Conditions: Acute Bacterial Skin and Skin Structure Infections
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 679
Healthy volunteers: no

Brief summary:
This was a randomized, double-blind, active-controlled, parallel-group, multicenter study in adult hospitalized patients to establish the safety and efficacy of ceftobiprole medocaril compared with vancomycin plus aztreonam in the treatment of acute bacterial skin and skin structure infections (ABSSSIs).

Detailed description:
This was a randomized, double-blind, active-controlled, parallel-group, multicenter study in adult hospitalized patients with ABSSSIs. Randomization was stratified by study site and type of ABSSSI (with major cutaneous abscess comprising ≤ 30% of the Intent-to-Treat \[ITT\] population).

Primary endpoint for FDA: Early clinical response based on the percent reduction in lesion size at 48-72 hours compared to baseline in patients who did not receive rescue therapy and were alive, in the ITT population.

Primary endpoint for EMA: Investigator-assessed clinical success at the test-of-cure (TOC) visit 15-22 days after randomization, in the co-primary ITT and Clinically Evaluable (CE) populations.

Arms:
arm 1: Patients treated with ceftobiprole medocaril 500 mg q8h (with dose adjustment for renal impairment). arm 2: Patients treated with vancomycin 1000 mg (or 15 mg/kg) q12h plus aztreonam 1000 mg q12h (both with dose adjustment for renal impairment).

Interventions: intervention 1: ceftobiprole medocaril intervention 2: vancomycin+aztreonam
Intervention descriptions: intervention 1: ceftobiprole 500 mg was to be administered every 8 hours as a 2-hour IV infusion (with dose adjustment for renal impairment). The treatment duration was for a minimum of 5 days and a maximum of 10 days. Treatment could be extended up to 14 days if in the investigator's opinion this was required, and the extension was approved by the sponsor's medical monitor. intervention 2: Vancomycin 1000 mg (or 15 mg/kg) was to be administered every 12 hours (with dose adjustment for renal impairment) as 2-hour IV infusion. Vancomycin dose adjustment for morbidly obese and hypermetabolic patients was to be done according to local standard of care. When locally available, vancomycin trough testing (VTT) might have been used by the unblinded pharmacist or delegate to adjust the vancomycin dose. The treatment duration was for a minimum of 5 days and a maximum of 10 days. Treatment could be extended up to 14 days if in the investigator's opinion this was required, and the extension was approved by the sponsor's medical monitor.

Aztreonam 1000 mg was to be administered as a 0.5-hour IV infusion every 12 hours. If CLCR was \< 30 mL/min (i.e., severe renal impairment), the aztreonam dosage regimen was to be adjusted. The requirement to continue aztreonam therapy beyond Day 3 was to be reassessed at the 72-hour study visit.

Protocol document:
Prot_000.pdf: 
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Ceftobiprole medocaril
Clinical Study Protocol
BPR-CS-008
Version 6.0
11 July 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 2 of 98
SPONSOR SIGNATURES
Protocol Number/Version:
BPR-CS-008 / Version 6.0
Study title:
A randomized, double-blind, multicenter study to 
establish the safety and efficacy of ceftobiprole medocaril 
compared with vancomycin plus aztreonam in the 
treatment of acute bacterial skin and skin structure 
infections
Compound:
Ceftobiprole medocaril
Phase of development:
3
Date: 
11 July 2018
Project Physician:
Project Statistician: 
Sponsor:
Basilea Pharmaceutica International Ltd
Grenzacherstrasse 487
CH-4058 Basel/Switzerland
Tel + 41 61 606 1111
Name/Title
Date
Signature
Project Physician
Project Statistician


Ceftobiprole medocaril
Clinical Study Protocol
BPR-CS-008
Version 6.0
11 July 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 3 of 98
Protocol Synopsis
TITLE
A randomized, double-blind, multicenter study to establish the safety 
and efficacy of ceftobiprole medocaril compared with vancomycin plus 
aztreonam in the treatment of acute bacterial skin and skin structure 
infections
SPONSOR
Basilea Pharmaceutica International Ltd, Switzerland
STUDY PHASE
3
INDICATION
Acute bacterial skin and skin structure infections
U.S. IND NUMBER:
64,407
EUDRACT NUMBER:
2017-001605-32
PROTOCOL NUMBER: BPR-CS-008 Version 6.0
OBJECTIVES
Primary objective
To demonstrate the non-inferiority of ceftobiprole to vancomycin plus aztreonam in patients with 
acute bacterial skin and skin structure infections (ABSSSIs) with respect to early clinical response 
based on percentage reduction in lesion size at 48–72 hours (h) after first treatment in the Intent-to-
Treat (ITT) population.
Main secondary objective
To demonstrate the non-inferiority of ceftobiprole to vancomycin plus aztreonam in patients 
with ABSSSIs, with respect to investigator-assessed clinical success at the test-of-cure (TOC) visit 
15–22 days after randomization, in the co-primary ITT and Clinically Evaluable (CE) populations.
Note: The primary and the main secondary objectives will be region-specific. The above primary and main 
secondary objectives are for submission to the US FDA; in the EU, the above main secondary objective will 
be the primary objective, and the primary objective listed above will be the main secondary objective. 
Two separate Statistical Analysis Plans (SAPs) will be prepared for submission to the FDA and the EMA to 
reflect the different primary and main secondary objectives in each region.
Other secondary objectives
To compare ceftobiprole with vancomycin plus aztreonam with respect to: 
1.
Early clinical response based on percentage reduction in lesion size at 48–72 h after first 
treatment (CE population).
2.
Clinical response based on percentage reduction in lesion size at the end-of-treatment (EOT) 
and TOC visits (ITT and CE population).
3.
Sustained reduction in lesion size at the EOT and TOC visits (ITT population).
4.
Investigator-assessed clinical success evaluated at 48–72 h after first treatment and the EOT 
visit, and sustained clinical success at the last follow-up (LFU) visit (ITT and CE populations). 
5.
All-cause mortality through Day 28 (±2 days) (ITT population).
6.
Microbiological response at Day 3, Day 5, and the EOT, TOC and LFU visits (mITT and ME 
populations). 


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Clinical Study Protocol
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Version 6.0
11 July 2018
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7.
Change in patient-reported pain from baseline at all visits except the Day 28 visit (ITT and CE 
populations). 
8.
Health economic outcome measures (ITT and CE populations).
9.
Safety: incidence, type, severity and relationship to study medication of adverse events and 
changes in laboratory tests (hematology, biochemistry, and chemistry, including haptoglobin, 
urinalysis, Coombs test) (Safety population). 
10. To assess the pharmacokinetics (PK) of ceftobiprole (PK population).
STUDY DESIGN
Randomized, double-blind, active-controlled, parallel-group, multicenter study in adult hospitalized 
patients with ABSSSIs. Randomization will be stratified by study site and type of ABSSSI (with 
major cutaneous abscess comprising ≤30% of the ITT population).
PLANNED NUMBER OF PARTICIPANTS
Approximately 674 patients will be randomized in a 1:1 ratio to ceftobiprole or the comparator 
regimen.
DURATION OF PARTICIPATION
Treatment duration: minimum 5 days, maximum 10 days. (Treatment may be extended up to 
14 days if in the investigator’s opinion this is required, and the extension is approved by the 
sponsor’s medical monitor).
Study participation: approximately 5–7 weeks.
NUMBER OF CENTERS/LOCATIONS
Approximately 80 centers in North America and Europe.
INCLUSION CRITERIA
Patients meeting all of the following: 
1.
Male or female, aged ≥18 years.
2.
Diagnosis of ABSSSI, meeting at least one of the definitions in (a) to (c) below. Local 
symptoms must have started within the 7 days prior to the Screening visit.
(a) Cellulitis/erysipelas, defined as a diffuse skin infection characterized by all of the following 
within 24 h:
i.
Rapidly spreading areas of erythema, edema, and/or induration with a minimum total 
lesion surface area of 75 cm2. 
ii.
No collection of pus apparent upon visual examination. 
iii. At least two of the following local signs of infection: 

erythema 

induration

localized warmth

pain or tenderness on palpation

swelling/edema


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11 July 2018
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(b) Major cutaneous abscess, defined as infection characterized by a collection of pus within the 
dermis or deeper that is apparent upon visual examination before or after therapeutic 
intervention and is accompanied by all of the following within 24 h:
i.
Erythema, edema and/or induration with a minimum total lesion surface area of 75 cm2. 
ii.
At least two of the following local signs of infection: 

fluctuance

incision and drainage required

purulent or seropurulent drainage

localized warmth

pain or tenderness on palpation
(c) Wound infection, defined as infection of any apparent break in the skin characterized by at 
least one of the following:
i.
Superficial incision/surgical site infection meeting all of the following criteria: 

involves only the skin or subcutaneous tissue around the incision (does not involve 
fascia). 

occurs within 30 days of procedure. 

purulent drainage (spontaneous or therapeutic) with surrounding erythema, edema 
and/ or induration with a minimum total lesion surface area of 75 cm2. 
ii.
Post-traumatic wound (including penetrating trauma, e.g., needle, nail, knife, insect and 
spider bites) meeting the following criterion within 24 h: 

Purulent drainage (spontaneous or therapeutic) with surrounding erythema, edema 
and/or induration with a minimum total lesion surface area of 75 cm2. 
3.
At least one of the following regional or systemic signs of infection at the Screening visit:
(a) Lymph node tenderness and volume increase, or palpable lymph node proximal to the 
primary ABSSSI. 
(b) Fever > 38 °C/100.4 °F measured orally, > 38.5 °C / 101.3 °F measured tympanically, 
> 37.5 °C / 99.5 °F measured by the axillary method, or > 39 °C / 102.2 °F measured 
rectally.
(c) White blood cell (WBC) count ˃ 10.0 × 109/L or < 4.0 × 109/L.
(d) > 10% immature neutrophils (band forms). 
4.
Requirement for intravenous (IV) antibacterial treatment.
5.
Willing and able to adhere to study procedures (including prohibitions and restrictions) as 
specified in this protocol.
6.
Willing and able to remain hospitalized (in a hospital or equivalent medical confinement or 
clinical research unit) until completion of the early-clinical-response assessment for the primary 
endpoint. 
7.
Informed consent signed by the patient, or their legally acceptable representative if appropriate, 
indicating that they understand the purpose of, and procedures required for, the study, and are 
willing to participate.


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EXCLUSION CRITERIA
Patients meeting any one of the following: 
1.
Use of any systemic antibacterial treatment within 14 days, or topical antibacterial 
administration on the primary lesion within 96 h, before first infusion of study drug. 
Exception: Receipt of a single dose of a short-acting (half-life ≤12 h, see Appendix 1) 
antibacterial therapy (e.g., for surgical prophylaxis) within ˃ 3 days before randomization (i.e., 
patients cannot have received any antibacterial treatment within 72 h of randomization).*
2.
Contraindication to the administration of either of the study treatments, including known 
clinically-relevant hypersensitivity to related antibacterial treatments (e.g., beta-lactam and 
glycopeptide antibiotics), or to metronidazole if required as adjunctive therapy.
3.
Participation in any other clinical study within the 30 days prior to randomization, or any prior 
participation in this study.
4.
The primary ABSSSI is an uncomplicated skin and skin structure infection, such as furuncles, 
minor abscesses (area of suppuration not surrounded by cellulitis/erysipelas), impetiginous lesions, 
superficial or limited cellulitis/erysipelas, or minor wound infections (e.g., stitch abscesses).
5.
The primary ABSSSI is due to, or associated with, any of the following:
(a) Diabetic foot infection, gangrene, or perianal abscess. 
(b) Concomitant infection at another site (e.g., septic arthritis, endocarditis, osteomyelitis), not 
including a secondary ABSSSI lesion. 
(c) Infected burns. 
(d) Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease (arterial 
or venous). 
(e) Any evolving necrotizing process (e.g., necrotizing fasciitis). 
(f) Infections at vascular catheter sites, or involving thrombophlebitis. 
6.
The primary ABSSSI is associated with, or in close proximity to, a prosthetic device.
7.
Patients who are placed in a hyperbaric chamber as adjunctive therapy for the ABSSSI.
8.
Patients expected to require more than two surgical interventions in the operating room for the 
ABSSSI.
9.
Severe sepsis or septic shock.
10. Significant or life-threatening condition (e.g., endocarditis, meningitis) that would confound, or 
interfere with, the assessment of the ABSSSI.
11. Another severe, acute or chronic medical condition, psychiatric condition, or laboratory 
abnormality that may increase the risks associated with study participation or administration of the 
investigational product, or may interfere with the interpretation of study results, and which, in the 
judgment of the investigator, would make the patient inappropriate for entry into this study.
12. Receiving treatment for active tuberculosis.
                                                
* The proportion of patients who have received a single dose of a short-acting antibacterial drug within 14 days before 
randomization will be limited to 25% of the patient population.


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Version 6.0
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13. Absolute neutrophil count < 0.5 × 109/L.
14. Recent history of opportunistic infections (i.e., within 30 days) if the underlying cause of these 
infections is still active (e.g., leukemia, transplant, acquired immunodeficiency syndrome [AIDS]).
15. Patients receiving systemic steroids (> 40 mg per day prednisolone, or equivalent), or receiving 
immunosuppressant drugs.
16. Requirement for peritoneal dialysis, plasmapheresis, hemodialysis, venovenous dialysis, or other 
forms of renal filtration, or expected to require such treatment before the TOC visit.
17. Alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥8× the upper limit of 
normal, OR severe hepatic disease with Child-Pugh class C.
18. Women who are pregnant or nursing.
19. 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.
20. Inability to start study-drug therapy within 24 h of Screening.
21. Patients with illicit drug use within 12 months of screening, including heroin, other opioids (unless 
prescribed for medical reasons unrelated to heroin substitution), cocaine / crack cocaine, and 
amphetamine/methamphetamine.
Exception: Cannabis use.
STUDY-DRUG ADMINISTRATION
The two intravenous treatment regimens to be administered are:
1.
Ceftobiprole 500 mg q8h (with dose adjustment for renal impairment).
2.
Vancomycin 1000 mg (or 15 mg/kg) q12h plus aztreonam 1000 mg q12h (both with dose 
adjustment for renal impairment). Vancomycin dose adjustments for obese and hypermetabolic 
patients are according to local standards of care (see Section 6.2.2).
The requirement for aztreonam therapy will be reassessed at the 72-h study visit (Visit 4). 
Termination of aztreonam is permitted when all of the following criteria are fulfilled:

a Gram-positive pathogen has been isolated, and 

the presence of Gram-negative organisms is highly unlikely based on the investigator’s 
assessment, and

Gram-negative coverage is clinically not required based on the investigator’s assessment


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In cases where (blinded) aztreonam is discontinued after 72 h, re-administration of (blinded)
aztreonam is permitted at any point during the study treatment period, at the discretion of the 
investigator, when there is confirmation or suspicion of a concomitant Gram-negative infection.
Concomitant systemic antibacterials and topical antibacterials (applied to the primary lesion) are 
prohibited during the study up to the TOC visit, with the following exceptions:
1.
Vancomycin PO 125 mg or 250 mg q6h, fidaxomicin PO 200 mg q12h, or metronidazole IV or 
PO 500 mg q8h, may be used in both treatment groups for the treatment of Clostridium difficile
infections.
2.
Metronidazole IV may also be used as adjunctive therapy in both treatment groups for coverage 
of anaerobic bacteria.
3.
Nitrofurantoin may be used at any time during the study in both treatment groups as it does not 
achieve therapeutic blood levels. 
Study drug will be administered IV in accordance with the following schedule:
Time 
(h)
Drug
Dose 
(mg)
Volume 
(mL)
Infusion 
time (h)
Drug
Dose 
(mg)
Volume 
(mL)
Infusion 
time (h)
0
Ceftobiprole
Placebo
500
NA
250
100
2
0.5
Vancomycin
Aztreonam
1000*
1000
250
100
2
0.5
8
Ceftobiprole
500
250
2
Placebo
NA
250
2
12
Placebo
Placebo
NA
NA
250
100
2
0.5
Vancomycin
Aztreonam
1000*
1000
250
100
2
0.5
16
Ceftobiprole
500
250
2
Placebo
NA
250
2
* Or 15 mg/kg vancomycin: the decision to use vancomycin at a fixed or weight-based dose is to be made by the investigator on the basis 
of the site’s standard of care and needs to be communicated prior to randomization to the unblinded pharmacist or delegate.
The vancomycin dose may be adjusted according to the local standard of care by the unblinded pharmacist or 
delegate. Dose adjustment of study drugs is described in detail in the protocol body.
The requirement for aztreonam therapy will be reassessed at the 72-h study visit (Visit 4).
BLINDING
Double-blind with unblinded pharmacist or delegate.
TREATMENT DURATION
Treatment duration: minimum 5 days, maximum 10 days. (Treatment may be extended up to 
14 days if in the investigator’s opinion this is required, and the extension is approved by the 
sponsor’s medical monitor).
MAIN STUDY ENDPOINTS
The primary and the main secondary endpoints are region-specific. The primary and main secondary 
endpoints listed below are for submission to the US FDA. In the EU, the main secondary endpoint
listed below will be the primary endpoint, and the primary endpoint listed below will be the main 
secondary endpoint. Two separate SAPs will be prepared for submission to the FDA and the EMA 
to reflect the different primary and main secondary endpoints in each region.


