is extended up to 42 days 
(Cohort 2), after discussion with the United States FDA.
The decision rules for the DSMB interim safety assessment of Cohort 1 are provided in 
Appendix 7.
At a minimum, further interim safety assessments will be performed by the DSMB after 
enrollment of 200 and 300 patients; details are provided in the DSMB Charter.


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9
STUDY ADMINISTRATION AND REGULATORY ASPECTS
9.1
Study records
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.
9.1.1
Investigator site file
The ISF must contain all essential documents as required by International Council for 
Harmonisation (ICH) E6 and applicable regulations, including the 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 or authorized site 
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 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 investigator must keep all study documents on file for at least 15 years after completion 
or discontinuation of the study. Subsequently, the sponsor will inform the investigator when 
the study documents can be destroyed, subject to 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 investigator wish to assign the study records to another party, or move them to 
another location, the sponsor must be notified in advance.
If the investigator cannot guarantee the archiving requirement at the investigational site for 
any or all of the study documents, arrangements must be made between the investigator and 
the sponsor for appropriate storage.
9.1.5
Sample retention………………
All central laboratory isolates may be stored for up to 5 years after completion of the study 
for future medical and/or scientific research projects related to ceftobiprole. All patients will 
be asked to provide informed consent for this purpose, authorizing the sponsor to use their 
study information and samples for future research projects.
After a maximum of 5 years after completion of the study, all stored samples will be safely 
destroyed.
Bacterial isolates may be transferred in a fully anonymized form for use in epidemiological 
surveillance databases, without a time restriction.
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 and the 
site staff.
The Monitor must visit the investigator and the study facilities on a regular basis throughout 
the study to verify adherence to Good Clinical Practice (GCP) and the protocol, and the 
completeness, consistency and accuracy of the data being entered into the CRFs. The 
Monitor must also ensure that the study drug is being stored, dispensed, and accounted for 
according to specifications.
The investigator must ensure that the Monitor has direct access to all required study data 
(source documents) during the regular monitoring visits. This includes all patient records 
needed to verify the entries in the CRFs.
The investigator must cooperate with the Monitor to ensure that any protocol deviations or 
other issues detected in the course of monitoring visits are resolved.
Monitoring reports must be written after each monitoring visit, per site and per visit. These 
monitoring reports must be reviewed and approved by the respective supervisors of the 
Monitors.
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, 


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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 appropriate notification.
In the event of an audit or an inspection, the investigator must ensure that direct access to all 
study documentation, including source documents, is granted to the auditors or inspectors.
9.4
Protocol amendments
Protocol amendments must be prepared by a representative of the sponsor, and be reviewed 
and approved 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 investigator must ensure that 
adequate consideration is given to the protection of the interests of all patients enrolled in the 
study.
9.6
Publication policy
The sponsor is committed to registering 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 multi-center 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 Guideline E6 and any 
relevant supplementary guidance on GCP, and applicable laws and regulations.
10.2 Informed consent
Eligible patients may only be included in the study after providing written 
IEC/IRB-approved informed consent, or, if incapable of doing so, after such consent has 
been provided by a legally acceptable representative of the patient. Written informed consent 
must be obtained from each patient prior to initiation of any study procedures.
It is the responsibility of the investigator, or a person designated by the investigator if 
acceptable by local regulations, to obtain prior written informed consent from each 
individual participating in this study, after adequate explanation of the aims, methods, 
objectives and potential risks of the study. It must also be explained to patients that they are 
completely free to refuse to enter the study, or to withdraw from the study at any time for 
any reason. Appropriate forms for obtaining written informed consent will be provided to the 
investigator by the sponsor.
Written consent must be witnessed and countersigned by the investigator or a qualified 
designee, as appropriate. In obtaining and documenting informed consent, the investigator
must comply with applicable regulatory requirements and GCP as outlined in ICH Guideline 
E6 and other relevant guidelines, and the ethical principles having their origin in the 
Declaration of Helsinki.
Copies of signed consent forms must be given to the patient and the originals filed at the 
study site.
For patients not qualified to give legal consent, or incapable of doing so, written consent 
must be obtained from the patient’s legally acceptable representative. In the event that both 
the patient and his or her legally acceptable representative are unable to read the consent 
document, an impartial witness must be present during the entire informed consent 
discussion. After the patient and representative have verbally consented to participation in 
the study, the witness’ signature must be obtained on the form to attest that the information 
in the consent form was accurately explained and understood.
The CRFs for this study contain a section for documenting informed patient consent, and this 
must be completed appropriately. If new safety information results in significant changes in 
the benefit/risk assessment for ceftobiprole or for one of the comparator drugs, the consent 
form must be reviewed and updated. All patients currently enrolled in the study who have 
not yet completed the treatment or post-treatment phases must be given the new information 
and a copy of the revised form, and asked to give their consent to continuing in the study.


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Blood cultures that were positive for S. aureus and were conducted in the context of routine 
clinical diagnostic work-up practice prior to obtaining informed consent, but were drawn 
within the 72 h prior to randomization, may be used for the study to determine patient 
eligibility (see Section 5.2.1). Details of the microbiological work-up are provided in 
Section 5.2.1 and Table 7.
10.3 Patient confidentiality and data protection
The investigator 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 investigator
must keep a confidential patient identification code list, as described in Section 8.3.21 of 
ICH Guideline E6.
The sponsor is responsible for ensuring compliance with all applicable data protection laws.
10.4 Independent Ethics Committees / Institutional Review Boards
This protocol and any accompanying material provided to the patient, including patient 
information sheets or descriptions of the study used to obtain informed consent, as well as 
any advertising material and information about any compensation provided to the patient, 
must be submitted to an IEC/IRB operating in compliance with ICH Guideline E6 and any 
relevant supplementary guidance on GCP, and with applicable laws and regulations. 
Approval from the IEC/IRB must be obtained and documented before starting the study.
Amendments made to the protocol after receipt of IEC/IRB approval must also be submitted 
to the IEC/IRB in accordance with local procedures and applicable laws and regulations.


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11
PROTOCOL VERSION HISTORY
In the process of designing clinical study BPR-CS-009 and submitting it for approval to 
regulatory authorities, the protocol went through the following stages of development before 
commencement of the study:

Protocol Version 1.0 dated 27 April 2016 was submitted to the US FDA for special 
protocol assessment (SPA).

Protocol Version 2.0 dated 26 August 2016 (synopsis only) was submitted to the US 
FDA.

Protocol Version 3.0 dated 30 November 2016 was submitted to the US FDA.

Protocol Version 4.0 dated 9 February 2017 was submitted to the US FDA for SPA.

Protocol Version 5.0 dated 20 April 2017 was used for regulatory and IEC/IRB approval
for commencement of this clinical study.

Protocol Version 6.0 dated 25 May 2018 implemented Protocol Amendment 1 dated 
25 May 2018. 

Protocol Version 7.0 dated 31 July 2018 implemented Protocol Amendment 2 dated 
31 July 2018.

Protocol Version 8.0 dated 5 April 2019 implemented Protocol Amendment 3 dated 5 
April 2019.

Protocol Version 9.0 dated 27 February 2020 implemented Protocol Amendment 4 dated 
27 February 2020.