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Primary endpoint
Early clinical response 48–72 h after start of treatment based on the patient meeting all of the 
following criteria: 
1.
≥ 20% reduction from baseline in the area (length × width of erythema, edema, or induration) of 
the primary lesion. 
2.
Survival for ≥ 72 h from the time of administration of the first dose of study drug.
3.
No use of concomitant systemic antibacterial treatments, or topical antibacterial administration
on the primary lesion. 
4.
No additional unplanned surgical procedure for the ABSSSI after start of therapy (other than 
debridement at bedside or local bedside wound care), with the exception of cellulitis where there 
is a conversion into an abscess within 48 h of study treatment initiation, or, for post-surgery 
patients, when an extension of the original incision is indicated.
The primary endpoint is to be assessed in the ITT population.
Standardized measurement of the lesion area (i.e., erythema, edema, or induration, whichever is 
largest) is to be performed with a flexible plastic ruler or tape measure, by multiplying the longest 
length of the lesion by the widest width perpendicular to that length. 
In addition, a measurement of the maximum width of erythema or edema/induration from the edge 
of the wound (surgical or traumatic) or abscess will be recorded. If abscess, the measurement should 
be taken from the end of the fluctuance before drainage or from the edge of the drainage site after 
drainage.
A digital photograph will be obtained at Screening, at the early clinical response assessment 
(48–72 h after first treatment), and at the EOT and TOC visit, for each patient (primary ABSSSI
lesion), and will be used for documentation purposes and as source data. Digital photography will 
not be used for the measurement of the ABSSSI lesion size area; the determination of the ABSSSI 
lesion size area will be solely based on the ruler measurements. 
Main secondary endpoint
Investigator-assessed clinical success at the TOC visit 15–22 days after randomization. The TOC 
visit should be performed at least 5 days after EOT.
Clinical success is defined as complete or nearly complete resolution of baseline signs and 
symptoms of the primary infection, such that no further antibacterial treatment is needed.
A patient meeting this definition cannot be classified as a clinical success if any of the following 
criteria are met:
1.
Death from any cause prior to TOC.
2.
Additional antibacterial therapy received for treatment of the primary lesion.
3.
Initiation of non-study antibacterial treatment of another infection, unless the antibacterial agent 
lacks efficacy in the treatment of ABSSSI.
4.
Requirement for an unplanned surgical procedure for the ABSSSI after start of therapy, (other 
than debridement at bedside or local bedside wound care), with the exception of cellulitis where 
there is a conversion into an abscess within 48 h of study treatment initiation, or, for post-
surgery patients, when an extension of the original incision is indicated.


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5.
Indeterminate assessment at TOC for any reason, including but not limited to:
(a) missing TOC visit
(b) lost to follow-up
(c) patient withdrew consent
(d) missing data in relation to signs and symptoms of the ABSSSI
(e) discontinuation from the study due to the need for hemodialysis
The main secondary endpoint is to be assessed in the ITT and CE populations.
Other secondary endpoints
1.
Early clinical response based on percentage reduction in lesion size at 48–72 h after first 
treatment in the CE population, using the same definition for response as for the primary 
endpoint.
2.
Clinical response defined as ≥ 80% decrease in lesion area at the EOT visit, and ≥90% decrease 
in lesion area at the TOC visit (ITT population), with improvement of local signs of the 
infection in patients surviving up to the respective visit with no use of any concomitant systemic 
antibacterial treatment or topical antibacterial administration on the primary lesion, and no 
unplanned additional surgical procedure (other than debridement at bedside or local bedside 
wound care), with the exception of cellulitis where there is a conversion into an abscess within 
48 h of study treatment initiation, or, for post-surgery patients, when an extension of the original 
incision is indicated.
3.
Sustained reduction in lesion size at the EOT and TOC visits (ITT population).
Sustained reduction in lesion size is defined as ≥ 20% decrease in lesion area 48–72 h after start 
of treatment (primary endpoint) that is sustained at the EOT and TOC visits.
4.
Investigator-assessed clinical success evaluated at 48–72 h after first treatment and the EOT 
visit, and sustained clinical success at the LFU visit (ITT and CE populations).
Clinical success at the EOT visit is defined by the same criteria as for the main secondary 
endpoint, with an indeterminate assessment to include a missing EOT visit. 
Sustained clinical success requires that all criteria listed for the main secondary endpoint are met 
and there were no new signs or symptoms of the ABSSSI between the TOC and LFU visits.
5.
ACM at Day 28 (±2 days).
Assessment of survival status at Day 28 (±2 days).
6.
Microbiological response at Day 3, Day 5, and the EOT, TOC and LFU visits (mITT and ME 
populations).
Eradication: No growth of the baseline pathogen(s) based on post-therapy cultures obtained 
from the primary infection site at the respective time points.
Presumed eradication: No post-therapy culture due to lack of culturable material, accompanied
by investigator-assessed clinical success. 
Persistence: Evidence of continued growth of the baseline pathogen.
Presumed persistence: No post-therapy culture due to lack of culturable material, accompanied 
by the absence of investigator-assessed clinical success. 


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Clinical Study Protocol
BPR-CS-008
Version 6.0
11 July 2018
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Superinfection: Emergence of a new pathogen(s) at the primary site of infection, accompanied 
by the absence of an investigator-assessed clinical success. 
Relapse or recurrence: Pre-therapy pathogen isolated between the EOT and TOC visits, or 
between the TOC and LFU visits, after a pathogen response of ‘eradication’ or ‘presumed 
eradication’ at the EOT or TOC visits.
7.
Patient-reported pain (ITT and CE populations)
Time points: all visits, (with exception of Day 28) 
Patient-reported pain, assessed at baseline and throughout the study, using a visual analogue 
scale (VAS) with a 100 mm line, on which the 0 point indicates ‘no pain’ and the 100 mm point 
indicates ‘worst pain ever’, and a Wong-Baker FACES® Pain Rating Scale. 
8.
Health economic outcome measures (ITT and CE population)
Time point: From start of study medication until the LFU visit 
Resource requirements and health economic data will be derived from study-specific data, or 
collected ancillary to study conduct, to perform health economics analyses. These analyses will 
aim to enable economic comparisons of ceftobiprole with vancomycin and aztreonam.
9.
Safety 
Time point: First dose of study drug until LFU
Adverse events, laboratory tests (including hematology, biochemistry, and haptoglobin), 
Coomb’s test, vital signs, physical examination, and concomitant medications.
10. Pharmacokinetics
Time points: Day 4 
Plasma levels of ceftobiprole.
Sparse PK sampling

Day 4: predose, 2 h (end of infusion), 4 to 6 h
Rich PK sampling

Day 4: predose, 2 h (end of infusion), 3 h, 4 h, 6 h and 8 h 
STATISTICAL ANALYSIS 
Sample size justification
The study is designed to determine whether ceftobiprole is non-inferior to vancomycin plus 
aztreonam for the outcome measure of early clinical response at 48–72 h after start of treatment, 
defined as a ≥20% reduction from baseline in the area (longest length × perpendicular width of 
erythema, edema, or induration) of the primary lesion, survival for ≥ 72 h from the time of 
administration of the first dose of study drug, and no use of concomitant systemic antibacterial 
treatment or topical antibacterial administration on the primary lesion.


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A sample size of 674 patients (337 per group) will provide at least 90% 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: Pvancomycin/aztrenonam minus Pceftobiprole ≥ 0.10 versus 
HA: Pvancomycin/aztrenonam minus Pceftobiprole < 0.10.
Early clinical response rates of an at least 20% reduction in lesion area size (primary endpoint) and 
clinical cure rates at the TOC visit (main secondary endpoint) from recent Phase 3 studies in 
ABSSSI are summarized in tabular form in protocol Section 8.1. These clinical study data support 
an estimate of early clinical response rates of > 80%. 
The sample size estimate is therefore based on:

a point estimate for early clinical response of 80% in each treatment group in the ITT 
population. 

one-sided alpha level of 0.025. 

non-inferiority margin of 10 percentage points for the between-group difference of the primary 
endpoint.
Based on these assumptions, randomization of 337 patients per treatment group (total 674 patients) 
would provide > 90% power to demonstrate the non-inferiority of ceftobiprole compared to 
vancomycin plus aztreonam. Patients with cutaneous abscesses will comprise ≤ 30% of those 
randomized. 
Two separate SAPs will be provided for submission to the FDA and EMA, where the SAP prepared 
for the FDA will use the protocol-defined primary and secondary objectives, and the SAP prepared 
for the EMA will use the main secondary objective as the primary objective.
For the EMA primary endpoint, the point estimates of clinical cure at the TOC visit in the co-
primary ITT and CE populations are 80% and 90%, respectively, which are supported by previous 
ABSSSI Phase 3 studies (see Section 8.1).
With randomization of 337 patients per treatment group, the statistical power at a one-sided alpha 
level of 0.025 is 90% (ITT population) and 97% (CE population) for the key secondary endpoint 
(i.e., the primary endpoint for the EMA), assuming that 85% of the ITT population is in the CE 
population using the same non-inferiority margin.
Analysis populations
The following analysis populations are defined for this study:
Intent-to-Treat population (ITT): all randomized patients. Patients will be analyzed according to 
the study medication assigned at randomization. 
Microbiological Intent-to-Treat population (mITT): the subset of patients in the ITT population 
who have had causative pathogens confirmed from skin lesion or blood cultures. 
Clinically Evaluable population (CE): the subset of patients in the ITT population who have 
complied with important aspects of the study, e.g., no major protocol deviations, a completed 
response outcome assessment, and no concomitant systemic antibacterial treatment or topical 
antibacterial applied to the primary lesion. 
Microbiologically Evaluable population (ME): the subset of patients in the mITT population who 
are also in the CE population.


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Safety population: all randomized patients who received at least one dose of study drug. Patients in 
the safety population will be analyzed according to the first study drug 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.
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 for ceftobiprole versus vancomycin plus aztreonam. 
Exploratory analyses may also be performed. 
For between-group comparisons, a two-sided 95% confidence interval (CI) for the difference in 
outcome rates between the two treatment groups will be derived, unless otherwise specified. 
Unless otherwise specified, the latest evaluation prior to the initiation of study drug will be 
considered the ‘baseline’ evaluation for statistical analyses.
Demographic and baseline characteristics, prior and concomitant medications, and surgical 
procedures will be summarized by treatment group. Additional summaries will be provided for prior 
and concomitant antibacterial treatment use.
Analysis of the primary endpoint
The primary analysis will be based on the ITT population.
The study is designed to determine whether ceftobiprole is non-inferior to vancomycin plus 
aztreonam for the primary endpoint of early clinical response based on percentage reduction from 
baseline in lesion size at 48–72 h after first study-drug administration (see Section 3.1.1). 
The numbers and percentages of responders and non-responders will be determined in each 
treatment group. The observed difference in percentage of responders at 48–72 h (ceftobiprole group 
minus the vancomycin plus aztreonam group) will be determined, and a 95% CI for the observed 
difference will be computed, with adjustment by geographical region (North America and Europe), 
and type of ABSSSI.
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 95% CI for the difference in response rates (ceftobiprole minus 
vancomycin plus aztreonam) in the ITT population is greater than −10%, the non-inferiority of 
ceftobiprole to vancomycin plus aztreonam will be concluded. If non-inferiority is declared at the 
one-sided significance level of 0.025, then superiority will be tested.
The primary efficacy analysis is based on the difference in the early clinical response rates between 
the two treatment groups. Analyses using risk ratio and odds ratio will also be performed.
Sensitivity analyses and subgroup analyses will be performed for the primary efficacy outcome, as 
described in protocol Section 8.7.1.
Analysis of the main secondary endpoint
The main secondary endpoint is the investigator-assessed clinical success at the TOC visit according 
to the following definition: complete or nearly complete resolution of baseline signs and symptoms 
of the primary infection such that no further antibacterial treatment is needed (see Section 3.1.2). 


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This main secondary endpoint will be specified in a separate SAP as the primary endpoint for the 
EMA, with non-inferiority assessed by the two-sided 95% CI of the between-group difference 
(ceftobiprole minus vancomycin plus aztreonam) using a 10% non-inferiority margin in the co-
primary ITT and CE populations. 
Sensitivity analyses and subgroup analyses will be performed for the main secondary efficacy 
outcome, as described in Section 0.
Analysis of other secondary endpoints
The following additional secondary endpoints will be analyzed using the same statistical methods as 
for the primary endpoint:
1.
Early clinical response based on percentage reduction in lesion size at 48–72 h after first 
treatment (CE population).
2.
Clinical response defined as ≥ 80% decrease in lesion area at the EOT visit, and ≥90% decrease 
in lesion area at the TOC visit (ITT population), with improvement of local signs of the 
infection in patients surviving up to the respective visit with no use of any concomitant systemic 
antibacterial treatment or topical antibacterial administration on the primary lesion, and no 
unplanned additional surgical procedure (other than debridement at bedside or local bedside 
wound care), with the exception of cellulitis where there is a conversion into an abscess within 
48 h of study treatment initiation, or, for post-surgery patients, when an extension of the original 
incision is indicated.
3.
Sustained reduction in lesion size, defined as ≥ 20% decrease in lesion area 48–72 h after start 
of treatment (primary endpoint), that is sustained at the EOT and TOC visits (ITT population).
4.
Investigator-assessed clinical success evaluated at 48–72 h after first treatment and the EOT 
visit, and sustained clinical success at the LFU visit (ITT and CE populations).
Clinical success at the EOT visit is defined by the same criteria as for the main secondary
endpoint, with an indeterminate assessment to include a missing EOT visit. 
Sustained clinical success requires that all criteria listed for the main secondary endpoint are met 
and there were no new signs or symptoms of the ABSSSI between the TOC and LFU visits.
5.
All-cause mortality through Day 28 (±2 days) (ITT population).
A time to event analysis using the Kaplan-Meier method will also be performed for all-cause 
mortality.
6.
Microbiological response at Day 3, Day 5, and the EOT, TOC and LFU visits in the mITT and 
ME populations, based on post-therapy cultures obtained from the primary infection site at the 
respective time points, using the definitions in Section 3.1.3.
Additional analyses of secondary endpoints are described in Section 0. 
Additional analyses may be conducted at the sponsor’s discretion; the details of such analyses will 
be described in the SAPs.
Safety analyses
Safety will be assessed through summaries of adverse events (AEs), safety laboratory evaluations, 
physical examinations, and vital signs. Analyses will be based on the Safety population and 
presented by treatment group, as described in Section 8.8.


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Pharmacokinetics
Plasma concentration data will be analyzed at each time point as described in Section 5.3.12, and 
will be presented with descriptive statistics (mean, SD, CV%, min, median, max). 
Blinded interim analysis
One blinded interim analysis for sample size re-estimation will be conducted based solely on pooled 
information across the two treatment arms when early clinical response data are available for 60% of 
the patients planned to be randomized (approximately 404 patients). No statistical adjustment is 
required. The interim analysis will involve a sample size re-estimation to assess whether the initial 
sample size estimate is adequate for evaluating the primary endpoint of the study.
Details will be provided in the Data and Safety Monitoring Board (DSMB) charter. 
For safety monitoring, the DSMB will be utilised periodically throughout the study. Blinded interim 
safety assessments will be performed twice in each year after enrollment of the first patient. Details 
will be provided in the DSMB Charter. 
Investigators, sponsor employees, and others who are involved in the conduct and the analyses of 
the study (with the exception of the unblinded pharmacist or delegate) will remain blinded to the 
treatment codes and interim analysis results until all monitoring decisions have been made, and the 
database has been locked for final analysis.


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TABLE OF CONTENTS
TABLE OF CONTENTS ......................................................................................................16
LIST OF TABLES ................................................................................................................20
LIST OF APPENDICES .......................................................................................................20
LIST OF ABBREVIATIONS ...............................................................................................21
1
BACKGROUND AND RATIONALE...........................................................................23
1.1 Disease characteristics and treatment ..........................................................................23
1.2 Investigational medicinal products ..............................................................................24
1.3 Nonclinical studies with ceftobiprole ..........................................................................24
1.3.1
Microbiology………….…….................................................................................24
1.3.2
Pharmacokinetics and product metabolism in animals ..........................................25
1.3.3
Toxicology………….……. ...................................................................................25
1.4 Clinical studies with ceftobiprole ................................................................................26
1.4.1
Pharmacokinetics, product metabolism, and tissue distribution in humans...........26
1.4.2
Pharmacodynamics.................................................................................................27
1.4.3
Susceptibility testing breakpoints...........................................................................27
1.4.4
Efficacy in ABSSSIs/cSSTIs .................................................................................27
1.4.5
Efficacy in community-acquired pneumonia .........................................................28
1.4.6
Efficacy in hospital-acquired pneumonia...............................................................28
1.4.7
Safety………….…….............................................................................................28
1.5 Rationale for study BPR-CS-008.................................................................................29
1.5.1
Summary of study design.......................................................................................29
1.5.2
Study design rationale............................................................................................29
1.5.3
Study drug and dose ...............................................................................................30
2
OBJECTIVES OF THE STUDY....................................................................................32
2.1 Primary objective.........................................................................................................32
2.2 Secondary objectives ...................................................................................................32
2.2.1
Main secondary objective.......................................................................................32
2.2.2
Other secondary objectives ....................................................................................32
3
STUDY DESIGN ...........................................................................................................33
3.1 Overview of study design and dosing regimen............................................................33
3.1.1
Primary endpoint…………………........................................................................34
3.1.2
Main secondary endpoint .......................................................................................35
3.1.3
Other secondary endpoints.....................................................................................36
3.2 Treatment plan .............................................................................................................37


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3.2.1
Duration of treatment .............................................................................................37
3.2.2
Missed-dose management ......................................................................................37
3.2.3
Overdose………….……........................................................................................38
3.3 Definition of end of study............................................................................................38
3.4 Data and Safety Monitoring Board..............................................................................38
4
STUDY POPULATION.................................................................................................39
4.1 Target population.........................................................................................................39
4.2 Inclusion criteria ..........................................................................................................39
4.3 Exclusion criteria .........................................................................................................40
4.4 Patient withdrawal .......................................................................................................42
4.5 Criteria for discontinuation of treatment......................................................................42
4.6 Replacement of patients...............................................................................................43
5
STUDY ASSESSMENTS AND PROCEDURES..........................................................43
5.1 Summary of schedule of assessments..........................................................................43
5.2 Study visits...................................................................................................................48
5.2.1
Visit 1: Screening (Day −1; within 24 h before first dose)....................................48
5.2.2
Visit 2: Active treatment Day 1..............................................................................49
5.2.3
Visit 3: Active treatment Day 2..............................................................................49
5.2.4
Visit 4: Active treatment Day 3..............................................................................50
5.2.5
Visit 5: Active treatment Day 4..............................................................................50
5.2.6
Visit 6: Active treatment Day 5..............................................................................51
5.2.7
Visit 7: Active treatment Day 8..............................................................................51
5.2.8
Visit 8: Active treatment Day 14............................................................................52
5.2.9
Visit 9: Post-treatment EOT visit...........................................................................52
5.2.10 Visit 10: Post-treatment TOC visit.........................................................................53
5.2.11 Visit 11: Post-treatment Day 28 (survival status via phone or visit) .....................53
5.2.12 Visit 12: Post-treatment LFU visit .........................................................................54
5.3 Study procedures..........................................................................................................54
5.3.1
Screening/baseline/informed consent.....................................................................54
5.3.2
Patient registration and Interactive Voice/Web Response System ........................54
5.3.3
Physical examination..............................................................................................55
5.3.4
Body temperature measurement.............................................................................55
5.3.5
Vital signs………….……......................................................................................55
5.3.6
Pregnancy testing ...................................................................................................55
5.3.7
Safety laboratory parameters..................................................................................55
5.3.8
Reticulocytes, haptoglobin and Coombs test .........................................................57


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5.3.9
WBC count and CRP testing..................................................................................57
5.3.10 Creatinine clearance...............................................................................................57
5.3.11 Microbiological assessments..................................................................................57
5.3.12 PK blood sample collection....................................................................................59
5.3.13 Vancomycin trough level testing (central laboratory)............................................59
5.3.14 Vancomycin trough level testing (local laboratory)...............................................59
5.3.15 Patient-reported pain assessment ...........................................................................60
5.3.16 Investigator infection-site assessment....................................................................60
5.3.17 Investigator assessment of clinical success............................................................61
5.4 Medical history, prior and concomitant medications...................................................61
5.4.1
Medical history………….……..............................................................................61
5.4.2
Prior medications………….……...........................................................................61
5.4.3
Permitted concomitant medications .......................................................................61
5.4.4
Prohibited concomitant medications......................................................................62
5.4.5
Non-drug adjunctive therapy..................................................................................62
5.4.6
Restrictions………….……....................................................................................63
5.5 Health economics outcome measures..........................................................................63
5.6 Safety assessments.......................................................................................................63
5.6.1
Adverse event monitoring ......................................................................................63
6
STUDY DRUGS.............................................................................................................64
6.1 Dose and schedule........................................................................................................64
6.2 Administration .............................................................................................................64
6.2.1
Ceftobiprole………….……...................................................................................66
6.2.2
Vancomycin………….……. .................................................................................66
6.2.3
Aztreonam………….……. ....................................................................................68
6.3 Randomization.............................................................................................................68
6.4 Blinding........................................................................................................................68
6.5 Methods for ensuring blinding.....................................................................................68
6.6 Unblinding methods.....................................................................................................69
6.7 Drug accountability and compliance check .................................................................69
6.8 Packaging and labeling ................................................................................................69
6.9 Shipping and storage conditions..................................................................................70
6.10Drug supply………….…….........................................................................................70
6.11Drug disposal………….……. .....................................................................................70
7
SAFETY .........................................................................................................................71
7.1 Definitions....................................................................................................................71


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7.1.1
Adverse occurrence……………………................................................................71
7.1.2
Adverse event…………………….........................................................................71
7.1.3
Serious adverse event.............................................................................................71
7.2 Evaluation of adverse events .......................................................................................72
7.2.1
Severity………….……..........................................................................................72
7.2.2
Relationship………….……...................................................................................72
7.3 Handling of safety information and collection periods................................................72
7.3.1
Handling of safety data during the pre-treatment period .......................................72
7.3.2
Handling of safety data during the treatment period and up to the last scheduled 
follow-up………….…….......................................................................................73
7.3.3
Handling of post-study safety data.........................................................................75
7.3.4
Reporting of SAEs to regulatory authorities..........................................................75
7.4 Pregnancy.....................................................................................................................75
7.4.1
Contraception for women of childbearing potential ..............................................75
7.4.2
Reporting and handling of pregnancies..................................................................76
8
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN............................77
8.1 Sample size justification ..............................................................................................77
8.2 Analysis populations....................................................................................................79
8.3 General statistical considerations.................................................................................79
8.4 Demographic and baseline characteristics...................................................................79
8.5 Prior and concomitant medications..............................................................................80
8.6 Surgical procedures......................................................................................................80
8.7 Study endpoints............................................................................................................80
8.7.1
Analysis of the primary endpoint...........................................................................80
8.7.2
Analysis of secondary endpoints............................................................................81
8.8 Safety analyses.............................................................................................................84
8.9 Pharmacokinetics.........................................................................................................84
8.10Blinded interim analysis ..............................................................................................85
9
STUDY ADMINISTRATION AND REGULATORY ASPECTS ...............................86
9.1 Study records ...............................................................................................................86
9.1.1
Investigator site file................................................................................................86
9.1.2
Case report forms………….……. .........................................................................86
9.1.3
Patient source documents………….……..............................................................86
9.1.4
Document retention and archiving………….……. ...............................................86
9.1.5
Sample retention………….……............................................................................87
9.2 Clinical monitoring......................................................................................................87


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9.3 Audits and inspections.................................................................................................87
9.4 Protocol amendments...................................................................................................88
9.5 Premature termination of the study..............................................................................88
9.6 Publication policy ........................................................................................................88
10 ETHICS AND GOOD CLINICAL PRACTICE ............................................................89
10.1Good Clinical Practice.................................................................................................89
10.2Informed consent .........................................................................................................89
10.3Patient confidentiality and data protection ..................................................................90
10.4Independent Ethics Committees / Institutional Review Boards ..................................90
11 PROTOCOL VERSION HISTORY...............................................................................91
12 REFERENCES ...............................................................................................................92
13 APPENDICES ................................................................................................................95
LIST OF TABLES
Table 1
Ceftobiprole MICs established by EUCAST............................................... 27
Table 2
Summary of treatment and follow-up schedule........................................... 33
Table 3
Study-drug administration ........................................................................... 34
Table 4
Schedule of assessments.............................................................................. 44
Table 5
Local laboratory safety parameters mandatory (for patient eligibility) 
at Screening ................................................................................................. 56
Table 6
Central laboratory safety parameters........................................................... 56
Table 7
Acceptable methods for ABSSSI specimen collection................................ 58
Table 8
Dosing 
and 
dose 
adjustment 
for 
ceftobiprole 
and 
vancomycin/aztreonam based on CLCR ....................................................... 65
Table 9
Early clinical response rates and clinical cure rates at the TOC visit in 
previous ABSSSI studies............................................................................. 78
LIST OF APPENDICES
Appendix 1 List of antibiotics meeting the criterion of a half-life ≤ 12 hours................ 95
Appendix 2 Criteria for evaluating relationship between adverse events and study 
treatment ...................................................................................................... 96
Appendix 3 Investigator’s protocol signature page......................................................... 98


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LIST OF ABBREVIATIONS
ABSSSI
Acute bacterial skin and skin structure infection
ACM
All-cause mortality
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome 
ALT
Alanine transaminase
AST
Aspartate transaminase
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
CAP
Community-acquired pneumonia
CE
Clinically evaluable
CI
Confidence interval
CLCR
Creatinine clearance
CLSI
Clinical and Laboratory Standards Institute
CRP
C-reactive protein
CRF
Case report form
cSSTI
Complicated skin and soft tissue infection
DSMB
Data and Safety Monitoring Board
EOT
End-of-treatment
EMA
European Medicines Agency
ESBLs
Extended-spectrum beta-lactamases 
ESRD
End-stage renal disease 
EUCAST
European Committee on Antimicrobial Susceptibility Testing 
FDA
United States Food and Drug Administration 
FSH
Serum follicle stimulating hormone 
GGT
Gamma-glutamyl transferase
GISA
Glycopeptide-intermediate Staphylococcus aureus
HAP
Hospital-acquired pneumonia
HCT
Hematocrit
HGB
Hemoglobin
IB
Investigator’s Brochure 
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IDSA
Infectious Diseases Society of America
ISF
Investigator Site File


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ITT
Intent-to-Treat
IUD
Intrauterine device
IV
Intravenous(ly)
IWRS
Interactive Web Response System
LDH
Lactate dehydrogenase
LFU
Last follow-up (visit)
LPLV
Last Patient Last Visit
MHRA
UK Medicines & Healthcare products Regulatory Agency
MIC
Minimum inhibitory concentration
MRSA
Methicillin-resistant Staphylococcus aureus
MSSA
Methicillin-susceptible Staphylococcus aureus
NOAEL
No-observed-adverse-effect level
NSAID
Nonsteroidal anti-inflammatory drug
PBPs
Penicillin-binding proteins 
PD
Pharmacodynamics
PK
Pharmacokinetics
PO
Oral(ly)
PT
Preferred Term
PT
Prothrombrin time
RBC
Red blood cell
RSI
Reference safety information
SAE
Serious adverse event
SAP
Statistical analysis plan
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
TOC
Test-of-cure
VAP
Ventilator-associated pneumonia 
VAS
visual analogue scale
VISA
Vancomycin-intermediate Staphylococcus aureus
VRSA
Vancomycin-resistant Staphylococcus aureus
Vss
Volume of distribution at steady state
WBC
White blood cell 


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1
BACKGROUND AND RATIONALE
1.1
Disease characteristics and treatment
Acute bacterial skin and skin structure infections (ABSSSIs), previously referred to as 
complicated skin and soft tissue infections (cSSTIs), are among the most common 
infections encountered in both community and hospital settings, and include infections 
with resistance to previously effective antibacterial treatments (Dryden 2010). Increasing 
in incidence, they have become a challenging medical problem associated with high 
direct and indirect costs to both the medical system and society (Pollack 2015). Infections 
due to bacteria with resistance to previously effective antibacterial treatments, such as 
methicillin-resistant Staphylococcus aureus (MRSA), are increasing in incidence and 
have led to higher rates of complications and hospitalization. MRSA has emerged as the 
most common cause of purulent infections in the United States and many other areas.
In 2013, the United States Food and Drug Administration (FDA) issued the Guidance for 
Industry, Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for 
Treatment, standardizing the nomenclature to be used in the evaluation of new 
antibacterial treatments for complicated skin and skin structure infections, which are now 
referred to as ABSSSIs:
ABSSSIs include cellulitis/erysipelas, wound infection, and major cutaneous abscess 
with a minimum lesion surface area of 75 cm2. Diabetic foot ulcers and burn wound 
infections are excluded. Bacterial pathogens that commonly cause ABSSSI include 
Streptococcus pyogenes and Staphylococcus aureus, including MRSA strains. Less 
commonly identified bacteria include other Streptococcus species, Enterococcus 
faecalis, and Gram-negative bacteria.
Considerations in selection of an empiric antibacterial for the treatment of ABSSSIs
include suspected bacteriologic etiology, susceptibility, spectrum, host status 
(e.g., neutropenia, immunocompromised, diabetes), compliance, allergies, and location. 
Current Infectious Diseases Society of America (IDSA) recommendations (with dose 
recommendations for non-pregnant adult patients with normal hepatic and renal function) 
for the treatment of ABSSSIs when MRSA is suspected or identified are shown below
(IDSA 2014, Pollack 2015).

Vancomycin, 15–20 mg/kg/dose intravenously (IV) every 8–12 hours (q8–12h)

Linezolid, 600 mg PO/IV q12 h

Daptomycin, 4 mg/kg/dose IV q24 h

Telavancin, 10 mg/kg/dose IV q24 h

Clindamycin, 600 mg PO/IV q8h

Tedizolid, 200 mg PO/IV q24 h

Dalbavancin, 1000 mg IV on Day 1, then 500 mg IV on Day 8

Oritavancin, 1200 mg IV single dose


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1.2
Investigational medicinal products

Ceftobiprole 500 mg q8h (with dose adjustment for renal impairment). 

Vancomycin 1000 mg or 15 mg/kg q12h plus aztreonam 1000 mg q12h (both with 
dose adjustment for renal impairment)
The requirement for aztreonam therapy will be reassessed at the 72-h study visit 
(see Section 6.1).
Ceftobiprole medocaril plus placebo is the test product; vancomycin plus aztreonam is 
the comparator regimen.
1.3
Nonclinical studies with ceftobiprole
1.3.1
Microbiology………….…….
Ceftobiprole has a strong affinity for several penicillin-binding proteins (PBPs), 
including PBP2a and PBP2x, which mediate resistance to other beta-lactams in 
staphylococci 
and 
pneumococci, 
respectively 
(Hebeisen 2001, 
Lovering 2012, 
Davies 2007, Davies 2010, Henry 2013, Entenza 2002). In contrast to earlier generation 
cephalosporins, ceftobiprole effectively prevents the intracellular growth of both 
methicillin-susceptible S. aureus (MSSA) and MRSA strains in macrophages and 
keratinocytes, due in part to its ability to better bind PBP2a under both neutral and acidic 
pH conditions (Lemaire 2009). Ceftobiprole also binds to and saturates several other 
essential PBPs (Davies 2010, Henry 2013), distinguishing it from other available beta-
lactams, and is stable to hydrolysis by the S. aureus PC1 Class A beta-lactamase, 
conserving its activity against staphylococci (Queenan 2007). 
Ceftobiprole is also relatively stable against AmpC cephalosporinases and common class 
A beta-lactamases produced by Gram-negative bacteria, but not to extended-spectrum 
beta-lactamases (ESBLs), carbapenemases, or OXA beta-lactamases (Queenan 2007). 
In vitro
single-
and multiple-passage selection studies performed with several 
Gram-positive pathogens, including MRSA, demonstrated a very low propensity for 
resistance 
after 
exposure 
to 
ceftobiprole 
(Queenan 2007, 
Bogdanovich 2006, 
Queenan 2005, Kosowska 2005, Bogdanovich 2005, Queenan 2010), which is due to 
ceftobiprole’s unique ability to bind to multiple target sites. 
No emergence of resistance was seen throughout the extensive clinical development 
program and no MIC shifts were seen in surveillance studies.
In vitro, ceftobiprole has shown a bactericidal mode of action against MSSA, MRSA 
and many other resistant S. aureus strains, including glycopeptide-intermediate (GISA), 
vancomycin-intermediate 
(VISA), 
vancomycin-resistant 
(VRSA), 
daptomycin 
non-susceptible, and linezolid non-susceptible strains, using both broth microdilution and
time-kill methods (Borbone 2010, Leonard 2008, Rouse 2007, Deshpande 2013, 
Farrell 2014). 
Ceftobiprole also effectively reduced the colony-counts of MSSA and MRSA strains 
tested in an in vitro biofilm model, none of which were affected by daptomycin, 
vancomycin or rifampicin (Abbanat 2014).


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Further details on the microbiology of ceftobiprole medocaril are provided in the 
Investigator’s Brochure (IB).
1.3.2
Pharmacokinetics and product metabolism in animals
In animals after single IV dose pharmacokinetic (PK) 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 ring-open product BAL1029 as the main metabolite. After 
multiple doses to rats, rabbits, marmosets, cynomolgus monkeys, and dogs, high and 
dose-proportional exposures to ceftobiprole in all species were achieved, exceeding the 
expected human therapeutic exposure at the no-observed-adverse-effect level (NOAEL). 
There were no relevant indications of accumulation, differences related to sex, or time-
dependent PK. 
Whole-body autoradiography in animals demonstrated rapid and large distribution of 
ceftobiprole in all organs without specific accumulation in any organs, with the exception 
of the kidney as excretory organ. Results from a reproductive toxicology study in rats 
indicated that nursing pups were not systemically exposed to ceftobiprole. Protein 
binding of ceftobiprole in plasma in all species was low, and concentration-independent. 
Mean plasma protein binding in humans was 16%. In rats, excretion was almost complete 
(> 94%) within 4 days after IV administration of the prodrug. 
Based on in vitro cytochrome P450 inhibition and induction data, the lack of a specific 
enzyme involved in 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, PK and pharmacodynamics (PD) of 
ceftobiprole medocaril are provided in the IB.
1.3.3
Toxicology………….…….
The primary targets of toxicity after IV administration in animals were the kidneys and 
the infusion site. 
Renal toxicity was attributable to the high rate of glomerular filtration leading to high 
concentrations of ceftobiprole in urine, precipitation of ceftobiprole in distal parts of 
the nephron, and resultant renal tissue damage. This effect is not thought to apply to 
humans because glomerular filtration of ceftobiprole in humans is much slower, and 
urinary concentrations of ceftobiprole do not approach the limit of solubility. 
Local tolerance: In 4- and 13-week studies in rats and marmosets, concentration-
dependent slight to moderate local endothelial irritation was observed when 
ceftobiprole medocaril was administered over 4–8 h into the vena cava at 
concentrations up to 62 mg/mL. 


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In a local tolerability study in rabbits, repeated IV administration of ceftobiprole into the 
auricular vein (8 consecutive days with a 3-minute endothelial contact period per day) 
caused no irritation at ceftobiprole concentrations of 2 and 10 mg/mL (nominal 
ceftobiprole medocaril concentrations of 2.66 and 13.3 mg/mL). 
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. 
No cardiac or pulmonary toxicity was observed.
Further details on the non-clinical toxicology of ceftobiprole medocaril are provided in 
the IB.
1.4
Clinical studies with ceftobiprole
1.4.1
Pharmacokinetics, product metabolism, and tissue distribution in humans
The PK of ceftobiprole in adults 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 (q8h), and no appreciable 
accumulation is observed in adults 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 hours.
Ceftobiprole is eliminated primarily unchanged by renal excretion, with minimal 
metabolism to an open-ring metabolite, which accounts for approximately 4% of total 
exposure. The predominant mechanism responsible for elimination is glomerular 
filtration. As the systemic clearance of ceftobiprole correlates with creatinine clearance 
(CLCR), dose regimen adjustments are recommended in patients with moderate or severe 
renal impairment, patients with end-stage renal disease (ESRD), and patients with 
CLCR > 150 mL/min. At comparable CLCR, the PK of ceftobiprole in patients in an 
intensive-care unit setting, and in patients from studies in hospital-acquired pneumonia 
(HAP) Awad 2014 and community-acquired pneumonia (CAP) Nicholson 2012, were 
similar to the PK in healthy subjects. Given no underlying renal impairment, the primary 
PK/PD driver of ceftobiprole (time that drug concentration exceeds the minimum
inhibitory concentration [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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Following administration of 500 mg ceftobiprole q8h for 7 days, ceftobiprole could not 
be detected in the feces of healthy subjects, there were no significant changes in the 
aerobic or anaerobic intestinal microflora, and no new colonizing aerobic or anaerobic 
bacteria resistant to ceftobiprole were observed. 
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 colony-forming units (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 PK analysis of subjects in the Phase 3 
HAP study demonstrated the probability of target attainment to be 100% for 
Gram-positive pathogens and > 96% for Gram-negative pathogens with the 
recommended clinical dose regimen for ceftobiprole (i.e. 500 mg administered q8h as a 
120-minute IV infusion). 
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 
ABSSSIs/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 2008a). Study BAP00154 compared ceftobiprole 500 mg q12h (N=397) with 
vancomycin 1 g q12h (N=387) in patients with Gram-positive ABSSSIs/cSSTIs 
(Noel 2008b). 
Clinical cure at the test-of-cure (TOC) visit was the primary endpoint in both studies. 
Clinical cure rates in study BAP00414 were 81.9% (ceftobiprole) vs 80.8% 


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(vancomycin/ceftazidime) in the Intent-to-Treat (ITT) analysis set (95% confidence 
interval [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 administered every 8 hours as a 2-hour infusion to 
treatment with ceftriaxone with or without linezolid for patients 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 patients in the ceftobiprole group 
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 
PORT Risk Classes ≥ III (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 
to ceftazidime plus linezolid was demonstrated within the pre-specified 15% margin for 
the primary efficacy endpoint of clinical cure rate at the TOC visit for all patients 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 pre-
specified subgroup of patients with HAP (excluding ventilator-associated pneumonia 
[VAP]) subjects (N=571). Non-inferiority of ceftobiprole was not demonstrated in the 
smaller subset of VAP patients (N=210).
1.4.7
Safety………….…….
The current safety experience from clinical studies of ceftobiprole comprises 
3037 subjects (1404 from Phase 3 pneumonia studies, 1633 from Phase 2 and Phase 3 
cSSTI studies, and 511 subjects from Phase 1 studies). The observed safety profile is 
consistent with that of the cephalosporin class as a whole.
The most common adverse reactions, occurring in ≥3% of subjects treated with 
ceftobiprole, were nausea, vomiting, diarrhea, infusion site reactions, hypersensitivity 
(including urticaria, pruritic rash and drug hypersensitivity), and dysgeusia.