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13 APPENDICES
Appendix 1
Modified Duke’s Criteria for the diagnosis of infective endocarditis
Established in 1994 by the Duke Endocarditis Service and revised in 2000, Duke’s Criteria 
are a collection of major and minor criteria used to establish a diagnosis of infective 
endocarditis (IE).
These criteria have been adjusted for the definition of SAB, i.e. microbiological criteria 
related to organisms other than S. aureus have been removed. In addition, references to 
prosthetic valve infections have been removed, as these patients will be excluded from the 
study.
According to Duke’s Criteria, diagnosis of IE can be definite, possible, or rejected.
A diagnosis of IE is definite if either the following pathological or clinical criteria are met:
1. Pathologic criteria:
– pathologic lesions: vegetation or intracardiac abscess demonstrating active endocarditis 
on histology, or
– microorganism: demonstrated by culture or histology of a vegetation or intracardiac 
abscess
2. One of these combinations of clinical criteria (see definitions below):
– two major clinical criteria
– one major and three minor criteria
– five minor criteria
Diagnosis of IE is possible if one of the following combinations of clinical criteria (see
definitions below) are met:
– one major and one minor criteria
– three minor criteria are fulfilled
Diagnosis of IE is rejected if one of the following criteria are met:
– a firm alternate diagnosis is made
– resolution of clinical manifestations after ≤ 4 days of antibacterial treatment
– no pathological evidence of IE is found at surgery or autopsy after antibacterial 
treatment therapy for ≤ 4 days
– clinical criteria for possible or definite IE are not met


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Major criteria for the diagnosis of infective endocarditis
1. Positive blood culture with S. aureus from two separate blood cultures
2. Evidence of endocardial involvement with positive echocardiogram defined as
– oscillating intracardiac mass on valve or supporting structures, in the path of 
regurgitant jets in the absence of an alternative anatomic explanation
– abscess
– new valvular regurgitation (worsening or changing of preexisting murmur not 
sufficient)
Minor criteria for the diagnosis of infective endocarditis
1. Predisposing factor: intravenous drug use or presence of a predisposing heart condition (a 
valve lesion associated with significant regurgitation or turbulence of blood flow)
2. Fever ≥38 °C (100.4 °F)
3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic 
aneurysm, intracranial hemorrhage, conjunctival hemorrhages or Janeway lesions
4. Immunological phenomena: glomerulonephritis, Osler's nodes, Roth's spots, Rheumatoid 
factor
5. A single positive blood culture with S. aureus
Table A1
Description of minor criteria
Criterion
Description
Glomerulonephritis
Glomerular disease that usually presents with one of two patterns, nephrotic or 
nephritic, based upon the urine sediment and the degree of proteinuria.
Janeway lesions
Nontender erythematous macules on the palms and soles
(reflecting microabscesses with neutrophil infiltration of capillaries).
Mycotic aneurysm
Abnormal focal arterial dilation due to S. aureus infection.
Osler nodes
Tender subcutaneous violaceous nodules mostly on the pads of the fingers and 
toes, which may also occur on the thenar and hypothenar eminences 
(assumed to reflect sequelae of vascular occlusion by microthrombi leading to 
localized immune-mediated vasculitis).
Rheumatoid factor
Antibodies directed against the Fc portion of immunoglobulin G (IgG); 
commonly measured in clinical practice, is an IgM RF.
Roth spots
Exudative, edematous hemorrhagic lesions of the retina with pale centers
(assumed to reflect sequelae of vascular occlusion by microthrombi leading to 
localized immune-mediated vasculitis).


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Appendix 2
Minimum diagnostic requirements for the assessment of deep-seated 
infections and metastatic or other complications related to S. aureus
bacteremia (related to Inclusion criterion 8) at baseline
Condition
Minimum diagnostic requirement
ABSSSI
Clinical findings consistent with major wound, abscess, or erysipilas.
Septic arthritis or bacterial 
joint infection/empyema
Positive culture or Gram stain suggestive of S. aureus from arthrocentesis 
and/or synovial biopsy showing polymorphonuclear leukocytes or causative 
organism and/or MRI with typical findings for acute intraarticular infection 
(e.g., combination of bony erosions with marrow edema).
Septic or suppurative 
thrombophlebitis
Local findings of induration, redness, and tenderness along the course of the 
vein plus thrombus imaging using duplex ultrasound for peripheral septic or 
suppurative thrombophlebitis; CT*, MRI, ultrasound for pelvic vein, portal 
vein, superior or inferior vena cava, internal jugular vein or other veins.
Visceral soft-tissue abscesses 
requiring ≤ 42 days of study 
antibacterial treatment
Positive imaging finding based on CT (including PET/CT)* and/or MRI and/or 
ultrasound and/or positive culture (e.g., through drainage).
Septic pulmonary 
emboli/infarction
The diagnosis of a septic pulmonary embolism will be made by the investigator
based on clinical symptoms of fever, cough, sputum/hemoptysis in the 
presence of an extrapulmonary infection, sepsis, or risk factors for septic 
emboli (e.g., intravenous drug use) and will be based on the following 
radiological signs:
Contrast-enhanced CT (preferred):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of 
cavitation) or wedge-shaped infiltrates 
–
with/without a feeding vessel sign (vessel leading to the nodule)
–
with/without pleural effusion or features suggestive of pleural empyema
Non-contrast enhanced CT (e.g., in patients with a contraindication for contrast 
administration):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of 
cavitation) or wedge-shaped infiltrates 
–
with/without pleural effusion or features suggestive of pleural empyema
Plain X-ray (e.g., in patients unable to undergo a CT):
Multifocal nodular densities or wedge-shaped infiltrates in varying stages of 
cavitation with or without pleural effusion or features suggestive of pleural 
empyema
* Radioisotope studies (e.g., PET or PET-CT) may be conducted as an adjunct to diagnosis, as primary diagnostic approach,
or when radiographic changes on MRI or CT scans are absent or equivocal.
Abbreviations: ABSSSI=acute bacterial skin and skin structure infection; CT=computed tomography; PET/CT=positron 
emission tomography/computed tomography; MRI=magnetic resonance imaging.


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Appendix 3
Minimum diagnostic requirements for the assessment of deep-seated 
infections and metastatic or other complications related to S. aureus
bacteremia post-baseline
Condition
Minimum diagnostic requirement
Metastatic foci in the vertebral 
columns (vertebral abscess, 
osteomyelitis, discitis or 
epidural abscess)
Positive imaging finding based on CT (including PET/CT)* and/or MRI and/or 
positive biopsy/culture
Cerebral abscess or infarction
Positive imaging finding on MRI and/or contrast CT (including PET/CT)* and/or 
positive biopsy/culture
Splenic abscess or infarction
Positive imaging finding based on ultrasound and/or contrast CT (including
PET/CT)* and/or MRI and/or positive culture (e.g., from samples obtained during 
surgery)
Renal abscess or infarction
Positive imaging finding based on ultrasound and/or contrast CT (including
PET/CT)* and/or MRI and/or positive culture (e.g., through drainage or urine)
Psoas abscess
Positive imaging finding based on ultrasound and/or contrast CT (including
PET/CT)* and/or positive culture (e.g., through drainage)
Other metastatic infection of 
native tissue
Positive imaging finding based on CT (including PET/CT)* and/or MRI and/or 
ultrasound and/or positive biopsy/culture
Septic arthritis or bacterial 
joint infection/empyema
Positive culture or Gram stain suggestive of S. aureus from arthrocentesis and/or 
synovial biopsy showing polymorphonuclear leukocytes or causative organism 
and/or MRI with typical findings for acute intraarticular infection (e.g., combination 
of bony erosions with marrow edema)
Septic or suppurative 
thrombophlebitis
Local findings of induration, redness, and tenderness along the course of the vein 
plus thrombus imaging using duplex ultrasound for peripheral septic or suppurative 
thrombophlebitis; CT*, MRI, ultrasound for pelvic vein, portal vein, superior or 
inferior vena cava, internal jugular vein, or other veins.
Septic pulmonary 
emboli/infarction
The diagnosis of a septic pulmonary embolism will be made by the investigator
based on clinical symptoms of fever, cough, sputum/hemoptysis in the presence of an 
extrapulmonary infection, sepsis, or risk factors for septic emboli (e.g., intravenous 
drug use) and will be based on the following radiological signs:
Contrast-enhanced CT (preferred):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of 
cavitation) or wedge-shaped infiltrates 
–
with/without a feeding vessel sign (vessel leading to the nodule)
–
with/without pleural effusion or features suggestive of pleural empyema
Non-contrast enhanced CT (e.g., in patients with a contraindication for contrast 
administration):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of 
cavitation) or wedge-shaped infiltrates 
–
with/without pleural effusion or features suggestive of pleural empyema
Plain X-ray (e.g., in patients unable to undergo a CT):
Multifocal nodular densities or wedge-shaped infiltrates in varying stages of 
cavitation with or without pleural effusion or features suggestive of pleural empyema
* Radioisotope studies (e.g. PET or PET-CT) may be conducted as adjunct to diagnosis, as primary diagnostic approach or 
when radiographic changes on MRI or CT scans are absent or equivocal.


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Appendix 4
DRC process
The DRC process is briefly outlined below. More details are provided in the DRC Charter.
Role of the DRC
For each patient randomized in study BPR-CS-009 who has confirmed SAB based on a 
blood culture obtained within 72 h prior to randomization and who has received study 
medication (the mITT population), the Data Review Committee will
adjudicate, 
independently from the sponsor and the study investigators:

the diagnosis (SAB, complicated forms of SAB, uncomplicated SAB)

the response to study treatment (overall success or failure)

for deaths occurring during the study, a blinded assessment of the attribution of death to 
the SAB or to another cause
Organization and communication
The DRC will comprise independent experts with experience in the diagnosis and 
management of patients with SAB. The DRC Chair will be responsible for final sign-off of 
the Charter on behalf of all DRC members, and for working with the sponsor to manage any 
procedural or other issues that may be raised by DRC members throughout the DRC process.
Each DRC member will remain blinded to patient treatment assignment until the study is 
completed.
Review of patient data
Each patient randomized in study BPR-CS-009 who has confirmed SAB based on a blood 
culture obtained within 72 h prior to randomization and who has received study medication, 
will be reviewed independently by a minimum of two DRC members. Signs and symptoms 
will be assessed by the investigator on a predefined scale to assess whether signs and 
symptoms have resolved or improved from baseline or are unchanged or worsened, and this 
scaled assessment will be reviewed by the DRC. For each case, one DRC member will be 
designated as the primary reviewer, and one DRC member as the secondary reviewer.
Case assessment is to be initiated when the data for a given patient are considered clean. The 
Data Management Group will generate patient profiles, which will be assigned to DRC 
reviewers. Patient profiles will include all data relevant to assessment of the SAB baseline 
condition and the response to study treatment (overall success or failure), including medical 
history, demographics, prior and ongoing therapy and concomitant non-drug procedures, 
vital 
signs, 
physical 
examination, 
microbiological 
and 
laboratory 
results, 
investigator-assessed clinical signs and symptoms of complicated SAB, evidence of 
metastatic or other complications of SAB, modified Duke's criteria, and AEs.


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The DRC may request supporting information or source documentation via the Basilea DRC 
Manager or designee, as needed. These requests will be forwarded to the investigator for a 
response. The blinded sponsor’s Clinical Program Manager or designee will be responsible 
for tracking queries, ensuring their resolution in a timely manner, and providing the site 
response to the DRC.
Radiological imaging results (e.g., CT, MRI, ultrasound) will be captured in a consistent way 
across all study sites using a standardized form which includes method details, summary of 
results and assessments. These forms will be provided to the DRC members as part of the 
patient profiles.
The DRC members will review, independently from each other, the data for the 
assigned patients, and will give their opinion on the diagnosis and classification of the 
SAB (Table B1), and the response assessment (overall success or failure) at the PTE visit 
(Table B2).
A successful outcome will be defined as the normalization of all (resolution) or some 
(improvement) baseline symptoms, without deterioration in any baseline symptoms or the 
occurrence of any new symptoms. Patients in whom no improvement or resolution of 
symptoms is observed (i.e., whose baseline symptoms remain unchanged or worsen) will be 
considered failures.
In addition, for deaths occurring during the study, a blinded assessment of the attribution of 
death to the SAB or to another cause will be performed by the DRC members.
Reconciliation and finalization of DRC assessments
The DRC reviewers will enter their individual assessments into an electronic CRF system.
Once the database contains the individual assessments of the assigned DRC reviewers, the 
sponsor or a designated third party will compare the DRC members’ assessments for 
consensus, and provide the reviewers and the DRC Chair with a concordance report. Each 
case will be discussed at a consensus meeting which includes at least three DRC members,
including the DRC Chair and the assigned primary and secondary reviewers of the cases to 
be adjudicated. If necessary, the DRC Chair may decide that a case should be deferred for 
discussion with additional DRC members or with the full DRC.
The primary reviewer will be responsible for presenting each case to the DRC for discussion. 
When possible, the DRC reviewers should reach a consensus on an overall DRC opinion. 
However, if consensus is not reached, the majority opinion will prevail, and if there is no
majority opinion, the opinion of the DRC Chair will prevail.
The final opinion of the DRC is to be entered into the CRF by the assigned primary reviewer.


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Table B1 Confirmation and baseline classification of the diagnosis of SAB
Criterion
Source for assessment by the DRC
1
Uncomplicated SAB
Clinical database/patient profiles:

Medical history and demographics, prior and 
ongoing therapy

Vital signs

Physical examination 

Laboratory assessments

Investigator-assessed clinical signs and 
symptoms of complicated SAB 

Investigator-assessed evidence of metastatic or 
other complications of SAB, including 
examinations regarding intravascular or 
extravascular devices and foreign materials
Central and local microbiology laboratory reports
Structured imaging reports
Modified Duke’s criteria
2
Any complicated SAB
3
SAB in patients undergoing chronic intermittent 
hemodialysis or peritoneal dialysis
Patients meeting the criteria for complicated SAB 
who have a medical history of undergoing chronic 
intermittent hemodialysis or peritoneal dialysis
4
Persistent SAB
Central and local microbiology laboratory reports
5
Forms of complicated SAB with signs or 
symptoms of metastatic foci of S. aureus
infection, or other complications
Clinical database/patient profiles:

Vital signs

Physical examination 

Laboratory assessments

Investigator-assessed clinical signs and 
symptoms of complicated SAB 

Investigator-assessed evidence of metastatic or 
other complications of SAB
Central and local microbiology laboratory reports
Structured imaging reports
6
Definite native-valve RIE, by Modified Duke’s 
Criteria.
Modified Duke’s criteria


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Table B2 Efficacy response assessments at the PTE visit (overall success or failure)
Success criterion
Source for assessment by the DRC
1
Patient alive at Day 70 (± 5 days) post-randomization.
Clinical database/patient profiles:

Vital status 
2
No new metastatic foci or complications of the SAB 
infection.
Clinical database/patient profiles:

Investigator-assessed clinical signs and 
symptoms of complicated SAB 

Investigator-assessed evidence of metastatic or 
other complications of SAB

Laboratory assessments
Central and local microbiology laboratory reports
Structured imaging reports
3
Resolution or improvement of SAB-related clinical 
signs and symptoms.Signs and symptoms will be 
assessed by the investigator on a predefined scale to 
assess whether signs and symptoms have resolved or 
improved from baseline or are unchanged or worsened.
Clinical database/patient profiles:

Investigator-assessed clinical signs and 
symptoms of complicated SAB 

Vital signs

Physical examination

Laboratory assessments
4
Two negative blood cultures for S. aureus (without any 
subsequent positive blood culture for S. aureus):

at least one while the patient is on active study 
treatment; AND

confirmed by at least one subsequent negative blood 
culture for S. aureus
- either in the period between 7 days after the 
EOT visit and the PTE visit
- or at the PTE visit
Clinical database/patient profiles:

Study treatment duration information
Central and local microbiology laboratory reports
Failure criterion
Source for assessment by the DRC
1
Premature discontinuation of study treatment due to 
DRC-assessed lack of efficacy (e.g., worsening of signs 
and symptoms) or for an AE that represents
manifestation of disease progression or relapse, at any 
time between first dose of study drug and the PTE visit. 
Clinical database/patient profiles:

Study treatment duration information

Study completion information and/or 
investigator-assessed reason for premature 
study discontinuation

Laboratory assessments

AEs

Investigator-assessed clinical signs and 
symptoms of complicated SAB 

Investigator-assessed evidence of metastatic or 
other complications of SAB

Laboratory assessments
Central and local microbiology laboratory reports
Structured imaging reports
2
Development of new metastatic or other complications 
related to SAB (see Section 5.4.5.3.2) between Day 8
and the PTE visit. (Development of new metastatic or 
other complications of SAB prior to Day 8 is to be 
assessed by the DRC on a case-by-case basis to assess 
whether these constitute a delayed manifestation of the 
baseline disease or new complications).
3
SAB relapse or reinfection based on evidence from a 
positive blood culture (after documented clearance of 
S. aureus from the bloodstream and clinical 
improvement) between the EOT and PTE visits.


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Failure criterion
Source for assessment by the DRC
4
Receipt of systemic non-study antibacterial treatment, 
other than those permitted under the protocol, for the 
treatment of SAB. This includes patients who are 
prematurely discontinued from study therapy due to an 
AE, but who require continuation of antibacterial 
treatment for SAB.
Clinical database/patient profiles:

Study treatment duration information

Concomitant medication with information on 
the indication for which the medication was
used

Study completion information and/or 
investigator-assessed reason for premature 
study discontinuation

AEs
5
Treatment of infections other than SAB with systemic 
non-study antibacterial treatment which is potentially 
effective against S. aureus (see Appendix 6), and which 
is considered by the DRC to have a relevant impact on 
the primary endpoint in accordance with the guidelines 
provided in Appendix 7.
Clinical database/patient profiles:

Study treatment duration information

Concomitant medicationswith information on 
the indication for which the medication was 
used
DRC assessment to be based on the process 
described in Appendix 7.
6
Death for any reason between first administration of 
study drug and the PTE visit.
Clinical database/patient profiles:

Study treatment duration information

Vital status information
7
Indeterminate outcome, defined as any data needed to 
determine whether the outcome is success or failure 
missing at the PTE visit, including but not limited to: 
a) missing PTE visit, or missing key data to 
evaluate the primary endpoint
b) lost-to-follow-up, or withdrawal of consent prior 
to the PTE visit
c) not meeting the criteria for success or failure, or 
not meeting all criteria for overall success
Clinical database/patient profiles:

Study treatment duration information

Study completion information 

Missing PTE visit, or missing relevant 
microbiology laboratory or imaging data
8
Requirement for systemic antibacterial treatment for 
SAB beyond EOT.
CRF: Clinical database/patient profiles:

Study treatment duration information

Concomitant medication with information on 
the indication for which the medication was
used

Study completion information and/or 
investigator-assessed reason for premature 
study discontinuation


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Appendix 5
Systemic antibacterial treatments considered to be potentially effective 
against S. aureus
Half-life ≤ 12 h
Half-life > 12 h
Amoxicillin
Dicloxacillin
Azithromycin
Amoxicillin/Clavulanic acid
Doripenem
Dalbavancin
Ampicillin
Ertapenem
Doxycycline
Ampicillin/Sulbactam
Erythromycin
Linezolid
Cefaclor
Flucloxacillin
Minocycline
Cefadroxil
Fosfomycin
Oritavancin
Cefamandole
Gemifloxacin
Tigecycline
Cefazolin
Imipenem/cilastatin
Teicoplanin
Cefdinir
Levofloxacine
Omadacycline
Cefditoren pivoxil
Loracarbef
Cefepime
Meropenem
Cefixime
Meropenem/vaborbactam
Cefoperazone
Mezlocillin
Cefotaxime
Moxifloxacin
Cefotetan
Nafcillin
Cefoxitin
Ofloxacin
Cefpodoxime proxetil
Oxacillin
Cefprozil
Penicillin G
Ceftaroline fosamil
Penicillin V
Ceftazidime
Piperacillin
Ceftazidime/avibactam
Piperacillin/tazobactam
Ceftibuten
Quinupristin/dalfopristin
Ceftizoxime
Rifampin
Ceftolozane/tazobactam
Tedizolid
Cetriaxone
Telavancin
Cefuroxime
Telithromycin
Cephalexin
Tetracycline
Chloramphenicol
Ticarcillin
Ciprofloxacin
Ticarcillin/clavulanate
Clarithromycin
Trimethoprim
Clindamycin
Trimethoprim-sulfamethoxazole
Daptomycin
Vancomycin
Delafloxacin
Note: The table should be considered as a general guide for potentially effective antibacterials against S.aureus, without 
differentiation between MSSA and MRSA.
Oral vancomycin is considered a non-systemic antibiotic and may be used at any time during the study.


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Appendix 6
DRC assessment of potentially-effective antibacterial treatment
Each patient enrolled in study BPR-CS-009 who has received at least one dose of study drug 
is to be reviewed by at least two members of the DRC. The DRC comprises experts in the 
field of SAB who will review, independently of each other, the data for the assigned patients 
related to categorization of the SAB (uncomplicated or complicated), and to the primary and 
selected secondary endpoints. Details of these DRC assessments are provided in the DRC 
charter.
In addition to these functions, the DRC is also required to review and assess the impact on 
the primary endpoint of potentially effective concomitant systemic antibacterial treatment
received by patients enrolled in the study. This assessment must take into account:
1. The susceptibility of the SAB-causing S. aureus strain to the concomitantly-administered 
antibacterial agent, and
2. The clinical status of the patient (improved or cured, versus ongoing, unchanged, or 
worsened SAB) at the time of concomitant use of the antibacterial treatment, and
3. The duration of the concomitantly-administered antibacterial treatment.
The use of systemic non-study antibacterial treatment is not considered to impact the primary 
outcome if any of the following conditions apply (see Table C1):

The 
S. 
aureus
strain 
causing 
the 
SAB 
is 
not 
susceptible
to 
the 
concomitantly-administered antibacterial agent.