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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.
The development of a positive direct-antiglobulin test may occur during treatment with a 
cephalosporin. In clinical studies with ceftobiprole there was no evidence of hemolytic
anemia. However, the possibility that hemolytic anemia may occur in association with 
ceftobiprole treatment cannot be ruled out. Patients experiencing anemia during or after 
treatment with ceftobiprole should be investigated for this possibility.
It is not known whether ceftobiprole, like some other cephalosporins, interferes with the 
alkaline picrate assay to measure serum creatinine (Jaffé reaction), which may lead to 
erroneously high creatinine measurements. During treatment with ceftobiprole it is 
recommended that an enzymatic method of measuring serum creatinine be used.
During treatment with ceftobiprole it is recommended that an enzymatic method to detect 
glucosuria be used, because of potential interference with tests using the copper reduction 
technique.
Further details can be found in the IB.
1.5
Rationale for study BPR-CS-008
Ceftobiprole, a novel cephalosporin is potentially an important addition to ABSSSI 
treatment options. Ceftobiprole has broad in vitro activity against Gram-positive 
pathogens, including MSSA/MRSA, and against P. aeruginosa and other Gram-negative 
organisms.
Therefore, due to the beneficial profile of this compound as well as the need for 
additional agents to treat ABSSSIs, including those caused by MRSA, this Phase 3 study 
will evaluate ceftobiprole therapy against standard therapy in terms of safety, efficacy 
and resource utilization.
1.5.1
Summary of study design 
This is a randomized, double-blind, active-controlled, parallel-group, multicenter study in 
adult hospitalized patients to establish the safety and efficacy of ceftobiprole medocaril 
compared with vancomycin plus aztreonam in the treatment of ABSSSIs.
1.5.2
Study design rationale
The study design is in accordance with the current FDA Guidance for Industry, Acute 
Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment (October 
2013). In parallel, in 2014 the European Medicines Agency (EMA) published the 
Addendum to the guideline on the evaluation of medicinal products indicated for 
treatment of bacterial infections. Whereas the disease description and patient selection 
appear to be quite similar between both guidance documents, the recommended primary 
endpoints to evaluate treatment success are different. 


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For the primary analysis, the FDA recommends an early clinical success endpoint:
Clinical response should be based on the percent reduction in the lesion size at 48 to 
72 hours compared to baseline, measured in patients who did not receive rescue 
therapy and are alive. A clinical response in a patient generally is defined as a 
percent reduction in lesion size greater than or equal to 20 percent compared to 
baseline.
The EMA recommends the assessment of clinical outcome at a later timepoint,
approximately 7–14 days after the end of therapy:
Clinical outcome documented at a test of cure (TOC) visit timed from randomization
so that it occurs within a window of approximately 7–14 days after the last day of 
treatment would be an acceptable primary endpoint.
The data obtained during course of the study will be analyzed and presented using similar 
timeframes; however the TOC visit will be linked to the time of randomization, rather 
than to the EOT. Separate statistical analysis plans (SAPs) will be prepared for the FDA 
and EMA.
1.5.3
Study drug and dose
1.5.3.1 Ceftobiprole medocaril
Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, a novel 
cephalosporin which has been developed for IV administration. Ceftobiprole is 
characterized
by 
potent, 
broad-spectrum 
antimicrobial 
activity 
against 
both
Gram-positive and Gram-negative pathogens, including those that have developed 
various forms of antibacterial resistance.
Ceftobiprole medocaril is a powder for concentrate for solution for infusion. The volume 
of distribution at steady state of ceftobiprole is 18 L, suggesting that distribution is 
restricted to the extracellular water compartment, which is comparable to other 
beta-lactam antibiotics. 
The total body clearance of ceftobiprole is approximately 5 L/h. The mean apparent 
half-life of ceftobiprole approximately 3 to 4 hours. Protein binding in human is low and 
concentration independent, with a mean plasma protein binding value of 16% 
Ceftobiprole is eliminated primarily unchanged by renal excretion, where renal clearance 
is approximately 4 L/h; the predominant mechanism responsible for elimination is
glomerular filtration.
The recommended dose of ceftobiprole is 500 mg administered as a 2-hour IV infusion 
q8h.
1.5.3.2 Vancomycin
Vancomycin is an antibacterial agent inhibiting bacterial cell wall synthesis and altering 
cell-membrane permeability and RNA synthesis, which can be administered either orally 
or parenterally, with a mean half-life of 4–6 hours. Vancomycin is not metabolized, and 
about 75% is excreted in the urine by glomerular filtration. Administered IV, vancomycin


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is 55% protein-bound and distributes in pleural, pericardial, ascitic, and synovial fluids,
in urine, in peritoneal dialysis fluid, and in atrial appendage tissue.
Vancomycin is administered IV for the treatment of serious or severe infections caused 
by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci, and 
the treatment of staphylococcal, streptococcal, enterococcal, or diphtheroid endocarditis.
Oral absorption of vancomycin is poor, and is limited to the treatment of 
C. difficile-associated diarrhea or staphylococcal enterocolitis. 
The usual daily IV dose of vancomycin is 2000 mg, either as 500 mg every q6h or 
1000 mg q12h. Patient factors, such as age, obesity, or renal function, may require
modification of the daily IV dose.
Vancomycin steady state trough levels measured immediately prior to the next 
dose should be 10–15 mg/L. Ototoxicity has been associated with serum drug levels of 
80–100 mg/L, but this is rarely seen when serum levels are kept at or below 30 mg/L.
1.5.3.3 Aztreonam  
Aztreonam is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. 
It confers selective activity against Gram-negative aerobic bacteria, and is not efficacious 
against Gram-positive bacteria. Aztreonam is 56% protein-bound. Hepatic metabolism is 
minor, and aztreonam is renally excreted. Mean half-life is 1.7 hours. Aztreonam has 
been used in previous Phase 3 ABSSSI studies with a dose regimen of 1000 mg q12h 
(Corey 2010) in combination with vancomycin,
which lacks efficacy against 
Gram-negative bacteria.
The requirement for aztreonam therapy will be reassessed at the 72-h study visit 
(see Section 6.1).


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2
OBJECTIVES OF THE STUDY
2.1
Primary objective
To demonstrate the non-inferiority of ceftobiprole to vancomycin plus aztreonam in 
patients with ABSSSIs with respect to early clinical response based on percentage 
reduction in lesion size at 48–72 hours after first treatment in the ITT population.
2.2
Secondary objectives
2.2.1
Main secondary objective
To demonstrate the non-inferiority of ceftobiprole to vancomycin plus aztreonam in 
patients with ABSSSIs, with respect to investigator-assessed clinical success at the 
test-of-cure (TOC) visit 15–22 days after randomization, in the co-primary ITT and 
Clinically Evaluable (CE) populations.
Note: The primary and the main secondary objectives will be region-specific. The above primary 
and main secondary objectives are for submission to the US FDA; in the EU, the above main 
secondary objective will be the primary objective, and the primary objective listed above will be 
the main secondary objective. Two separate Statistical Analysis Plans (SAPs) will be prepared for 
submission to the FDA and the EMA to reflect the different primary and main secondary 
objectives in each region.
2.2.2
Other secondary objectives 
To compare ceftobiprole with vancomycin plus aztreonam with respect to: 
1. Early clinical response based on percentage reduction in lesion size at 48–72 h after 
first treatment (CE population).
2. Clinical response based on percentage reduction in lesion size at the end-of-treatment 
(EOT) and TOC visits (ITT and CE population).
3. Sustained reduction in lesion size at the end-of-treatment (EOT) and TOC visits (ITT 
population).
4. Investigator-assessed clinical success evaluated at 48–72 h after first treatment and 
the EOT visit, and sustained clinical success at the last follow-up (LFU) visit (ITT 
and CE populations). 
5. All-cause mortality (ACM) through Day 28 (±2 days) (ITT population).
6. Microbiological response at Day 3, Day 5, and the EOT, TOC and LFU visits 
(Microbiological Intent-to-Treat population [mITT] and Microbiologically Evaluable 
[ME] populations). 
7. Change in patient-reported pain from baseline at all visits except the Day 28 visit 
(ITT and CE populations). 
8. Health economic outcome measures (ITT and CE populations). 
9. Safety: incidence, type, severity and relationship to study medication of adverse 
events (AEs) and changes in laboratory tests (hematology, biochemistry, and 
chemistry, including haptoglobin, urinalysis, Coombs test) (Safety population). 
10. To assess the PK of ceftobiprole (PK population).


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3
STUDY DESIGN
3.1
Overview of study design and dosing regimen
This is a randomized, double-blind, active-controlled, parallel-group, multicenter study in 
adult hospitalized patients to establish the safety and efficacy of ceftobiprole medocaril 
compared with vancomycin plus aztreonam in the treatment of ABSSSIs.
Table 2
Summary of treatment and follow-up schedule
Study phase
1
2
3
Pre-treatment
Active treatment
Post-treatment
Screening
Randomization 
and study-drug 
treatment
End of treatment
(EOT)
Test-of-cure
(TOC)
Survival 
status
Last follow-up
(LFU)
Day −1
baseline
From Day 1
at least 5 days, up to 
10 days*
Within 24 h
after last
treatment
15–22 days after 
randomization
Day 28
(±2 days)
28–35 days after 
last treatment
*Study treatment may be extended up to 14 days if required in the investigator`s opinion and approved by the sponsor’s 
medical monitor.
The study comprises three phases: 
1. Pre-treatment: Screening and baseline, duration up to 24 h. 
2. Active treatment: Randomization and at least 5 days, up to 10 days, of study drug 
administration with IV ceftobiprole, or IV vancomycin plus aztreonam. (Study 
treatment may be extended up to 14 days if in the investigator’s opinion this is required,
and the extension is approved by the sponsor’s medical monitor).
3. Post-treatment:

an EOT visit within 24 h after last treatment

a TOC visit 15–22 days after randomization

an LFU visit 28–35 days after last treatment
In addition, at 28 days after randomization, survival status is to be verified for evaluation 
of ACM. 
The total duration of the study for each patient is approximately 5–7 weeks. 
Study assessments are shown in Table 4 and outlined in more detail in Section 5. After 
randomization and during active treatment, patients will receive ceftobiprole and placebo 
or vancomycin and aztreonam according to the schedule outlined in Table 3.


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Table 3
Study-drug administration
Time 
(h)
Study drug
Dose 
(mg)
Volume 
(mL)
Infusion time 
(h)
Study drug
Dose 
(mg)
Volume 
(mL)
Infusion time 
(h)
0
Ceftobiprole
Placebo
500
NA
250
100
2
0.5
Vancomycin
Aztreonam**
1000*
1000
250
100
2
0.5
8
Ceftobiprole
500
250
2
Placebo
NA
250
2
12
Placebo
Placebo
NA
NA
250
100
2
0.5
Vancomycin
Aztreonam
1000*
1000
250
100
2
0.5
16
Ceftobiprole
500
250
2
Placebo
NA
250
2
* Or 15 mg/kg vancomycin: the decision to use vancomycin at a fixed or weight-based dose is to be made by the 
investigator on the basis of the site’s standard of care, and needs to be communicated prior to randomization to the 
unblinded pharmacist or delegate. If VTT is performed, the vancomycin dose may be adjusted according to trough 
levels.
** The requirement for aztreonam therapy will be reassessed at the 72-h study visit (see Section 6.1).
NA, not applicable.
On each treatment day, study-drug administration should be no more than ± 2 hours from 
the scheduled time point.
The vancomycin dose may be adjusted by the unblinded pharmacist or delegate in 
accordance with the local standard of care.
Dose adjustment of study drugs according to renal function is described in detail in 
Section 6.2.
The primary and the main secondary endpoints are region-specific. The primary and main 
secondary endpoints listed below are for submission to the US FDA. In the EU, the main 
secondary endpoint listed below will be the primary endpoint, and the primary endpoint 
listed below will be the main secondary endpoint. Two separate SAPs will be prepared 
for submission to the FDA and the EMA to reflect the different primary and main 
secondary endpoints in each region.
3.1.1
Primary endpoint…………………
Early clinical response 48–72 h after start of treatment based on the patient meeting all of 
the following criteria: 
1. ≥ 20% reduction from baseline in the area (length × width of erythema, edema, or 
induration) of the primary lesion.
2. Survival for ≥ 72 h from the time of administration of the first dose of study drug.
3. No use of concomitant systemic antibacterial treatments, or topical antibacterial 
administration on the primary lesion.
4. No additional unplanned surgical procedure for the ABSSSI after start of therapy 
(other than debridement at bedside or local bedside wound care), with the exception 
of cellulitis where there is a conversion into an abscess within 48 h of study treatment 
initiation, or, for post-surgery patients, when an extension of the original incision is 
indicated.


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The primary endpoint is to be assessed in the ITT population.
Standardized measurement of the lesion area (i.e., erythema, edema, or induration, 
whichever is largest) is to be performed with a flexible plastic ruler or tape measure, by 
multiplying the longest length of the lesion by the widest width perpendicular to that 
length. In addition, a measurement of the maximum width of erythema or 
edema/induration from the edge of the wound (surgical or traumatic) or abscess will be 
recorded. If abscess, the measurement should be taken from the end of the fluctuance 
before drainage or from the edge of the drainage site after drainage.
A digital photograph will be obtained at Screening, at the early clinical response 
assessment (48–72 h after first treatment), and at the EOT and TOC visit, for each patient 
(primary ABSSSI lesion), and will be used for documentation purposes and as source 
data. Digital photography will not be used for the measurement of the ABSSSI lesion size 
area; the determination of the ABSSSI lesion size area will be solely based on the ruler 
measurements.
3.1.2
Main secondary endpoint
Investigator-assessed clinical success at the TOC visit 15–22 days after randomization. 
The TOC visit should be performed at least 5 days after the end of treatment.
Clinical success is defined as complete or nearly complete resolution of baseline signs 
and symptoms of the primary infection, such that no further antibacterial treatment is 
needed.
A patient meeting this definition cannot be classified as a clinical success if any of the 
following criteria are met:
1. Death from any cause prior to TOC
2. Additional antibacterial therapy received for treatment of the primary lesion
3. Initiation of non-study antibacterial treatment of another infection, unless the 
antibacterial agent lacks efficacy in the treatment of ABSSSI
4. Requirement for an unplanned surgical procedure for the ABSSSI after start of 
therapy, (other than debridement at bedside or local bedside wound care), with the 
exception of cellulitis where there is a conversion into an abscess within 48 h of study 
treatment initiation, or, for post-surgery patients, when an extension of the original 
incision is indicated.
5. Indeterminate assessment at TOC for any reason, including but not limited to:
(a) missing TOC visit
(b) lost to follow-up
(c) patient withdrew consent
(d) missing data in relation to signs and symptoms of the ABSSSI
(e) discontinuation from the study due to the need for hemodialysis
The main secondary endpoint is to be assessed in the ITT and CE populations.


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3.1.3
Other secondary endpoints 
1. Early clinical response based on percentage reduction in lesion size at 48–72 h after 
first treatment in the CE population, using the same definition for response as for the 
primary endpoint.
2. Clinical response defined as ≥ 80% decrease in lesion area at the EOT visit, and 
≥90% decrease in lesion area at the TOC visit (ITT population), with improvement of 
local signs of the infection in patients surviving up to the respective visit with no use 
of any concomitant systemic antibacterial treatment or topical antibacterial 
administration on the primary lesion, and no unplanned additional surgical procedure 
(other than debridement at bedside or local bedside wound care), with the exception 
of cellulitis where there is a conversion into an abscess within 48 h of study treatment 
initiation, or, for post-surgery patients, when an extension of the original incision is
indicated.
3. Sustained reduction in lesion size at the EOT and TOC visits (ITT population).
Sustained reduction in lesion size is defined as ≥ 20% decrease in lesion area 48–72 h 
after start of treatment (primary endpoint) that is sustained at the EOT and TOC 
visits.
4. Investigator-assessed clinical success evaluated at 48–72 h after first treatment and 
the EOT visit, and sustained clinical success at the LFU visit (ITT and CE 
populations).
Clinical success at the EOT visit is defined by the same criteria as for the main 
secondary endpoint, with an indeterminate assessment to include a missing EOT visit. 
Sustained clinical success requires that all criteria listed for the main secondary 
endpoint are met and there were no new signs or symptoms of the ABSSSI between 
the TOC and LFU visits.
5. ACM at Day 28 (±2 days).
Assessment of survival status at Day 28 (±2 days).
6. Microbiological response at Day 3, Day 5, and the EOT, TOC and LFU visits (mITT 
and ME populations)
Eradication: No growth of the baseline pathogen(s) based on post-therapy cultures 
obtained from the primary infection site at the respective time points.
Presumed eradication: No post-therapy culture due to lack of culturable material, 
accompanied by investigator-assessed clinical success. 
Persistence: Evidence of continued growth of the baseline pathogen.
Presumed persistence: No post-therapy culture due to lack of culturable material, 
accompanied by the absence of investigator-assessed clinical success. 
Superinfection: Emergence of a new pathogen(s) at the primary site of infection, 
accompanied by the absence of an investigator-assessed clinical success. 
Relapse or recurrence: Pre-therapy pathogen isolated between the EOT and TOC 
visits, or between the TOC and LFU visits, after a pathogen response of ‘eradication’ 
or ‘presumed eradication’ at the EOT or TOC visits.


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7. Patient-reported pain (ITT and CE populations)
Time points: all visits, (with exception of Day 28) 
Patient-reported pain, assessed at baseline and throughout the study, using a visual 
analogue scale (VAS) with a 100 mm line, on which the 0 point indicates ‘no pain’ 
and the 100 mm point indicates ‘worst pain ever’, and a Wong-Baker FACES® Pain 
Rating Scale. 
8. Health economic outcome measures (ITT and CE population)
Time point: From start of study medication until the LFU visit 
Resource requirements and health economic data will be derived from study-specific 
data, or collected ancillary to study conduct, to perform health economics analyses. 
These analyses will aim to enable economic comparisons of ceftobiprole with 
vancomycin and aztreonam.
9. Safety 
Time point: First dose of study drug until LFU
Adverse events, laboratory tests (including hematology,
biochemistry, and 
haptoglobin), Coomb’s test, vital signs, physical examination, and concomitant 
medications.
10. Pharmacokinetics
Time points: Day 4 
Plasma levels of ceftobiprole.
Sparse PK sampling

Day 4: predose, 2 h (end of infusion), 4 to 6 h
Rich PK sampling

Day 4: predose, 2 h (end of infusion), 3 h, 4 h, 6 h and 8 h 
3.2
Treatment plan
3.2.1
Duration of treatment
Treatment duration will be for at least 5 days and up to 10 days. The required treatment 
duration within the 5–10 day window will be determined for each patient by the treating 
investigator. Study treatment may be extended up to 14 days if in the investigator’s 
opinion this is required, and the extension is approved by the sponsor’s medical monitor.
3.2.2
Missed-dose management
If one or more doses are missed due to administrative reasons, no doses are to be 
administered other than in accordance with the schedule provided in Table 3. In such 
cases, the investigator may consider exclusion of the patient from the study after 
discussion with the sponsor’s medical monitor.


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3.2.3
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 
every 8 hours). If an overdose occurs, it should be treated symptomatically. Ceftobiprole 
plasma concentrations can be reduced by hemodialysis.
Vancomycin: Supportive care is advised, with maintenance of glomerular filtration. 
Vancomycin is poorly removed by dialysis. Hemofiltration and hemoperfusion with 
polysulfone resin have been reported to result in increased vancomycin clearance. 
The median non-clinical lethal IV dose was 319 mg/kg in rats, and 400 mg/kg in mice.
Aztreonam: There have been no reported cases of overdoses of aztreonam. If necessary, 
aztreonam may be cleared from the serum by hemodialysis and/or peritoneal dialysis. 
Aztreonam has been shown to be cleared from the serum by continuous arteriovenous 
hemofiltration.
3.3
Definition of end of study
The end of the 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).
3.4
Data and Safety Monitoring Board
For safety monitoring, a Data and Safety Monitoring Board (DSMB) will be utilised 
periodically throughout the study. Additional blinded interim safety assessments will be 
performed twice in each year after enrollment of the first patient. Details are provided in 
the DSMB Charter. 


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4
STUDY POPULATION
4.1
Target population
Adult male or female patients with an ABSSSI meeting all of the inclusion criteria and 
none of the exclusion criteria are eligible for enrollment in this study.
4.2
Inclusion criteria
Patients meeting all of the following:
1. Male or female, aged ≥18 years. 
2. Diagnosis of ABSSSI, meeting at least one of the definitions in (a) to (c) below. 
Local symptoms must have started within the 7 days prior to the Screening visit.
(a) Cellulitis/erysipelas, defined as a diffuse skin infection characterized by all of the 
following within 24 h:
i.
Rapidly spreading areas of erythema, edema, and/or induration with a 
minimum total lesion surface area of 75 cm2. 
ii. No collection of pus apparent upon visual examination. 
iii. At least two of the following local signs of infection: 

erythema 

induration

localized warmth

pain or tenderness on palpation

swelling/edema
(b) Major cutaneous abscess, defined as infection characterized by a collection of pus 
within the dermis or deeper that is apparent upon visual examination before or after 
therapeutic intervention and is accompanied by all of the following within 24 h:
i.
Erythema, edema and/or induration with a minimum total lesion surface area 
of 75 cm2. 
ii. At least two of the following local signs of infection: 

fluctuance

incision and drainage required

purulent or seropurulent drainage

localized warmth

pain or tenderness on palpation
(c) Wound infection, defined as infection of any apparent break in the skin 
characterized by at least one of the following:
i.
Superficial incision/surgical site infection meeting all of the following criteria: 

involves only the skin or subcutaneous tissue around the incision (does not 
involve fascia). 

occurs within 30 days of procedure. 

purulent drainage (spontaneous or therapeutic) with surrounding erythema, 
edema and/or induration with a minimum total lesion surface area of 
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ii. Post-traumatic wound (including penetrating trauma, e.g., needle, nail, knife, 
insect and spider bites) meeting the following criterion within 24 h: 

Purulent drainage (spontaneous or therapeutic) with surrounding 
erythema, edema and/or induration with a minimum total lesion surface 
area of 75 cm2. 
3. At least one of the following regional or systemic signs of infection at the Screening
visit:
(a) Lymph node tenderness and volume increase, or palpable lymph node proximal to 
the primary ABSSSI. 
(b) Fever > 38 °C / 100.4 °F measured orally, > 38.5 °C / 101.3 °F measured 
tympanically, > 37.5 °C / 99.5 °F measured by the axillary method, or > 39 °C /
102.2 °F measured rectally.
(c) White blood cell (WBC) count ˃ 10.0 × 109/L or < 4.0 × 109/L.
(d) > 10% immature neutrophils (band forms). 
4. Requirement for intravenous (IV) antibacterial treatment.
5. Willing and able to adhere to study procedures (including prohibitions and 
restrictions) as specified in this protocol.
6. Willing and able to remain hospitalized (in a hospital or equivalent medical 
confinement or clinical research unit) until completion of the early-clinical-response 
assessment for the primary endpoint. 
7. Informed consent signed by the patient, or their legally acceptable representative if 
appropriate, indicating that they understand the purpose of, and procedures required 
for, the study, and are willing to participate.
4.3
Exclusion criteria
Patients meeting any one of the following: 
1. Use of any systemic antibacterial treatment within 14 days, or topical antibacterial 
administration on the primary lesion within 96 h, before first infusion of study drug.
Exception: Receipt of a single dose of a short-acting (half-life ≤ 12 h, see 
Appendix 1) antibacterial therapy (e.g., for surgical prophylaxis) within ˃ 3 days 
before randomization (i.e., patients cannot have received any antibacterial treatment 
within 72 h of randomization).*
2. Contraindication to the administration of either of the study treatments, including 
known clinically-relevant hypersensitivity to related antibacterial treatments (e.g., beta-
lactam and glycopeptide antibiotics), or to metronidazole if required as adjunctive 
therapy.
                                                
* The number of patients who have received a single dose of a short-acting antibacterial drug within 14 
days before randomization will be limited to 25% of the patient population.


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3. Participation in any other clinical study within the 30 days prior to randomization, or 
any prior participation in this study.
4. The primary ABSSSI is an uncomplicated skin and skin structure infection, such as 
furuncles, 
minor 
abscesses
(area 
of 
suppuration 
not 
surrounded 
by 
cellulitis/erysipelas), impetiginous lesions, superficial or limited cellulitis/erysipelas, 
or minor wound infections (e.g., stitch abscesses).
5. The primary ABSSSI is due to, or associated with, any of the following: 
(a) Diabetic foot infection, gangrene, or perianal abscess. 
(b) Concomitant infection at another site (e.g., septic arthritis, endocarditis, 
osteomyelitis), not including a secondary ABSSSI lesion. 
(c) Infected burns. 
(d) Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular 
disease (arterial or venous). 
(e) Any evolving necrotizing process (e.g., necrotizing fasciitis). 
(f) Infections at vascular catheter sites, or involving thrombophlebitis. 
6. The primary ABSSSI is associated with, or in close proximity to, a prosthetic device.
7. Patients who are placed in a hyperbaric chamber as adjunctive therapy for the 
ABSSSI.
8. Patients expected to require more than two surgical interventions in the operating room 
for the ABSSSI.
9. Severe sepsis or septic shock.
10. Significant or life-threatening condition (e.g., endocarditis, meningitis) that would 
confound, or interfere with, the assessment of the ABSSSI.
11. Another severe, acute or chronic medical condition, psychiatric condition, or 
laboratory abnormality that may increase the risks associated with study participation 
or administration of the investigational product, or may interfere with the 
interpretation of study results, and which, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study. 
12. Receiving treatment for active tuberculosis.
13. Absolute neutrophil count < 0.5 × 109/L. 
14. Recent history of opportunistic infections (i.e., within 30 days) if the underlying cause 
of these infections is still active (e.g., leukemia, transplant, acquired immunodeficiency 
syndrome [AIDS]).
15. Patients receiving systemic steroids (> 40 mg per day prednisolone, or equivalent), or 
receiving immunosuppressant drugs.
16. Requirement for peritoneal dialysis, plasmapheresis, hemodialysis, venovenous 
dialysis, or other forms of renal filtration, or expected to require such treatment before 
the TOC visit.


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17. Alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥8× the upper 
limit of normal, OR severe hepatic disease with Child-Pugh class C. 
18. Women who are pregnant or nursing.
19. 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.
20. Inability to start study-drug therapy within 24 h of Screening.
21. Patients with illicit drug use within 12 months of screening, including heroin, other 
opioids (unless prescribed for medical reasons unrelated to heroin substitution), 
cocaine / crack cocaine, and amphetamine/methamphetamine.
Exception: Cannabis use.
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
Patients may continue to receive treatment for up to 14 days unless disease progression 
(lack of efficacy) or unacceptable toxicity occurs. Reasons for discontinuation of 
treatment must be recorded.
Reasons for premature discontinuation of treatment may include:

AE

abnormal laboratory value

abnormal test procedure result

intercurrent illness that prevents or interfere with further administration of treatment

death

protocol deviation

lost to follow-up

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A patient must be discontinued from study treatment if any of the following events occur:

need for the use of systemic non-study antibacterial therapy to treat ABSSSI (e.g., due 
to lack of efficacy)

hemodialysis

pregnancy
All patients must have an LFU visit at 28–35 days after last study-drug administration. 
If a patient who has received at least one dose of study drug 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 so far, and to have the patient complete the post-treatment EOT, TOC and 
LFU visits.
For patients who fail to return for EOT, TOC, or LFU visits, the investigator must make 
every effort to contact the patient (by telephone or mail correspondence). The outcome of 
this contact must be documented by the investigator and filed in the source data. The 
reasons for this must be recorded in the case report form (CRF).
4.6
Replacement of patients 
Patients failing Screening procedures are to be replaced.
Patients who discontinue participation in the study for any reason after receiving the first 
dose of study drug are not to be replaced.
Any patient withdrawn from the study or patients failing Screening procedures may not 
re-enter the study.
Any patient having completed the study is not allowed to re-enroll into the study again.
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Summary of schedule of assessments
Table 4 presents a summary of the schedule of assessments to be performed from 
Screening to the LFU visit.
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. Actual elapsed time (rather than calendar days) will be used to measure the time:

from first dose of study drug to the 48–72 h early-response assessment

from randomization to the TOC visit (15–22 days)

from last dose of study drug to the LFU visit (28–35 days)

from randomization to recording of survival status (28 days)


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Table 4
Schedule of assessments
Screening
Pre-treatment
Active treatment1
Post-treatment
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
Time
Within 24 h 
before first dose Day 1 Day 2 Day 3 Day 4 Day 5
Day 8 Day 14 EOT* TOC*
Day 28
LFU*
Screening/baseline/informed consent/subject number
X
Medical history/demographics/ prior (within 30 days) 
antibacterial and other pre-study drug/non-drug 
therapy, Inclusion/exclusion criteria
X
Documentation of any ABSSSI surgical procedures 
anticipated during the course of the study and planned 
at baseline
X
Complete physical examination2
X
Randomization by IWRS
X
Brief physical examination3
X
X
X
X
Body temperature4
X
<-------------------------2X------------------------>
X
X
X
X
Vital signs5
X
<--------------------------X------------------------>
X
X
X
X
Pregnancy test6
X
X
Safety laboratory (local lab)7
X
Safety laboratory (central lab)
X
X
X
X
X
Haptoglobin and Coombs test (central lab)
X
X
Reticulocytes (central lab)
X
X
WBC count and CRP (central lab)
X
X
X
X
X
X
X
X
Infection-site specimen collection8
X
X
X
X
X
X
Blood culture 8, 9
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
PK blood sample collection10
X
Patient-reported pain assessment11
X
X
X
X
X
X
X
X
X
X
X


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Screening
Pre-treatment
Active treatment1
Post-treatment
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
Time
Within 24 h 
before first dose Day 1 Day 2 Day 3 Day 4 Day 5
Day 8 Day 14 EOT* TOC*
Day 28
LFU*
Study-drug administration
<-------------------------------X1----------------------------->
Drug accountability
<-------------------------------X----------------------------->
Investigator infection-site assessment12
X
2X
2X
2X
X
X
X
X
Digital photography13
X
X
X
X
Investigator assessment of clinical success14
X
X
X
X
X
X
X
X
Concomitant antibacterial and other therapies15
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant non-drug procedures15
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine clearance16
X 
X
X
X
X
X
X
Vancomycin trough level (central laboratory) 17
(X)
(X)
Vancomycin trough levels (local laboratory) 18
<-------------------------------X----------------------------->
Health economics outcome measures19
X
Adverse events
<-------------------------------X----------------------------->
X
X
X
X
Survival status20
X
*
EOT: ≤ 24 h after last treatment. TOC: 15–22 days after randomization. LFU: 28–35 days after last treatment.
1.
Patients will receive IV study-drug therapy for a minimum of 5 days and a maximum of 14 days.
2.
Physical examination includes general appearance, skin, neck inclusive thyroids, eyes, nose, throat, cardiovascular system, thorax/lungs, abdomen, lymph 
nodes, extremities, nervous system, and mental status. 
3.
Physical examination is to be focused on any changes from baseline. 
4.
Measured twice daily (morning and evening) during the visits on the first 8 days of treatment. Afterwards temperature measurements are to be taken once on 
each scheduled study-visit day except Day 28. The same method of measuring temperature should be chosen within a site for all patients during course of the 
study.
5.
Vital signs include height, weight, blood pressure, respiratory rate, pulse rate; to be taken once at each study visit at a time point when temperature assessment 
is performed (see Note 4). A patient’s height must only be assessed during the Screening visit.


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6.
Pregnancy testing is to be performed for women of childbearing potential; at Screening a serum pregnancy test is to be obtained; at the LFU visit 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 5.3.6). 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).
7.
Local safety laboratory includes hematology, biochemistry, glucose levels, coagulation and urinalysis. At Screening, an FSH measurement is to be obtained 
for post-menopausal (where menopause is defined as at least 12 months of amenorrhea) females aged < 50 years, or for those aged ≥ 50 years who have been 
post-menopausal for < 2 years. Local laboratory 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; results of additional tests should not be entered in the CRF laboratory results page, but if constituting an AE 
should be entered in the CRF AE page. Creatinine clearance is to be calculated using the Cockcroft-Gault formula.
8.
ABSSSI site specimens (obtained surgically or by aspiration, biopsy or deep swab) and blood specimens for culture are to be obtained from each patient 
during Screening, but results are not required to be available prior to randomization. If the specimen obtained during Screening was inadequate or was not 
available for testing, additional blood and ABSSSI site specimens are to be obtained within 24 h of study-drug administration. During the treatment period, 
additional ABSSSI site specimens (if material is available) are to be obtained at Day 3, Day 5, the EOT, TOC and LFU visits, and at any other time if 
clinically indicated, e.g., in the event of failure, or when no improvement in lesion(s), or deterioration of lesion(s), is observed and if easily accessible. 
Specimens are to be cultured by the local laboratory using standard microbiological procedures. All unique organisms from blood and the ABSSSI site are to 
be sent to the central microbiology laboratory for identification, and for susceptibility testing with all study drugs.
9.
Two blood samples are to be collected for cultures from all patients within the 6 h before randomization. If the result of the blood culture is positive, 
additional blood cultures should be collected at each visit, or more frequently if clinically indicated, until two consecutive negative results are obtained on 
separate days.
10. For the determination of plasma ceftobiprole levels, sparse PK sampling will be collected on Day 4 predose, 2 h (end of infusion), and 4 to 6 h after the start 
of infusion. Rich PK sampling will be collected on Day 4: predose, 2 h (end of infusion), 3 h, 4 h, 6 h, and 8 h after the start of infusion.
11. Patient-reported pain using a VAS with a 100 mm line; 0 point = “no pain”, 100 mm point = “worst pain ever”, and a Wong-Baker FACES® Pain Rating 
Scale.
12. Primary measurement of the target lesion size is to be performed using a flexible ruler, measuring longest length, and maximum width perpendicular to the 
length. Measurements are to be performed at Screening (prior to randomization and within the 6 h prior to first dose of study drug), twice on Day 2, Day 3,
and Day 4, and once on Day 8, and the EOT, TOC and LFU visits. On days when two measurements are obtained, the measurements are to be taken at least 
8 h apart. Infection-site assessment includes incision/drainage, erythema, heat/localized warmth, pain/tenderness to palpation, fluctuance, swelling/induration.
13. A digital photograph will be obtained at Screening, at the early clinical response assessment (48–72 h after first treatment), and at the EOT and TOC visit, for 
each patient (primary ABSSSI lesion), and will be used for documentation purposes and as source data. Digital photography will not be used for the 
measurement of the ABSSSI lesion size area; the determination of the ABSSSI lesion size area will be solely based on the ruler measurements.
14. Clinical success will be assessed by the investigator using a four-point scale relative to the baseline assessment: cured, improved, stable, or worsened. In case 
of worsened (e.g., bacteremia, osteomyelitis, amputation), signs and symptoms need to be documented as AEs.