The patient is clinically improving or cured, and received the concomitant antibacterial 
agent for no more than the maximum allowable duration shown in Table C1.

The patient is clinically not improving, and has received no more than a single dose of a 
non-study antibacterial agent.
All other instances of the use of concomitant systemic non-study antibacterial treatment
should be assessed by the DRC as an outcome of failure for the primary endpoint, unless it is 
the opinion of all DRC members that the overall clinical context strongly indicates that the 
concomitant non-study systemic antibacterial did not impact the primary outcome.
Any deviation by the DRC from the algorithm described above must be clearly documented, 
including the rationale for the DRC’s assessment.
The following is the rationale for these stipulations:
Concomitant treatment with a  non-study antibacterial agent to which the S. aureus strain 
causing the SAB is not susceptible is not expected to influence outcomes related to the 
SAB.


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If study treatment has already led to clinical improvement prior to receiving systemic non-
study antibacterial treatment (to which the  S. aureus strain causing the SAB is 
susceptible), then the effect of the study treatment may still be considered a successful 
outcome, depending on the timing and extent of the non-study antibacterial treatment
If study treatment has not led to clinical improvement prior to receiving systemic non-
study antibacterial treatment (to which the S. aureus strain causing the SAB is 
susceptible) then only a minimal amount of non-study antibacterial treatment should be 
allowable: i.e., any administration of more than a single dose of another antibiotic (which 
may have been administered e.g., for surgical prophylaxis, or given inadvertently) would 
mean the patient is considered a failure.
The proposed decision rules related to concomitant systemic non-study antibacterial 
treatments are summarized in Table C1.
Table C1 Maximum duration of concomitant systemic non-study antibacterial 
treatment that would permit a non-failure classification by the DRC 
1. S. aureus strain causing SAB is not susceptible to antibacterial agent
Concomitant antibiotic will not impact assessment of failure.
2. S. aureus strain causing SAB is susceptible to antibacterial agent
Study treatment 
period
Patient clinically improved or cured
Patient clinically unchanged or worsened
sABT t1/2
≤ 12 h*
sABT t1/2
> 12 h*
sABT t1/2
≤ 12 or > 12 h
Day 1 – 7
≤ 1 day#
≤ a single dose
≤ a single dose
Day 8 – 14
≤ 2 days#
≤ 1 day#
≤ a single dose
Day 15 – 28
≤ 4 days#
≤ 2 days#
≤ a single dose
Day 29 – 42
≤ 6 days#
≤ 4 days#
≤a single dose
*See Appendix 5# ≤  specified days of the maximum approved daily dose according to the US prescribing information
sABT=systemic antibacterial treatment.


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Appendix 7
DSMB Process and decision criteria for DSMB interim safety assessment 
of Cohort 1 and at subsequent DSMB meetings
1.
Overview of the Data and Safety Monitoring Board process
Independent DSMB
An independent Data and Safety Data Monitoring Board (DSMB) will be commissioned by 
the sponsor to evaluate accumulating safety data in patients enrolled in study BPR-CS-009, 
to ensure the safety of the patients in the study, and to provide recommendations to the 
clinical teams in charge of conducting the study.
The DSMB will comprise one or several experts in the field of infectious diseases, at least 
one member with expertise in the assessment of convulsion events, and at least one expert in 
statistics. All DSMB members will disclose their financial interests to the sponsor. None of 
the DSMB members may be involved in the conduct or reporting of any ongoing Basilea
clinical study.
DSMB statistics Group
The DSMB Statistics Group (DSG) will be a separate statistics/data management group, 
which is independent of the blinded study statistician and the data management group. The 
DSG will receive study data from the blinded statistician and the data management group,
and will separately receive patient treatment assignment data from the IWRS vendor. The 
data from the blinded study statistician and data management group, including all summary 
tables and listings specified in the DSMB statistical analysis plan, will use dummy 
randomization codes to maintain full blinding of the study. The DSG will then re-generate 
the summary tables and listings using true treatment assignments received from the IWRS 
vendor, and will mark treatment groups as A or B in the data presentation and distribute 
them to the DSMB members. DSMB members will also be separately provided with the 
actual treatment group assignment, i.e., will receive a separate notification whether group A 
is the ceftobiprole group or the daptomycin group, to enable a fully unblinded assessment by 
the DSMB.
Outputs provided to the DSMB members will include (but are not limited to):

Cumulative patient enrollment and patient exposure, and enrollment by center

Demographic description of the study cohort

Reasons for premature study discontinuation

Serious adverse events (including deaths) and non-serious AEs by Preferred Term and 
System Organ Class, subclassified by severity and relatedness to study drug

Convulsion events (including narratives)


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
Other events of special interest for ceftobiprole and/or daptomycin based on the known 
safety profile of both compounds:
–
Hypersensitivity reactions
–
Clostridium difficile-associated diarrhea
–
Myopathy
–
Rhabdomyolysis
–
Eosinophilic pneumonia
–
Peripheral neuropathy
The DSMB chair will receive:

SUSARs as 7-day or 15-day reports

Adverse events of special interest that do not qualify as SUSARs within 15 days of the 
investigator becoming aware of the event

Other SAEs on a quarterly basis

Non-serious AEs for scheduled or ad hoc DSMB meetings
Details of analyses provided to the DSMB will be specified in the DSMB statistical analysis 
plan.
Convulsion event assessment by the investigator and the DSMB
Convulsion events will be assessed as reported by the investigator using the Standard 
MedDRA Query ‘Convulsions (narrow)’.
In addition, convulsion events will be independently adjudicated by a member of the DSMB 
with expertise in the assessment of convulsion events, to permit an assessment of these 
events according to uniform criteria. Results of both the investigator-assessed convulsions 
and the DSMB-adjudicated events of convulsions will be separately analyzed and presented.
DSMB-adjudicated events of convulsions will be the primary analysis.
Expedited reporting of adverse events of special interest to the DSMB
All convulsion events will be considered SAEs, and reporting of these events from the
investigator to the sponsor will be expedited (reporting within 24 h of awareness of the 
investigator); these events will then be forwarded to the DSMB within 15 days of receipt by 
the sponsor.
The timelines outlined in Table D1 will apply to informing the DSMB about other AEs of 
special interest.


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Table D1 Timelines for reporting adverse events to the DSMB
Type of adverse event
Reporting timeline to DSMB
SUSAR
7-day or 15-day reports, as required by applicable regulations
Adverse event of special interest
Within 15 days (unless to be reported as a 7-day SUSAR)
Non-SUSAR/non-special interest SAE
Every 3 months
Other non-serious AE
At each DSMB meeting
DSMB meetings
Following a first organizational meeting, the need for DSMB data review meetings will be 
assessed on a 3-monthly basis between the DSMB Chair and the sponsor, with meetings 
scheduled based on patient enrollment. At a minimum, DSMB meetings will take place after 
enrollment of:

60 patients who received at least 21 days of study treatment, if no convulsion events were
observed in the ceftobiprole group or

80 patients who received at least 21 days of study treatment, if at least one-convulsion 
event was observed in the ceftobiprole group

200 patients

300 patients
The DSMB will review the data received, and at any time the DSMB Chair may convene an 
ad hoc DSMB meeting, or request unblinded patient information.
For AEs of special interest, the DSMB chair should consider convening a DSMB meeting, 
using the criteria in Table D2 as guidance.
Table D2 Thresholds for convening a DSMB meeting for adverse events of special 
interest
Adverse event of special interest
Frequency (%) threshold for 
convening a DSMB meeting*
Threshold number of events for 
convening a DSMB meeting*
Rhabdomyolysis
NA
≥ 2
Convulsions
NA
≥ 3
Hypersensitivity reactions
≥ 1% of SAEs
≥ 2 SAEs
Clostridium difficile-associated 
diarrhea
≥ 2 %
≥ 2
Myopathy
≥ 2 %
≥ 3 SAEs
Peripheral neuropathy
≥ 2 %
≥ 3 of moderate or severe intensity
Eosinophilic pneumonia
≥ 1 %
≥ 2
*A DSMB meeting should be convened if both the frequency (%) threshold (if applicable) AND the threshold number of 
events are met.


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It should be noted that the DSMB will receive cases of convulsions on an expedited basis 
(see above), and will be consulted as needed to assess any relevant emerging safety signal.
DSMB members are expected to participate in each meeting, preferably in person; however, 
if the DSMB members cannot meet in person, meetings may be held by videoconference or 
teleconference.
The DSMB meeting may begin with an open session followed by a closed session. 
Investigators or experts serving as ad hoc advisors may be requested to attend the open 
session of the meeting, during which only blinded data are discussed. The closed session will
be limited to the DSMB members and designated staff from the DSG for the presentation of 
unblinded data. At the request of the DSMB, the sponsor’s Head of Global Drug Safety may 
also be invited to closed DSMB sessions.
DSMB meeting minutes
DSMB meeting minutes and the DSMB Meeting Report summarizing the conclusions and 
recommendations of the DSMB are to be drafted after each meeting, without any reference 
to unblinded data. The DSMB Chair will oversee finalization of the DSMB meeting minutes 
and the DSMB Meeting Report and will sign both documents The DSMB meeting minutes 
should include important considerations that led to the DSMB recommendations; the 
meeting minutes will not be sent to the sponsor until after the completion of this study, and 
database lock of the relevant clinical database. The DSMB Meeting Report, which is sent to 
the sponsor’s Head of Global Drug Safety, will include DSMB conclusions and 
recommendations without reference to unblinded data.
2.
Overview of the decision criteria for the DSMB regarding the interim safety
assessment of Cohort 1
After finalization of the study treatment and post-treatment observation period of 80 patients 
who received at least 21 days of study treatment, the DSMB will review the unblinded safety 
data of this initial Cohort 1, and provide a decision whether:

The study can continue, with or without additional safety measures

The maximum study drug treatment duration can be extended from 28 to 42 days
3. Decision Rules 1 and 2
Decision Rules 1 and 2 are not binding. They may be used as a guide which can be 
considered by the DSMB in making the safety-related decision to assess whether an 
extension of the maximum study drug treatment duration from 28 days (Cohort 1) to 42 days 
(Cohort 2) is justified.
Decision rule 1 is based on the number of ceftobiprole-treated patients with convulsion 
events during treatment Weeks 3–4 (Period 2) versus treatment Weeks 1–2 (Period 1). 
A threshold of p≤0.1 (one-sided) for the difference in the number of patients with events 
(Period 2 −Period 1) will be used to guide the decision on whether the study continues from 
Cohort 1 to Cohort 2.


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Decision rule 2 is based on the number of ceftobiprole-treated patients with convulsion 
events during the entire 28-day treatment period for Cohort 1. The difference in the number 
of patients with events observed in this study (BPR-CS-009) versus the expected number of 
convulsions based on the pooled Phase 3 pneumonia studies (CAP-3001 and BAP248/307)
will be used to guide the decision on whether the study continues from Cohort 1 to Cohort 2, 
with a threshold of ≥2 patients (difference observed versus expected) with convulsion 
events.
Decision rule 2 (convulsion events over the entire 28-day period) will take into account the 
convulsion rate observed in daptomycin-treated patients. As daptomycin has not been 
associated with drug-related convulsions, convulsion events observed with daptomycin in 
this study will be considered to be reflective of the background rate of convulsions in the 
study population of SAB patients. An adjustment for daptomycin events will not be 
performed for Decision rule 1 because the temporal distribution of background convulsion 
events may be different from the temporal distribution of ceftobiprole-related convulsion 
events, e.g., background events could occur predominantly early during treatment when 
patients are more sick, and ceftobiprole-related events could occur predominantly later 
during treatment.
Decision rule 1: Convulsion events in Period 2 versus Period 1 in the ceftobiprole group
Under Decision Rule 1, a comparison of Period 2 (Weeks 3–4) versus Period 1 (Weeks 1–2) 
would be based on:

the observed convulsion events within the first 14 days of treatment (Period 1), using the 
expected total N=60 patients in the ceftobiprole group in Cohort 1 as denominator

the observed convulsion events within Days 15–28 of treatment (Period 2), using an 
expected n=45 patients in the ceftobiprole group with >14 days of treatment in Cohort 1 
as denominator
A ‘p≤0.1’ (1-sided Fisher’s exact test) threshold would result in the following example
decisions:
Ceftobiprole
events Period 2
(n/N)
Ceftobiprole
events Period 1
(n/N)
p-Value
Decision
1/45
0/60
0.43
Continue to Cohort 2
2/45
0/60
0.18
Continue to Cohort 2
3/45
0/60
0.08
Additional safety review (based on Decision rule 1)
2/45
1/60
0.39
Continue to Cohort 2
3/45
1/60
0.21
Additional safety review (based on Decision rule 2)
4/45
1/60
0.11
Additional safety review (based on Decision rule 2)
5/45
1/60
0.05
Additional safety review (based on Decision rules 1+2)


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Decision rule 2: Convulsion events in the entire 28-day study period
Under Decision Rule 2, the second assessment would be based on the total number of 
ceftobiprole-treated patients with convulsion events observed in the entire 28-day period.
In the pooled pneumonia studies (CAP-3001 and BAP248/307), the rate of convulsion events 
in the ceftobiprole group was 0.00196 events per study drug treatment day. With this rate, a 
total of 2 convulsion events would be expected under the following assumptions regarding 
days of treatment for the 60 patients treated with ceftobiprole in Cohort 1:
Days of treatment (average)
No. of patients
28
10
21–27 (24)
30
15–20 (17)
5
1–14 (7)
15
This scenario would result in a total of 1190 treatment days, and an expected number of 
2 convulsion events at the rate of 0.00196 convulsion events per treatment day observed in 
the pooled pneumonia studies.
A difference of ≥2 ‘observed minus expected’ convulsion events with ceftobiprole (adjusted 
for daptomycin events) would suggest grounds for an additional safety review, 
regardless of the outcome under Decision rule 1 (‘P2 versus P1’), resulting in the following 
example decisions:
Cefto-
biprole
events P2
(n/N)
Cefto-
biprole
events P1
(n/N)
Cefto-
biprole 
events
(total)
Dapto-
mycin
events*
(total)
Ceftobiprole events
Diff vs expected
(corrected for 
daptomycin)
Decision
2/45
0/60
2/60
0
0
Continue to Cohort 2
2/45
1/60
3/60
0
1
Continue to Cohort 2
2/45
2/60
4/60
0
2
Additional safety review (Decision rule 2) 
3/45
0/60
3/60
0
1
Additional safety review (Decision rule 1)
2/45
2/60
4/60
1
1
Continue to Cohort 2
2/45
3/60
5/60
1
2
Additional safety review (Decision rule 2) 
*Ceftobiprole convulsion events observed in the entire 28-day treatment period will be corrected by the number of observed 
events in the daptomycin group, i.e. ‘(ceftobiprole minus daptomycin events)’