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15. Concomitant antibacterial therapies, other drug therapies, and non-drug procedures will be assessed at all scheduled study visits.
16. Creatinine clearance: CLCR should be calculated using the Cockcroft-Gault formula based on local laboratory results, and should be performed at Screening,
and at a minimum on study Days 1, 2, 3, 4, 5, and 8. 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 vancomycin and ceftobiprole are adjusted in accordance with Table 8.
17. Vancomycin trough level (central laboratory assessment): a vancomycin trough level for central laboratory assessment is to be obtained approximately 
30 minutes before administration of the fourth dose of vancomycin (i.e., on Day 2 for patients who receive vancomycin on a q12h schedule, and on Day 4 for
patients who receive vancomycin on a q24h schedule). The central laboratory result will not be communicated to the study site. 
18. Vancomycin trough levels (local laboratory assessment): in study sites which use vancomycin trough level monitoring to guide vancomycin dosing and which
perform vancomycin trough level testing using a local laboratory, an additional blood sample for local laboratory testing of the vancomycin trough level 
should also be obtained before administration of the fourth dose of vancomycin on Day 2 (vancomycin q12h schedule) or Day 4 (vancomycin q24 h 
schedule). Additional local laboratory testing of vancomycin trough levels should be obtained according to institutional practices at the respective study site.
19. Information on health economics outcome measures from baseline to the LFU visit will be collected at the LFU visit, including study treatment duration, total 
length of stay in hospital, location of treatment within the healthcare system (e.g., Emergency Department), concomitant medications, post-study drug 
procedures and interventions including AEs and any treatment required by these events, re-admission rates, outpatient healthcare encounters, Emergency 
Department visits, antibacterial use, and surgical and non-surgical procedures, e.g., debridement, grafts, amputation, prostheses.
20. Survival status (by telephone or visit) must be obtained at Day 28 (±2 days).


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5.2
Study visits
5.2.1
Visit 1: Screening (Day −1; within 24 h before first dose)
The following assessments and procedures must be performed at the Screening visit: 

Screening/baseline/informed consent

Assign Subject number and Interactive Web Response System (IWRS) registration

Inclusion/exclusion criteria

Medical history/demographics/ prior (within 30 days) antibacterial and other pre-
study drug/non-drug therapy

Complete physical examination

Body temperature

Vital signs

Pregnancy test (serum)

Safety laboratory (local lab)

Safety laboratory (central lab)

Haptoglobin and Coombs test (central lab)

Reticulocytes (central lab)

WBC count and C-reactive protein (CRP) (central lab)

Infection-site specimen collection

Blood culture

Patient-reported pain assessment

Investigator infection-site assessment

Digital photography

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

CLCR should be calculated using the Cockcroft-Gault formula

Documentation of any ABSSSI surgical procedures anticipated during the course of 
the study and planned at baseline
The infection site assessment should occur before randomization, and within the 6 hours 
prior to the first dose of study drug. Infection-site specimens must be obtained from each 
patient during Screening (i.e., within 24 h prior to first dose of study treatment). Gram 
stain, culture, and susceptibility testing must be performed from the infection site 
specimens, but results are not required to be available prior to randomization.


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5.2.2
Visit 2: Active treatment Day 1
The following assessments and procedures are to be performed at Visit 2: 

Randomization

Body temperature (twice daily)

Vital signs

WBC count and CRP (central lab)

Blood culture (if positive result was obtained at baseline)

Patient-reported pain assessment

Study-drug administration

Drug accountability

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)

AEs
Intravenous study treatment is to be administered within 6 hours of randomization. 
5.2.3
Visit 3: Active treatment Day 2
The following assessments and procedures are to be performed at Visit 3: 

Body temperature (twice daily)

Vital signs

WBC count and CRP (central lab)

Vancomycin trough level (central laboratory) to be obtained 30 min prior to the fourth 
dose of vancomycin for patients on a q12h vancomycin schedule

Vancomycin trough level (local laboratory) in study sites which use vancomycin 
trough level monitoring to guide vancomycin dosing using a local laboratory; to be 
obtained 30 min prior to the fourth dose of vancomycin for patients on a q12h 
vancomycin schedule

Blood culture (if positive result was obtained at baseline)

Patient-reported pain assessment

Study-drug administration

Drug accountability

Investigator infection-site assessment (twice daily)

Investigator assessment of clinical success

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)

AEs


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5.2.4
Visit 4: Active treatment Day 3
The following assessments and procedures are to be performed at Visit 4: 

Brief physical examination

Body temperature (twice daily)

Vital signs

Safety laboratory (central lab)

WBC count and CRP (central lab)

Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)

Infection-site specimen collection

Blood culture (if positive result was obtained at baseline and two consecutive 
negative results have not been obtained on separate days)

Patient-reported pain assessment

Study-drug administration

Drug accountability

Investigator infection-site assessment (twice daily)

Investigator assessment of clinical success

Digital photography

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

AEs
5.2.5
Visit 5: Active treatment Day 4
The following assessments and procedures are to be performed at Visit 5: 

Body temperature (twice daily)

Vital signs

WBC count and CRP (central lab)

Vancomycin trough level (central laboratory) to be obtained 30 min prior to the fourth 
dose of vancomycin for patients on a q24h vancomycin schedule

Vancomycin trough level (local laboratory) in study sites which use vancomycin 
trough level monitoring to guide vancomycin dosing using a local laboratory; to be 
obtained 30 min prior to the fourth dose of vancomycin for patients on a q24h 
vancomycin schedule

PK blood sample collection

Patient-reported pain assessment

Blood culture (if positive result was obtained at baseline and two consecutive 
negative results have not been obtained on separate days)

Study-drug administration


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
Drug accountability

Investigator infection-site assessment (twice daily)

Investigator assessment of clinical success

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)

AEs
5.2.6
Visit 6: Active treatment Day 5
The following assessments and procedures are to be performed at Visit 6: 

Body temperature (twice daily)

Vital signs

Safety laboratory (central lab)

WBC count and CRP (central lab)

Infection-site specimen collection

Blood culture (if positive result was obtained at baseline and two consecutive 
negative results have not been obtained on separate days)

Patient-reported pain assessment

Study-drug administration

Drug accountability

Investigator assessment of clinical success

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)

AEs
5.2.7
Visit 7: Active treatment Day 8
The following assessments and procedures are to be performed at Visit 7: 

Body temperature (twice daily)

Vital signs

Blood culture (if positive result was obtained at baseline and two consecutive 
negative results have not been obtained on separate days)

Patient-reported pain assessment

Study-drug administration

Drug accountability

Investigator infection-site assessment


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
Investigator assessment of clinical success

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

Serum creatinine (local laboratory) and CLCR (calculated using the Cockcroft-Gault 
formula)

AEs
5.2.8
Visit 8: Active treatment Day 14
The following assessments and procedures are to be performed at Visit 8: 

Body temperature

Vital signs

Blood culture (if positive result was obtained at baseline and two consecutive 
negative results have not been obtained on separate days)

Patient-reported pain assessment

Study-drug administration

Drug accountability

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

AEs
5.2.9
Visit 9: Post-treatment EOT visit
The EOT visit is to take place within 24 h after last study-drug administration. 
For patients who terminate study-drug treatment early, the EOT visit should take place 
within 72 h of the discontinuation. 
The following assessments and procedures are to be performed at the EOT visit: 

Brief physical examination

Body temperature

Vital signs

Haptoglobin and Coombs test (central lab)

Safety laboratory (central lab)

Reticulocytes (central lab)

WBC count and CRP (central lab)

Infection-site specimen collection

Blood culture (if positive result was obtained at baseline and two consecutive 
negative results have not been obtained on separate days)

Patient reported pain assessment

Investigator infection-site assessment


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
Investigator assessment of clinical success

Digital photography

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

AEs
5.2.10
Visit 10: Post-treatment TOC visit
The TOC visit is to take place 15–22 days after randomization. The TOC visit should be
performed at least 5 days after EOT.
The following assessments and procedures are to be performed at the TOC visit: 

Brief physical examination

Body temperature

Vital signs

WBC count and CRP (central lab)

Infection-site specimen collection

Blood culture (if positive result was obtained at baseline and two consecutive 
negative results have not been obtained on separate days)

Patient-reported pain assessment

Investigator infection-site assessment

Investigator assessment of clinical success

Digital photography

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

AEs
5.2.11
Visit 11: Post-treatment Day 28 (survival status via phone or visit)
The following assessments and procedures are to be performed at the Day 28 
visit (±2 days): 

Concomitant antibacterial and other therapy

Concomitant non-drug procedures

AEs

Survival status


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5.2.12
Visit 12: Post-treatment LFU visit
The LFU visit is to take place 28–35 days after last treatment.
The following assessments and procedures are to be performed at the LFU visit: 

Brief physical examination

Body temperature

Vital signs

Pregnancy test (serum or urine)

Safety laboratory (central lab)

Infection-site specimen collection

Blood culture (if positive result was obtained at baseline and two consecutive 
negative results have not been obtained on separate days)

Patient-reported pain assessment

Investigator infection-site assessment

Investigator assessment of clinical success

Concomitant antibacterial and other therapies

Concomitant non-drug procedures

Health economics outcome measures

AEs
5.3
Study procedures
5.3.1
Screening/baseline/informed consent
The investigator must obtain the patient’s informed consent to participation in the study 
before carrying out any study procedures during Screening. 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 therapy, and review the 
inclusion/exclusion criteria.
The investigator is to assign a Subject number (Country code-Site ID-Subject ID) at 
Screening.
5.3.2
Patient registration and Interactive Voice/Web Response System
An IWRS will be used for this study.
The investigator will register eligible patients in the IWRS. Randomization, further 
registrations and events will be handled according to the IWRS manual.
Detailed handling instructions are provided in the IWRS manual.


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5.3.3
Physical examination
A complete physical examination must be performed in accordance with the schedule of 
assessments (see Table 4). Physical examination includes general appearance, skin, neck 
inclusive thyroids, eyes, nose, throat, cardiovascular system, 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 4). Brief physical examination is to be focused on any changes 
from baseline.
5.3.4
Body temperature measurement
Body temperature is to be measured twice daily (morning and evening) during the visits 
on the first 8 days of treatment, after which temperature measurements are to be taken 
once on each scheduled study visit day except Day 28. The same method of measuring 
temperature should be chosen within a site for all patients during the course of the study.
5.3.5
Vital signs………….…….
Vital signs must be assessed in accordance with the schedule of assessments 
(see Table 4), at the same time as the temperature assessment is performed.
Vital signs include height, weight, respiratory rate, radial pulse rate, systolic blood 
pressure and diastolic blood pressure. Pulse rates and blood pressures 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. 
A patient’s height must only be assessed during the Screening visit.
5.3.6
Pregnancy testing
Women of childbearing potential must have a negative serum pregnancy test result during 
Screening.
At the LFU visit 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, and the patient followed for safety, and assessment of 
the pregnancy outcome.
Further details regarding pregnancy are provided in Section 7.4.
5.3.7
Safety laboratory parameters
Local safety laboratory parameters to be used to assess patient eligibility at Screening 
include hematology, biochemistry, coagulation, blood glucose, and urinalysis. 
At Screening, a FSH measurement is to be obtained for post-menopausal (where 
menopause is defined as at least 12 months of amenorrhea) females aged < 50 years, or for 
those aged ≥ 50 years who have been post-menopausal for < 2 years. CLCR for dose 
determination is to be calculated using the Cockcroft-Gault formula.
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 


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laboratory results page of the CRF; if the results constitute an AE they should be entered 
in the CRF AE page.
Central laboratory safety parameters will be carried out in accordance with the schedule 
of assessments (see Table 4). Additional central testing may be performed at the 
discretion of the investigator whenever clinically indicated. All samples for a given study 
center 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.
Table 5
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.
Table 6
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
GGT
LDH
Bilirubin (direct & indirect)
Potassium
Sodium
Chloride
Creatinine
Urea
Uric acid
Glucose 
CRP
PT
INR
aPTT
ALT=alanine transaminase; AST=aspartate transaminase; AP=alkaline phosphatase; aPTT= activated 
partial thromboplastin time; CRP=C-reactive protein; GGT=gamma-glutamyl transferase; 
HCT=hematocrit; HGB=hemoglobin; INR=International Normalized Ratio; LDH=lactate dehydrogenase; 
PT=prothrombin time; RBC=red blood cell; WBC=white blood cell.


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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.
5.3.8
Reticulocytes, haptoglobin and Coombs test
Reticulocytes, haptoglobin and Coombs test will be assessed by central laboratory 
according to the schedule shown in Table 4.
5.3.9
WBC count and CRP testing
WBC counts and CRP levels will be assessed by central laboratory according to the 
schedule shown in Table 4. 
5.3.10
Creatinine clearance
Creatinine clearance (CLCR): CLCR should be calculated using the Cockcroft-Gault 
formula based on local laboratory results, and should be performed at Screening, and at a 
minimum on study Days 1, 2, 3, 4, 5, and 8. 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 vancomycin and ceftobiprole are adjusted in 
accordance with Table 8.
5.3.11
Microbiological assessments
A laboratory manual will be provided to each site which will provide guidance on the 
microbiological sampling, and processing and shipments of microbiological samples.
5.3.11.1 ABSSSI site specimen
An ABSSSI site specimen for Gram stain, culture, and susceptibility testing must be 
obtained from each patient within the 24 h prior to study-drug administration. The 
specimen must be maintained at room temperature and processed for Gram stain and 
culture as soon as possible (maximum 2 hours), unless using an appropriate transport 
medium. If the Screening-visit sample was inadequate or not available for testing, 
additional samples may be obtained if accessible on Day 1. During the Treatment Period, 
additional ABSSSI site specimens (if material is available) are to be obtained at Day 3, 
Day 5, at the EOT, TOC and LFU visits, and at any other time if clinically indicated, e.g., 
in the event of failure, or when no improvement in lesion(s), or deterioration of lesion(s), 
is observed and if easily accessible.
Samples will be obtained using sterile techniques for the methods outlined in Table 7. 
A superficial swab of the ABSSSI site is not acceptable.


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Table 7
Acceptable methods for ABSSSI specimen collection
Type of ABSSSI
Source of material
Method of collection*
Abscess
Purulent fluid
Aseptic aspiration of purulent fluid 
Biopsy material
Biopsy material obtained from incision and drainage
under sterile conditions
Cellulitis
Aspirate
Punch biopsy
After cleansing the skin at the leading edge of erythema, 
inject and aspirate saline, or perform a punch biopsy, as 
medically appropriate
Traumatic 
wound
Scrapings from wound 
base
After cleansing and debriding the wound bed, and using 
sterile techniques, scrape ulcer/wound base with sterile 
dermal curette or scalpel to obtain tissue
Biopsy material from 
wound base 
After following the above procedure, biopsy tissue at the 
base of the lesion
Surgical-site 
infection
Scrapings from base 
of surgical site
After cleansing and debriding the wound bed, and using 
sterile techniques, scrape the base of the lesion with 
sterile dermal curette or scalpel to obtain tissue
Biopsy material from 
base of surgical site
After following the above procedure, biopsy tissue at the 
base of the lesion
* Prior to collection of the ABSSSI site specimen, the ABSSSI site is to be prepared by a standard-of-care surgical site 
skin preparation method with the appropriate application of an antiseptic agent such as: an iodophor (e.g., 5% 
povidone-iodine), an alcohol-containing product (e.g., 70% ethyl alcohol, 70% isopropyl alcohol), chlorhexidine 
gluconate, or a combination product (e.g., 5% povidone iodine solution in 70% ethanol; or > 0.5% chlorhexidine with 
alcohol).
If possible, the local laboratory should retain all isolates until the end of the study, or 
until confirmation of a viable organism is received from the central laboratory. Back-up 
cultures are to be requested when the central laboratory does not receive a viable culture, 
or recovers an organism different from the one recorded by the local laboratory.
5.3.11.2 Gram staining
Gram stains are to be prepared and interpreted by the local laboratory according to the 
criteria provided in the Microbiology Manual, and results reported in the CRF. A review 
of each slide at the local laboratory should note the presence or absence of organisms, as 
well as squamous and polymorphonuclear cells. Further details are provided in the 
Microbiology Manual.
5.3.11.3 Cultures and susceptibility testing
Each local laboratory is to culture specimens and identify pathogens in accordance with 
the laboratory’s standard procedures. All isolated pathogens obtained from the infection 
site and considered clinically relevant are to be sub-cultured and sent to the central 
laboratory for identification to the species level. 
Each local laboratory is also to perform susceptibility testing in accordance with the 
laboratory’s standard procedures. Gram stain, culture, and susceptibility testing must be 


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performed from the infection site specimens, but results are not required to be available 
prior to randomization. All isolates sent to the central laboratory will be susceptibility 
tested to study drugs and other relevant antibacterial agents to current CLSI and 
EUCAST standards. Further details are provided in the Microbiology Manual.
5.3.11.4 Blood cultures
Two blood samples from two venipuncture sites must be obtained for cultures from all 
patients within the 6 h before randomization. Blood samples are to be taken 5 minutes 
apart by peripheral venous blood draw using sterile techniques. Each blood sample must
be at least 20 mL. The blood samples are then to be divided equally into aerobic (10 mL) 
and, where possible, anaerobic (10 mL) culture media, and incubated for a minimum 
of 5 days. 
If the result of the blood culture is positive, additional blood cultures should be collected 
using the same method as specified above at each visit, or more frequently if clinically 
indicated, until two consecutive negative results are obtained on separate days.
All isolated pathogens obtained from the cultures are to be sub-cultured and sent to the 
central laboratory for identification to the species level, and susceptibility testing.
5.3.12
PK blood sample collection
For determination of plasma ceftobiprole, PK blood samples are to be obtained at the 
following time points:
Sparse PK sampling (all sites)
In total, three blood samples of approximately 2 mL each are to be collected as follows:

Day 4: predose, 2 hours (end of infusion), and 4 to 6 hours after the start of infusion
Rich PK sampling (selected sites)
Six blood samples of approximately 2 mL each are to be collected as follows:

Day 4: predose, 2 hours (end of infusion), 3 hours, 4 hours, 6 hours and 8 hours after 
the start of infusion
5.3.13
Vancomycin trough level testing (central laboratory)
A vancomycin trough level for central laboratory assessment is to be obtained 
approximately 30 min before administration of the fourth dose of vancomycin (i.e., on 
Day 2 for patients who receive vancomycin on a q12h schedule, and on Day 4 for
patients who receive vancomycin on a q24h schedule). The central laboratory result will 
not be communicated to the study site.
5.3.14
Vancomycin trough level testing (local laboratory)
In study sites which use vancomycin trough level monitoring to guide vancomycin dosing 
and which perform vancomycin trough level testing using a local laboratory, an 
additional blood sample for local laboratory testing of the vancomycin trough level 
should be obtained before administration of the fourth dose of vancomycin on Day 2 
(vancomycin q12h schedule) or Day 4 (vancomycin q24 h schedule). Additional local 
laboratory testing of vancomycin trough levels should be obtained according to 
institutional practices at the respective study site.