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4. Early decision to continue to Cohort 2
If no events of convulsion have been observed after treatment of a total of 80 patients with 
approximately 60 patients treated for 21–28 days, the likelihood of observing three events of 
convulsion in the remaining 40 patients (assuming 120 patients would need to be enrolled for 
80 patients to be treated for 21–28 days) is low (one-sided p-value = 0.04). A situation of 
no convulsion events in 80 patients may therefore allow for a DSMB recommendation of an 
early decision to continue to Cohort 2.
If one convulsion event has been observed after treatment of 80 patients in total and 
60 patients treated for 21–28 days, then the DSMB will be unblinded to the treatment 
allocation of this patient; if the patient was in the daptomycin group, this may allow for a 
DSMB recommendation to proceed to Cohort 2. In this scenario, the likelihood of observing 
three events of convulsion in the remaining 20 patients in the ceftobiprole group, having seen 
no events among the first 40 patients in that group, is also low (one-sided p-value = 0.03).
The same process will apply if two convulsion events have been observed after treatment of 
80 patients in total and 60 patients treated for 21–28 days; if the convulsion events were both 
in patients in the daptomycin group, this may allow for a DSMB recommendation to proceed
to Cohort 2.
5. DSMB reviews after completion of Cohort 1
After completion of Cohort 1, for subsequent safety reviews, interim unblinded DSMB 
safety analyses are planned after enrollment of 200 and 300 patients.
In addition, an ad hoc DSMB meeting will be organized if the convulsion rate in the entire 
study population, or the rate of another event of special interest (hypersensitivity reactions, 
Clostridium 
difficile-associated 
diarrhea, 
myopathy, 
rhabdomyolysis, 
eosinophilic 
pneumonia, or peripheral neuropathy) first exceeds the threshold provided in Table D2.
The assessment of convulsions after completion of Cohort 1 would follow similar principles 
to those described for the assessment of Cohort 1, i.e., an analysis of convulsion events 
would be based on a comparison of early versus late-onset convulsion events, and an 
assessment of convulsion events across the entire treatment period up to 42 days.
Further details are provided in the DSMB Charter.


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Appendix 8
Justification of the non-inferiority margin
Determination of M1
M1 is defined as the entire effect of the active control assumed to be present, i.e., the effect 
of the active control compared with placebo.
Outcome (mortality) in untreated SAB patients
In the absence of placebo-controlled studies in SAB, literature from the pre-penicillin era 
(i.e., prior to 1942) was reviewed to determine the clinical outcome of patients with SAB 
who did not receive antibacterial treatment. As a standard search in Pubmed did not result in 
a consistent list of potentially relevant publications, these were derived from the reference 
lists of three review articles describing SAB outcomes in the pre-penicillin era: 
Mendell, 1939 (Mendell 1939), Spink and Hall, 1944 (Spink 1945), and Di Fiore, 1956
(Di Fiore 1956).
From these review articles, seven original articles were identified that described outcomes in 
case series of SAB in patients who did not receive antibacterial treatments: Lowenstein, 1936
(Lowenstein 1936), MacNeal and Frisbee, 1936
(MacNeal 1936), Mendell, 1939
(Mendell 1939); Neuhof, 1934 (Neuhof 1934); Rosenow et al., 1938 (Rosenow 1938); 
Scott, 1935 (Scott 1935); and Skinner and Keefer, 1941 (Skinner 1941). The characteristics 
of these studies are summarized in Table E1.
It should be noted that clinical/overall success was not separately reported in these studies 
and that survival in itself was considered success.
Table E1
Overview of studies from the pre-penicillin era reporting clinical outcome 
(survival) in untreated patients with SAB
Study
N 
with 
SAB
Setting
Predominant
clinical 
manifestation
ACM
(n/N)
ACM 
%
Lowenstein, 1936
(Lowenstein 1936)
38
US case series and literature review of 
staphylococcal septicaemia (St. Louis)
Skin
22/38
58%
MacNeal and Frisbee, 1936
(MacNeal 1936)
100
US case series of SAB, bacteriophage 
treatment (NY)
Skin, Osteoarticular 75/100
75%
Mendell, 1939
(Mendell 1939)
35
US case series of SAB
(Philadelphia/NY, 8-year period)
Skin, Osteoarticular
29/35
83%
Neuhof, 1934
(Neuhof 1934)
44
US case series of pyogenic sepsis
(NY, 5-year period)
Skin, Osteoarticular
29/44
66%
Rosenow et al., 1938
(Rosenow 1938)
29
US case series of SAB and streptococcal 
septicaemia, (Mayo Clinic, 3-year period)
Not specified for 
SAB
19/29
66%
Scott, 1935
(Scott 1935)
60
US case series septicaemia 
(Rochester, 9-year period)
Not specified for 
SAB
49/60
82%
Skinner and Keefer, 1941
(Skinner 1941)
122
US case series septicaemia 
(Boston, 7-year period)
Skin, Respiratory,
Osteoarticular
100/122 82%
ACM= all-cause mortality.


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The results of the random effects meta-analysis are shown in Figure E1, and suggest an 
all-cause mortality (ACM) of 76% (95% CI 0.71–0.79). The lower bound of the 95% CI of 
this mortality estimate is 0.71, suggesting a conservative estimate of 71% mortality for 
patients with SAB who did not receive antibacterial treatment.
Figure E1 Random effects meta-analysis of clinical outcome (mortality) in untreated 
patients with SAB


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Outcome (mortality) in SAB patients receiving antibacterial treatment
The outcome of SAB patients treated with antibacterial treatment is based on three 
randomized studies published since 1985. The characteristics of these studies are 
summarized in Table E2.
Table E2
Overview of studies reporting clinical outcome (survival) in patients 
receiving antibacterial treatment
Study
N with 
SAB
Setting
Predominant
clinical 
manifestation
ACM
(n/N)
ACM 
%
Fowler et al., 2006
(Fowler 2006)
235
(mITT)
Randomized clinical trial of 
daptomycin vs an 
antistaphylococcal penicillin or 
vancomycin
74% complicated 
SAB; endocarditis, 
osteoarticular
37/236
16%
Davis et al., 2016
(Davis 2016)
60
Randomized clinical trial of 
vancomycin vs vancomycin plus 
flucloxacillin
Primary bloodstream 
(28%), skin (22%)
11/60
(90 day)
18%
Van der Auwera et al., 
1985
(Van der Auwera 1985)
29
Randomized clinical trial of 
oxacillin or vancomycin alone vs 
combined with rifampicin
Primary bloodstream 
(24%); skin/bone 
(48%)
4/29
14%
ACM=all-cause mortality.
The results of the random effects meta-analysis are shown in Figure E2, and suggest an 
ACM of 16% (95% CI 0.12–0.20). The upper bound of the CI of the mortality estimate is 
0.20, suggesting an estimate of (up to) 20% mortality for patients with SAB who receive 
antibacterial treatment.


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Figure E2 Random effects meta-analysis of clinical outcome (mortality) in patients 
with SAB who receive antibacterial treatment
M1 conclusion
Based on the review of historical studies from the pre-penicillin era suggesting a mortality 
rate of at least 71%, and the review of mortality in contemporary studies in patients 
undergoing effective antibacterial treatment with a mortality rate of up to 20%, the M1 is 
estimated to be 51% for ACM.
An estimation of M1 for an overall success endpoint is not possible, as this was not reported 
in the historical studies, which considered survival to be success. However, the mortality 
data suggest that M1 for a clinical/overall success outcome for SAB would similarly be very 
large, i.e., in the range of 50%, when outcomes are compared for untreated patients and 
patients who received effective antibacterial treatment.