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5.3.15
Patient-reported pain assessment
Patient-reported pain, assessed at baseline and throughout the study, using a VAS with a 
100 mm line, on which the 0 point indicates ‘no pain’ and the 100 mm point indicates 
‘worst pain ever’, and a Wong-Baker FACES® Pain Rating Scale. 
Visual analog scale
0 mm
   100 mm
no pain
     worst pain ever
Wong-Baker FACES® Pain Rating Scale
5.3.16
Investigator infection-site assessment
Primary measurement of the target lesion size is to be performed using a flexible ruler, 
measuring length, and maximum width perpendicular to the length. 
Length of the lesion will be measured as the longest length. 
Width will be measured as the widest width perpendicular to the longest length. 
Measurements are to be performed at Screening (within the 6 hours prior to first dose of 
study drug), twice on Day 2, Day 3, and Day 4, and once on Day 8, EOT, and the TOC 
and LFU visits. 
On days when two measurements are obtained, the measurements are to be taken at least 
8 hours apart. 
A digital photograph will be obtained at Screening, at the early clinical response 
assessment (48–72 h after first treatment), and at the EOT and TOC visit, for each patient 
(primary ABSSSI lesion), and will be used for documentation purposes and as source 
data. Digital photography will not be used for the measurement of the ABSSSI lesion size 
area; the determination of the ABSSSI lesion size area will be solely based on the ruler 
measurements. 
The infection-site assessment is to include edema, erythema, induration, localized 
warmth, pain on palpation, tenderness on palpation, swelling, fluctuance, incision
required, incision performed (on the respective day of assessment), drainage required, 
drainage performed
(on the respective day of assessment), purulent drainage, 
seropurulent drainage.


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5.3.17
Investigator assessment of clinical success
Clinical success will be assessed by the investigator using a 4-point scale relative to the
baseline assessment: cured, improved, stable, or worsened. 
If the assessment is ‘worsened’ (e.g., bacteremia, osteomyelitis, amputation), the signs 
and symptoms must be documented as AEs.
5.4
Medical history, prior and concomitant medications
5.4.1
Medical history………….…….
A full medical history, including relevant abnormalities, surgeries, diseases, or disorders,
must be obtained at Screening, constituting the baseline characteristics of the patient.
Medical history also includes any relevant change in, or worsening of, a patient’s
condition which occurs after consent, but prior to the start of first study-drug 
administration (see Section 7.3.1).
5.4.2
Prior medications………….…….
All prior medications taken within 30 days of the Screening visit must be documented for 
each patient in the CRF, including the dosage, dose regimen, route of administration, 
therapeutic indication, and start/stop dates of use. 
Use of any systemic antibacterial treatment within 14 days, or topical antibacterial
administration on the primary lesion within 96 hours, before first infusion of study drug 
is not permitted, with the exception of the receipt of a single dose of a short-acting (half-
life ≤ 12 h) antibacterial therapy (e.g., for surgical prophylaxis) within ˃ 3 days before 
randomization (i.e., patients cannot otherwise have received any antibiotic treatment 
within 72 h of randomization). The number of patients who have received a single dose 
of a short-acting antibacterial drug within 14 days before randomization will be limited to 
25% of the patient population. 
A list of antibacterial therapies that meets the criterion of a half-life ≤12 h is provided in 
Appendix 1.
5.4.3
Permitted concomitant medications
All non-antibacterial
standard-of-care medications are allowed as concomitant 
medications.
The use of acetaminophen or paracetamol is allowed when an antipyretic medication is 
indicated. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) and systemic steroids (≤ 40 mg per day 
prednisolone or equivalent) are allowed from 72 h after start of treatment, only after early
clinical response has been determined.
Low-dose aspirin (≤ 200 mg per day) is allowed.
Any concomitant medications (including herbal medicines) that are taken by or 
administered to the patient during the course of the study must be recorded in the CRF, 
including the dosage, dose regimen, route of administration, therapeutic indication, and 
start/stop dates of use.


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5.4.4
Prohibited concomitant medications
Concomitant systemic antibacterials are prohibited during the study up to the TOC visit, 
with the following exceptions:
1. Vancomycin PO 125 mg or 250 mg q6h, fidaxomicin PO 200 mg q12h, or 
metronidazole IV or PO 500 mg q8h, may be used in both treatment groups for the 
treatment of C. difficile infections.
2. Metronidazole IV may also be used as adjunctive therapy in both treatment groups for 
coverage of anaerobic bacteria.
3. Nitrofurantoin may be used at any time during the study in both treatment groups as it 
does not achieve therapeutic blood levels. 
All NSAIDs are prohibited until 72 h after start of treatment, and only after early clinical 
response has been determined.
The administration of steroids (> 40 mg per day prednisolone, or equivalent), or 
immunosuppressant is prohibited between administration of first study drug and the TOC 
visit.
Chronic systemic therapy with calcineurin-inhibitors (e.g., tacrolimus, or ciclosporin), 
mycophenolate mofetil or mycophenolate sodium, azathioprine, or sirolimus, is 
prohibited from randomization up to the TOC visit.
The use of topical antibacterials on the primary lesion is not permitted from 
randomization through TOC.
The sponsor will not provide any concomitant medication.
5.4.5
Non-drug adjunctive therapy
Adjuvant surgical treatment is appropriate and necessary and is required to adequately 
treat wound infections and abscesses. On occasion a cellulitis will transform into an 
abscess which also requires proper surgical drainage of the abscess. At Screening, all 
patients should be evaluated, and a determination made whether or not more than one 
intra-operative surgical intervention should be planned.
Patients expected to require more than two surgical interventions in the operating room 
for the ABSSSI are excluded from the study. 
When indicated, the initial procedure should be performed before randomization, and 
subsequent procedures performed no later than 48 h after the start of treatment.
The reasons for the need for more than one planned intra-operative intervention must be 
timed and dated in the study source document at the time the decision is made that more 
than one intra-operative intervention is needed.
The following adjunctive therapies are permitted for the treatment of ABSSSI at any 
time:

debridement at the bedside

topical solutions, including antiseptic agents such as povidone-iodine (topical 
solutions should not contain any microbial agents)

local bedside wound care in accordance with hospital protocols


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5.4.6
Restrictions………….…….
Patients will be encouraged to continue their usual diet and level of activity, as dictated 
by their clinical condition. Activities that would impact clinical outcome should be 
avoided during the study period.
Participation in any other clinical study, including non-interventional studies and medical 
device investigations, is prohibited from 30 days prior to enrollment up to and including 
the LFU visit.
5.5
Health economics 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 vancomycin and aztreonam.
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 medications

Post-study drug procedures and interventions

AEs and any treatment required by these events

Re-admission rates

Outpatient healthcare encounters

Emergency Department visits

Antibacterial use

Surgical and non-surgical procedures, e.g.,
debridement, grafts, amputation, 
prostheses
5.6
Safety assessments
The investigator will evaluate patient safety by AE monitoring, physical examination, 
vital signs, and safety laboratory tests.
Safety assessments must be performed at intervals indicated in the schedule of 
assessments (see Table 4). More frequent assessments may be performed at the 
investigator’s discretion, if medically indicated.
5.6.1
Adverse event monitoring
The AE monitoring and collection period, and the reporting of serious AEs (SAEs), are 
described in Section 7.


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6
STUDY DRUGS
6.1
Dose and schedule
After randomization and during active treatment, patients will receive either ceftobiprole 
or vancomycin plus aztreonam, according to the schedule outlined in Table 8.
The requirement for aztreonam therapy will be reassessed at the 72-h study visit (Visit 4). 
Termination of aztreonam is permitted when all of the following criteria are met:

a Gram-positive pathogen has been isolated but no Gram-negative pathogen is 
present, and

the presence of Gram-negative organisms is unlikely based on the investigator’s 
assessment, and

Gram-negative coverage is clinically not required based on the investigator’s 
assessment
In cases where (blinded) aztreonam is discontinued after 72 h, re-administration of 
(blinded) aztreonam is permitted at any point during the study treatment period, at the 
discretion of the investigator, when there is confirmation or suspicion of a concomitant 
Gram-negative infection.
The dosing and schedule is to be adjusted based on five CLCR categories: > 100 mL/min; 
70–100 mL/min; 50–< 70 mL/min; 30–< 50 mL/min; and < 30 mL/min. The 
Cockcroft-Gault formula should be used to calculate the CLCR for each patient.
CLCR should be calculated for each patient on study Days 1, 2, 3, 5, and 8. 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 vancomycin and 
ceftobiprole are adjusted in accordance with Table 8.
6.2
Administration
All study drug will be administered IV. There is no switch to PO treatment in this study.
Hospitalization (in a hospital or equivalent medical confinement or clinical research unit)
of study participants is required for the 72 h after start of treatment, until early clinical 
response has been determined. 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. The 
admission of patients to medical confinement facilities is also permitted.
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.
On each treatment day, study-drug administration should occur no more than ± 2 hours 
from the scheduled time point.
The total daily volume of study-drug infusions is 1200 mL for study participants with 
CLCR ≥70 mL/min, 950 mL for patients with CLCR of 50 – < 70 mL/min, 700 mL for 
patients with CLCR of 30 to < 50 mL/min and 450 mL for patients with CLCR of < 30 
mL/min (see Table 8).


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Table 8
Dosing and dose adjustment for ceftobiprole and vancomycin/aztreonam based on CLCR
* Or 15 mg/kg vancomycin: The decision to use vancomycin at a fixed or weight-based dose is to be made by the investigator on the basis of the site’s standard of care, and needs to 
be communicated prior to randomization to the unblinded pharmacist or delegate. If VTT is performed, the vancomycin dose may be adjusted according to trough levels.
# Or 15 × CLCR (as determined by Cockcroft-Gault formula) as a total daily dose distributed q12h: The decision to use vancomycin at a fixed or CLCR-based dose is to be made by 
the investigator on the basis of the site’s standard of care, and needs to be communicated prior to randomization to the unblinded pharmacist or delegate. If VTT is performed, the 
vancomycin dose may be adjusted according to trough levels.
† After an initial dose of 1000 mg, all subsequent maintenance doses of aztreonam should be halved (i.e. 500 mg).
Ceftobiprole treatment group
Vancomycin plus aztreonam treatment group
Time (h)
Study drug
Dose (mg)
Volume (mL)
Infusion time (h) Study drug
Dose (mg)
Volume (mL)
Infusion time (h)
CLCR > 100 mL/min
0
Ceftobiprole
Placebo
500
NA
250
100
2
0.5
Vancomycin
Aztreonam
1000*
1000
250
100
2
0.5
8
Ceftobiprole
500
250
2
Placebo
NA
250
2
12
Placebo
Placebo
NA
NA
250
100
2
0.5
Vancomycin
Aztreonam
1000*
1000
250
100
2
0.5
16
Ceftobiprole
500
250
2
Placebo
NA
250
2
CLCR 70 to 100 mL/min
0
Ceftobiprole
Placebo
500
NA
250
100
2
0.5
Vancomycin
Aztreonam
750#
1000
250
100
2
0.5
8
Ceftobiprole
500
250
2
Placebo
NA
250
2
12
Placebo
NA
250
2
Vancomycin
750#
250
2
Placebo
NA
100
0.5
Aztreonam
1000
100
0.5
16
Ceftobiprole
500
250
2
Placebo
NA
250
2
CLCR 50 to < 70 mL/min
0
Ceftobiprole
Placebo
500
NA
250
100
2
0.5
Vancomycin
Aztreonam
1000#
1000
250
100
2
0.5
8
Ceftobiprole
500
250
2
Placebo
NA
250
2
12
Placebo
NA
100
0.5
Aztreonam
1000
100
0.5
16
Ceftobiprole
500
250
2
Placebo
NA
250
2
CLCR 30 to < 50 mL/min
0
Ceftobiprole
Placebo
500
NA
250
100
2
0.5
Vancomycin
Aztreonam
1000#
1000
250
100
2
0.5
12
Placebo
Ceftobiprole
NA
500
100
250
0.5
2
Aztreonam
Placebo
1000
NA
100
250
0.5
2
CLCR < 30 mL/min
0
Ceftobiprole
Placebo
250
NA
125
100
2
0.5
Vancomycin
Aztreonam
500#
1000†
125
100
2
0.5
12
Placebo
Ceftobiprole
NA
250
100
125
0.5
2
Aztreonam
Placebo
500†
NA
100
125
0.5
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6.2.1
Ceftobiprole………….…….
Ceftobiprole 500 mg is to be administered every 8 hours as a 2-hour IV infusion.

For patients with mild renal impairment (i.e., CLCR 50–80 mL/min), no dosage 
adjustment is necessary.

For patients with moderate renal impairment (CLCR 30–< 50 mL/min), the 
recommended dose of ceftobiprole is 500 mg q12h, as a 2-hour IV infusion (Table 8).

For patients with severe renal impairment (CLCR < 30 mL/min), the recommended 
dose of ceftobiprole is 250 mg q12h, as a 2-hour IV infusion (Table 8).
A patient who develops the need for hemodialysis must be discontinued from the study 
before hemodialysis commences (see Section 4.5). 
6.2.2
Vancomycin………….…….
6.2.2.1 Dose in patients with a CLCR > 100 mL/min
The IV vancomycin dose for adults with a CLCR > 100 mL/min is either fixed 1000 mg, 
or weight-based at 15 mg/kg every 12 h, administered as a 2-h IV infusion. The dosage 
regimen to be used for vancomycin at the study site must be agreed by the investigator 
and unblinded pharmacist (or delegate) prior to randomization. 
6.2.2.2 Dose in patients with a CLCR ≤ 100 mL/min
If dose adjustments are made based on CLCR values, the following recommendations 
apply (see Table 8):

CLCR 70–100 mL/min: vancomycin 750 mg  is to be administered as a 2-h IV infusion 
q12h (or a total daily dose of 15 × the CLCR in mL/min distributed q12h), from study 
Day 1 until EOT.

CLCr 30–< 70 mL/min: vancomycin 1000 mg, or 15 × the CLCR in mL/min, is to be 
administered as a 2-h IV infusion q24h, from study Day 1 until EOT.

CLCr < 30 mL/min: vancomycin 500 mg, or 15 × CLCR in mL/min, is to be 
administered as a 2-h IV infusion q24h, from study Day 1 until EOT.
A patient who develops the need for hemodialysis must be discontinued from the study 
before hemodialysis commences (see Section 4.5).
Dose adjustment in morbidly obese and hypermetabolic patients
If dictated by local standards of care, adjustments to the dose of vancomycin are 
permitted, for example in obese and hypermetabolic patients; adjustments to dosing in the 
morbidly obese (e.g., BMI > 35) are encouraged if consistent with local standards of care.
For doses that exceed 1.2 g of vancomycin (i.e., > 10 mg/min), care should be taken to
adjust (prolong) the infusion time appropriately, or to consider a change in the dosing 
interval. 
If adjustments to dosing for obese or hypermetabolic patients are standard at a site, 
the infusion rate and volume must be adjusted for all such patients at that site prior to first 
study drug administration, including those randomized to ceftobiprole who are receiving 
placebo-vancomycin.


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Every effort should be made to maintain the blind if changes in the vancomycin infusion 
duration (i.e., > 2-h infusion duration) or dosing schedule from twice daily to three times 
daily are implemented during the study (after administration of first study drug 
administration), e.g., based on a change in renal function or based on vancomycin trough 
levels.
Vancomycin trough level determination in all patients prior to the fourth 
vancomycin dose (central laboratory)
A vancomycin trough level for central laboratory assessment is to be obtained 
approximately 30 min before administration of the fourth dose of vancomycin (i.e., on 
Day 2 for patients who receive vancomycin on a q12h schedule, and on Day 4 for
patients who receive vancomycin on a q24h schedule). Because of the expected delay 
between sampling and the availability of results, the central laboratory results will not be 
communicated to the study site.
Vancomycin trough level determination using local laboratories
When locally available, the vancomycin dosage may be adjusted by the unblinded 
pharmacist or delegate based on vancomycin trough testing (VTT), to maintain 
steady-state trough levels of 10–15 mg/L; adjustments are to be managed according to 
local standards at each site.
In study sites which use vancomycin trough level monitoring to guide vancomycin dosing 
using a local laboratory, a blood sample for local laboratory testing of the vancomycin 
trough level should be obtained in addition to the central laboratory blood sample before 
administration of the fourth dose of vancomycin. Additional local laboratory testing of 
vancomycin trough levels should be obtained according to institutional practices at the 
respective study site.
If the local practice at a site is to take blood samples for VTT, for blinding purposes these
must be drawn from all patients at the site, regardless of study-drug treatment. The 
unblinded local laboratory technician must only provide the results of this testing to the 
unblinded pharmacist or delegate for patients randomized to vancomycin. If the patient is 
randomized to ceftobiprole, the local laboratory unblinded technician must discard 
samples and not report a vancomycin trough level. 
Local VTT results will be entered in the CRF by the unblinded pharmacist or delegate, 
together with the vancomycin dose. 
Guidelines for the dosing of vancomycin are available in Moellering 1981.
For suggested monitoring guidelines regarding the monitoring of vancomycin serum 
concentrations, see Rybak 2009.