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Selection of a non-inferiority margin for SAB (M2)
M2 is defined as the largest clinically acceptable difference (degree of non-inferiority) of the 
test drug compared to the active control.
The comparison of mortality data in untreated patients with SAB and patients receiving 
antibacterial treatment suggests that M1 is large (approximately 50%, see above), and that an 
M2 preserving half of the active-control-treatment effect (over untreated patients) could be 
defined at ≥ 20%.
As M2 is a matter of clinical judgement, and considering that the pivotal SAB study 
supporting the regulatory approval of daptomycin (Fowler 2006) used a non-inferiority 
margin (NIM) of 20%, NIMs of ≤ 20% could be considered clinically reasonable. To further 
explore the performance of NIMs ≤ 20%, the maximum allowable difference of the point 
estimate (investigational drug [ceftobiprole] minus the active comparator [daptomycin]) that 
would allow a conclusion of non-inferiority has been assessed for various margins and for 
various sample sizes, assuming a success rate of 40% in the active-control arm (see 
Table E3).
Table E3
Maximum allowable difference in the point estimate of overall response 
(investigational drug minus active comparator) that allows for 
determination of non-inferiority at margins of 15, 17.5 and 20%, assuming 
an overall response rate of 40 or 50% in the active-control group
Comparator Group = Active Group
N 
(mITT)
Assumed 
response rate 
N with response 
NIM
Maximum difference in 
point estimate that still 
meets NI*
Statistical 
Power
350
40
70
15
−5**
81
350
40
70
17.5
−7
91
350
40
70
20
−10
96
350
50
88
15
−4
80
350
50
88
17.5
−7
90
350
50
88
20
−9
96
300
40
60
15
−4
75
300
40
60
17.5
−6
87
300
40
60
20
−9
94
250
40
50
15
−2
67
250
40
50
17.5
−5
80
250
40
50
20
−8
89
N=number of subjects; NI=non-inferiority; NIM= non-inferiority margin.
* values rounded to nearest whole number.
** actual value is 4.6.


Ceftobiprole medocaril
Clinical study protocol
BPR-CS-009
Version 9.0
27 February 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 137 of 139
This analysis shows that for a sample size of 250–350 patients (in the mITT population), an
NIM of 15% would allow for the determination of non-inferiority only if the point estimate 
between ceftobiprole and daptomycin is < 5%. For an NIM of 17.5%, the allowable 
difference in the point estimates would be in a range of 5–7%, and for an NIM of 20%, the 
allowable differences in point estimates would be 8–10%.
Non-inferiority margin conclusion
Based on mortality, the overall data support a large treatment difference attributable to the 
active-control arm over untreated patients of approximately 50% in the treatment of SAB. 
While the treatment difference for an endpoint of overall success cannot be reliably 
estimated due to lack of reported data in the historical studies, the M1 for this endpoint is 
also estimated to be large.
The selection of an NIM therefore needs to be primarily based on clinical judgement. 
Assuming an overall success rate of 40% in the active-control group, a NIM that allows for a 
maximum difference in the point estimates of < 5% appears to be clinically justifiable. The 
scientific data thus provide support for the selection of an NIM of 15%, based on an endpoint 
of overall success.
Using an NIM of 15% in the context of a point estimate for overall success of 40% in each 
treatment group in the mITT population, tested at a one-sided alpha level of 0.025 and power 
of > 80%, a sample size of 350 patients in the mITT population is required.
With this sample size, the allowable differences in point estimates would be approximately 
5%, which is considered reasonable based on clinical judgement. If the overall success rate is 
50% (see Section 8.1), a sample size of 350 patients in the mITT population would still 
provide a power of 80% (see Table E3); in this case the allowable differences in point 
estimates using a NIM of 15% would be approximately 4%.


Ceftobiprole medocaril
Clinical study protocol
BPR-CS-009
Version 9.0
27 February 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 138 of 139
Appendix 9
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 drug, 
i.e., the time between the administration of study drug and occurrence of the event is not 
plausible. If the 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 drug, yet drug-relatedness clearly exists; e.g., [i] bone marrow depression, [ii] tardive 
dyskinesias). If the drug was re-administered it did not reappear.
2. It does not follow a known pattern of the response to the suspected 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 drug, 
i.e., the time between the administration of study drug and occurrence of the event is not 
plausible. If the drug was interrupted or stopped the event did not improve or disappear. 
If the drug was re-administered it did not re-appear.
2. It does not follow a known pattern of the response to the suspected 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 drug (see also 
additional explanations above) or it follows a known pattern of the response to the 
suspected drug or drugs of the same substance class.
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.


Ceftobiprole medocaril
Clinical study protocol
BPR-CS-009
Version 9.0
27 February 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 139 of 139
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.
PROBABLE 
This category is applicable to an AE that is considered, with a high degree of certainty, to be 
related to the test drug. An AE event may be considered probable if it meets the following 
three criteria:
1. It follows a reasonable temporal sequence from administration of the drug, i.e., the time 
between the administration of study drug and occurrence of the event is plausible. If the
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 drug, yet drug-
relatedness clearly exists; e.g., [i] bone marrow depression, [ii] tardive dyskinesias.) If 
the drug was re-administered it did re-appear.
2. It follows a known pattern of the response to the suspected 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 test 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.


Ceftobiprole medocaril
Clinical study protocol
BPR-CS-009
Version 9.0
27 February 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 140 of 140
Appendix 10 Investigator’s protocol signature page
BASILEA
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE
Protocol 
BPR-CS-009 Version 9.0
Basilea Product:
Ceftobiprole medocaril
Protocol Title:
A randomized, double-blind, multi-center study to establish the efficacy 
and safety of ceftobiprole medocaril compared to daptomycin in the 
treatment of Staphylococcus aureus bacteremia, including infective 
endocarditis
Basilea Pharmaceutica International Ltd.
Approval Date:
27 February 2020
Name of Principal Investigator:
Study Site: 
I agree to the conditions relating to this study as set out in the above named Protocol and Study 
Procedures. I fully understand that any changes instituted by the investigator(s) without previous 
discussion with the sponsor’s Project Clinician, Clinical Pharmacologist and Biostatistician (only 
if required) would constitute a violation of the protocol, including any ancillary studies or 
procedures performed on study subjects (other than those procedures necessary for the well-being of 
the subjects).
I agree to follow International Council for Harmonisation (ICH) guidelines for Good Clinical 
Practice (GCP), including the EU Clinical Trial Directive 2001/20/EC and specifically, to obtain 
approval from the Independent Ethics Committee / Institutional Review Board 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.
Please print name and date next to the signature
Signature
Name
Date
Principal Investigator

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!$LN!$T[X
!$LNWT[X
\d_^^T[X

OG	F
K	
"$LN!TX	
!LN
FM
\^_b^`LN"$TX	
"$LN!
FM
$LN$TX	
$LN"$
FM
N$TX	
N$
FM

at
	h	uatuggatg

g
a	h	uaatv	a	
GVa
uXtX	
w
	F	F
hvhHJh	v	xv	!hG		V	
	V	F	F		hvh
I	GFhHIJXv"F	F