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6.2.3
Aztreonam………….…….
Aztreonam 1000 mg is to be administered as a 0.5-hour IV infusion q12h. If CLCR is
< 30 mL/min (i.e., severe renal impairment), the aztreonam dosage regimen may be 
adjusted by the unblinded pharmacist or delegate (see Table 8).
The requirement for aztreonam therapy will be reassessed at the 72-h study visit 
(see Section 6.1).
Prolonged serum levels of aztreonam may occur in patients with transient or persistent 
renal impairment. Accordingly, for patients with estimated CLCR ≥ 10 and < 30 mL/min, 
after an initial usual dose of 1000 mg, the maintenance dose of aztreonam should be 
reduced to 500 mg.
A patient who develops the need for hemodialysis must be discontinued from the study 
before hemodialysis commences (see Section 4.5).
6.3
Randomization
Eligible 
patients
will 
be 
randomized 
in 
a 
1:1 
ratio 
to 
ceftobiprole 
or 
vancomycin/aztreonam, based on a computer-generated randomization schedule. 
The unblinded pharmacist or delegate will contact the IWRS to obtain the study treatment 
assignment, and dispense blinded therapy accordingly. The IWRS will associate that 
patient with the next available treatment in the appropriate stratum on randomization. 
Randomization will be stratified at baseline, using block randomization, by:

study site

type of ABSSSI (cellulitis/erysipelas, major cutaneous abscess, or wound infection) 
Patients with a major cutaneous abscess must comprise ≤ 30% of the ITT population.
Detailed randomization instructions are provided in the IWRS manual.
6.4
Blinding
The unblinded pharmacist or delegate will provide blinded and properly labeled study 
medication only to investigational staff.
Only the unblinded pharmacist or delegate at the site, will have access to treatment codes
via IWRS.
Investigators, other site staff, sponsor employees, and others involved in the conduct of
the study (with the exception of the above) will remain blinded to the treatment codes 
until the database has been locked for final analysis.
6.5
Methods for ensuring blinding
This study will be double-blind with regard to the administration of study drugs.
The following personnel may have access to details of the treatment allocation:

those performing PK analyses

those setting up the randomization scheme and IWRS


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
the unblinded pharmacist or delegate responsible for blinded study-drug adjustments, 
preparation, and documentation

the unblinded local lab technician responsible for VTT, reporting 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

the unblinded statistician, if required for safety reasons, or producing outputs for the 
blinded interim analysis, or for the DSMB.
These personnel must not disclose any details of the randomization scheme or the 
treatment code of study drugs.
6.6
Unblinding methods
Individual treatment codes for each randomized patient will be available to investigators 
from the IWRS. The treatment code should only be broken in medical emergencies. It is 
advisable to contact the medical monitor prior to breaking the blind. 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 allocation of the investigational product(s) 
for the patient must not be communicated further, unless required for the treatment and/or 
surveillance of the patient. Adverse events and SAEs must be reported as outlined in 
Section 7.
The sponsor/designee might break the blind via IWRS for regulatory reporting purposes.
This must be fully documented, and only the minimum number of staff necessary are to 
have access to the unblinded information.
Detailed handling instructions are provided in the IWRS Manual.
Systematic unblinding of the clinical database will occur after database lock as described 
in the Data Management Plan and SAP.
6.7
Drug accountability and compliance check
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.
6.8
Packaging and labeling
Study drugs will be packed and labeled in accordance with local regulations and the 
Annex 13 Good Manufacturing Practice rules, including but not limited to the identity of 


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the sponsor, protocol number, drug identification, storage conditions, content of study 
drug, and expiry date. 
Information on drug shipment, temperature logger and acknowledgement of receipt form 
to be completed by the receiver, will also be included.
6.9
Shipping and storage conditions
Study drug for IV administration will be presented as follows. Storage conditions are 
provided in the Pharmacy manual.

Ceftobiprole medocaril: vials of sterile lyophilized ceftobiprole medocaril for 
intravenous use after reconstitution containing the equivalent of 500 mg ceftobiprole.

Vancomycin: Vials of sterile vancomycin hydrochloride powder for intravenous use 
after reconstitution containing 500 mg, 750 mg, or 1000 mg of vancomycin; or as pre-
mixed intravenous solution (e.g., GALAXY or ADD-Vantage).

Aztreonam: Vials of sterile aztreonam powder for intravenous use after reconstitution 
containing 500 mg or 1000 mg of aztreonam; or as pre-mixed intravenous solution 
(GALAXY). 
All vials/containers of study drug for IV administration must be shipped to the study 
centers, protected from light, 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.
6.10
Drug supply………….…….
A Drug Dispensing Log must be kept up to date, and must contain the following 
information:

Site ID, subject number 

Investigator 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 unblinded Monitor. 
6.11
Drug disposal………….…….
Any remaining drug, including empty vials, may only be returned to the study supply 
packaging provider, or destroyed at the site after drug accountability by the unblinded 
Monitor and at the request of the sponsor. If drug is destroyed at the study site, the 
investigator or delegate 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 and before first study-drug administration.
7.1.2
Adverse event…………………….
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment.
7.1.2.1 Treatment-emergent adverse event
A treatment-emergent adverse event is any AE which occurs from the start of first dosing 
up to and including the scheduled LFU visit.
7.1.3
Serious adverse event 
A serious adverse event (SAE) is any AE that meets one or more of the following criteria:

results in death

is life-threatening

requires inpatient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor is appropriate, such as important medical events that may not be 
immediately life-threatening or result in death or 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: 

Death is considered an outcome of an AE. Whenever possible the underlying cause of 
death must be reported as the AE.

A life-threatening SAE is any adverse experience that places the patient at risk of 
death at the time of its occurrence, i.e., it does not include a reaction that, had it 
occurred in a more severe form, might have caused death.

Inpatient 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:


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
Routine treatment or monitoring of the ABSSSI, not associated with any deterioration 
in condition (e.g., hospitalizations related to study procedures, such as study-drug 
administration, PK assessments, etc.).

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
ABSSSI 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 by the 
sponsor to be related to the study treatment and for which the nature or severity is not 
consistent with the applicable reference safety information.
7.2
Evaluation of adverse events
7.2.1
Severity………….…….
The intensity of an AE will be graded on the following three-point scale:

Mild: discomfort but no disruption of normal daily activity

Moderate: discomfort sufficient to reduce or affect daily activity

Severe: inability to work or to perform normal daily activities
7.2.2
Relationship………….…….
The relationship of AEs to the study treatment must be assessed by the investigator as
one of the following:

not related

unlikely 

possible 

probable
Appendix 2 provides criteria for relationship assessments.
According to the sponsor’s criteria for causality assessment, a causal relationship will be
suspected for all AEs reported with a relationship of ‘possible’ or ‘probable’ and those 
with missing or unknown relationships.
7.3
Handling of safety information and collection periods 
7.3.1
Handling of safety data during the pre-treatment period
Any relevant change in, or worsening of, a patient’s condition occurring after consent, 
but prior to the start of first study-drug administration, will be recorded in the CRF as 
pre-dose medical history (see Section 5.4.1). 


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If a change in, or worsening of, a patient’s condition is considered to be serious 
(i.e., meets one or more of the criteria for an SAE in Section 7.1.3), this information must 
also be reported to the sponsor’s safety representative, using the same forms and 
procedures as for an SAE (see Section 7.3.2.2).
7.3.2
Handling of safety data during the treatment period and up to the last 
scheduled follow-up………….…….
From the start of first dosing up to and including the LFU visit, any change in, or 
worsening of, the patient’s condition must be collected and reported in the CRF as an AE 
(see Section 7.3.2.1). Serious adverse events must be additionally reported and recorded 
on SAE report forms (see Section 7.3.2.2).
7.3.2.1 Adverse event management
The 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. 
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 terms ‘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 ABSSSI.
2. Duration (start and end dates).
3. Severity grade (three-point scale, see Section 7.2.1). 
4. Relationship to study treatment (see Section 7.2.2 and Appendix 2).
5. Action(s) taken with regards to the study treatment or additional treatments given for 
the event.
6. Whether the event is an SAE (see Section 7.1.3). 
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.


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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 LFU 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 led to a patient withdrawal from the study

an SAE
These cases will be followed-up on the CRF unless otherwise agreed with the sponsor.
7.3.2.2 Serious adverse event recording and reporting 
In addition to being reported and followed-up as AEs (see Section 7.3.2.1), SAEs must be 
reported to the sponsor’s safety representative listed below, within 24 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: 
PrimeVigilance Limited
The Surrey Research Park
26–28 Frederick Sanger Road
Guildford, Surrey GU2 7YD, United Kingdom
Email:
Basilea@primevigilance.com
eFax (UK):
+44 (0)800 0669192
eFax (US):
+1 866 902 7489
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 
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7.3.3
Handling of post-study safety data
Any AE occurring after the LFU visit which is considered to be both:

serious (i.e., meets one or more of the criteria listed for SAEs, see Section 7.1.3), and 

related to the study drug (see Section 7.2.2 and Appendix 2) 
should be reported to the sponsor’s designated safety representative using the same forms 
and procedures as for an SAE (see Section 7.3.2.2).
Events occurring after the LFU visit should not be reported in the CRF.
7.3.4
Reporting of SAEs to regulatory authorities
7.3.4.1 Sponsor’s responsibilities
The sponsor’s safety representative will ensure the reporting of SUSARs and any 
expeditable SAEs to regulatory Authorities in accordance with applicable law.
In the event of a SUSAR, the sponsor will ensure that investigators active in 
Basilea-sponsored interventional studies with ceftobiprole are informed.
Expectedness of SAEs for regulatory expedited reporting will be assessed by the sponsor 
against the applicable reference safety information (RSI). 
For ceftobiprole, the ‘Undesirable effects’ subsection of Section 5 (‘Summary of data and 
guidance for investigators’) in the Investigator’s Brochure will serve as the RSI. 
For vancomycin, 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 UK Summary of Product 
Characteristics (decentralized procedure UK/H/5402/001-02/DC) for submission to non-
US regulatory authorities.
For aztreonam, 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 UK Summary of Product 
Characteristics of Azactam 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.


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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 first dose of study drug. If results of the pregnancy test are positive (see 
Section 5.3.6), the patient will not be enrolled in the study.
Women of childbearing potential must agree to use one of the following methods of 
contraception during the study:

Female sterilization (bilateral tubal occlusion or oophorectomy, or hysterectomy) or 
male partner vasectomy.

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.
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 study is designed to determine whether ceftobiprole is non-inferior to vancomycin 
plus aztreonam for the outcome measure of early clinical response at 48–72 h after start 
of treatment, defined as a ≥ 20% reduction from baseline in the area (longest 
length × perpendicular width of erythema, edema, or induration) of the primary lesion, 
survival for ≥ 72 h from the time of administration of the first dose of study drug, and no 
use of concomitant systemic antibacterial treatments
or topical antibacterial
administration on the primary lesion.
A sample size of 674 patients (337 per group) will provide at least 90% 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: Pvancomycin/aztrenonam minus Pceftobiprole ≥ 0.10
versus 
HA: Pvancomycin/aztrenonam minus Pceftobiprole < 0.10.
Early clinical response rates of an at least 20% reduction in lesion area size (primary 
endpoint) and clinical cure rates at the TOC visit (main secondary endpoint) from recent 
Phase 3 studies in ABSSSI are summarized in Table 9. These clinical study data support 
an estimate of early clinical response rates of > 80%. The Phase 3 ABSSSI studies with 
ceftaroline (CANVAS 1 and CANVAS 2) and ESTABLISH 1 (tedizolid) showed lower 
response rates; however the CANVAS1/CANVAS2 studies were not prospectively 
designed for an assessment of a primary endpoint of lesion size reduction between 48 and 
72 h after start of treatment, and the result reported for ESTABLISH 1 included the 
absence of fever in addition to lesion size reduction.


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Table 9
Early clinical response rates and clinical cure rates at the TOC visit in 
previous ABSSSI studies
Compound/
publication
Dosing regimen
% Success
Early response
(ITT)
Clinical cure at TOC
Ceftobiprole
Noel 2008a
N=828
Ceftobiprole 500 mg q8h vs
vancomycin 1000 mg q12 h plus 
ceftazidime 1000 mg q 8 h
Not evaluated
82 vs 81 (ITT)
91 vs 90 (CE)
Ceftaroline
Corey 2010
N=1378
Ceftaroline 600 mg q12 h vs vancomycin 
1000 mg q12 h 
plus aztreonam 1000 mg q12 h
60 vs 56
86 vs 86 (ITT)
92 vs 93 (CE)
Dalbavancin
Boucher 2014
Xydalba EPAR
18 Dec 2014
N=1312
Dalbavancin 1000 mg on Day 1 and 500 
mg on Day 1 vs
Vancomycin 1000 mg or 15mg/kg q12 h, 
option to switch to PO linezolid 600 mg 
q12 h
89 vs 88
86 vs 86 (ITT)*
91 vs 92 (CE)*
Oritavancin
Corey 2014
Corey 2015
N=1959
Oritavancin single dose of 
1200 mg vs vancomycin 1000 mg or 
15mg/kg q12 h
SOLO I:
87 vs 83
SOLO II:
86 vs 85
SOLO I :
80 vs 80 (ITT)
91 vs 89 (CE)
SOLO II:
83 vs 80 (ITT)
93 vs 95 (CE)
Tedizolid
Prokocimer 2013
Moran 2014
N=1333
Tedizolid 200 mg q24 h for 6 days vs
linezolid 600 mg q12 h for 10 days (PO)
Tedizolid 200 mg q24 h for 6 days vs
linezolid 600 mg q12 h for 10 days (IV 
with optional PO switch)
ESTABLISH I:
78 vs 76**
ESTABLISH II:
92 vs 90
ESTABLISH I :
86 vs 86 (ITT)
95 vs 95 (CE)
ESTABLISH II:
88 vs 88 (ITT)
92 vs 96 (CE)
* Based on clinical outcome at EOT.
** Includes reduction in lesion size by at least 20% plus the absence of fever.
ITT=Intent-to-Treat; TOC=test-of-cure; CE=Clinically Evaluable; EOT=end-of-treatment.
The sample size estimate is therefore based on:

a point estimate for early clinical response of 80% in each treatment group in the ITT 
population. 

one-sided alpha level of 0.025. 

non-inferiority margin of 10 percentage points for the between-group difference of the 
primary endpoint.
Based on these assumptions, randomization of 337 patients per treatment group 
(total 674 patients) would provide > 90% power to demonstrate the non-inferiority of 
ceftobiprole compared to vancomycin plus aztreonam. Patients with cutaneous abscesses 
will comprise ≤ 30% of those randomized. 
Two separate SAPs will be provided for submission to the FDA and EMA, where the 
SAP prepared for the FDA will use the protocol-defined primary and secondary 
objectives, and the SAP prepared for the EMA will use the main secondary objective as 
the primary objective.


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For the EMA primary endpoint, the point estimates of clinical cure at the TOC visit in the 
co-primary ITT and CE populations are 80% and 90%, respectively, which are supported 
by previous ABSSSI Phase 3 studies (see table above).
With randomization of 337 patients per treatment group, the statistical power at a 
one-sided alpha level of 0.025 is 90% (ITT population) and 97% (CE population) for the 
key secondary endpoint (i.e., the primary endpoint for the EMA), assuming that 85% of 
the ITT population is in the CE population using the same non-inferiority margin. 
8.2
Analysis populations
The following analysis populations are defined for this study:
Intent-to-Treat population (ITT): all randomized patients. Patients will be analyzed 
according to the study medication assigned at randomization. 
Microbiological Intent-to-Treat population (mITT): the subset of patients in the ITT 
population who have had causative pathogens confirmed from skin lesion or blood 
cultures. 
Clinically Evaluable population (CE): the subset of patients in the ITT population who 
have complied with important aspects of the study, e.g., no major protocol deviations, a 
completed response outcome assessment, and no concomitant systemic antibacterial 
treatment or topical antibacterial applied to the primary lesion. 
Microbiologically Evaluable population (ME): the subset of patients in the mITT 
population who are also in the CE population. 
Safety population: all randomized patients who received at least one dose of study drug. 
Patients in the safety population will be analyzed according to the first study drug 
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.
8.3
General 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 for ceftobiprole versus 
vancomycin plus aztreonam. Exploratory analyses may also be performed. 
For between-group comparisons, a two-sided 95% CI for the difference in outcome rates 
between the two treatment groups will be derived, unless otherwise specified. 
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
Disposition in the study, overview of analysis populations, protocol deviations, 
discontinuations from the study drug, and withdrawal from the study will be summarized 
by treatment group.


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Demographics and baseline characteristics will be summarized by treatment group for all 
analysis populations.
8.5
Prior and concomitant medications
Prior and concomitant medications will be summarized by treatment group. Additional 
summaries will be provided for prior and concomitant antibacterial use.
8.6
Surgical procedures
Planned procedures and interventions used for infection management will be summarized 
by treatment group, and by time period of procedure (prior to randomization or during 
treatment) for the ITT and CE populations. 
8.7
Study endpoints
The primary and the main secondary endpoints are region-specific. The primary and main 
secondary endpoints listed below are for submission to the US FDA. In the EU, the main 
secondary endpoint listed below will be the primary endpoint, and the primary endpoint 
listed below will be the main secondary endpoint. Two separate SAPs will be prepared 
for submission to the FDA and the EMA to reflect the different primary and main 
secondary endpoints in each region.
8.7.1
Analysis of the primary endpoint
The primary analysis will be based on the ITT population.
The study is designed to determine whether ceftobiprole is non-inferior to vancomycin 
plus aztreonam for the primary endpoint of early clinical response based on percentage 
reduction from baseline in lesion size at 48–72 h after first study-drug administration. 
Early clinical response 48–72 h after start of treatment will be based on the patients 
meeting all of the following criteria: 
1. ≥ 20% reduction from baseline in the area (longest length × perpendicular width of 
erythema, edema, or induration) of the primary lesion. 
2. Survival for ≥ 72 h from the time of administration of the first dose of study drug.
3. No use of any concomitant systemic antibacterial treatment or topical antibacterial
administration on the primary lesion.
4. No additional unplanned surgical procedure for the ABSSSI after start of therapy 
(other than debridement at bedside or local bedside wound care), with the exception 
of cellulitis where there is a conversion into an abscess within 48 h of study treatment 
initiation, or, for post-surgery patients, when an extension of the original incision is 
indicated.
If multiple lesions measurements are taken within 48–72 hours after the first dose of 
study drug, the latest lesion measurement will be used.
Standardized measurement of the lesion area (i.e., erythema, edema, or induration, 
whichever is largest) is to be performed with a flexible plastic ruler or tape measure, by 
multiplying the longest length of the lesion by the widest width perpendicular to that 
length. In addition, a measurement of the maximum width of erythema or 
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recorded. If abscess, the measurement should be taken from the end of the fluctuance 
before drainage or from the edge of the drainage site after drainage.
A digital photograph will be obtained at Screening, at the early clinical response 
assessment (48–72 h after first treatment), and at the EOT and TOC visit, for each patient 
(primary ABSSSI lesion), and will be used for documentation purposes and as source 
data. Digital photography will not be used for the measurement of the ABSSSI lesion size 
area; the determination of the ABSSSI lesion size area will be solely based on the ruler 
measurements. 
The numbers and percentages of responders and non-responders will be determined in 
each treatment group. Patients with missing data relevant for the assessment of the 
primary endpoint, or who are lost to follow-up, will be considered non-responders for the 
primary analysis. The observed difference in percentage of responders at 48–72 h 
(ceftobiprole group minus the vancomycin plus aztreonam group) will be determined, and 
a 95% CI for the observed difference will be computed, with adjustment by geographical 
region (North America and Europe), and type of ABSSSI. Cochran-Mantel-Haenszel 
weights will be used for the stratum weights 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 95% CI for the difference in response rates 
(ceftobiprole minus vancomycin plus aztreonam) in the ITT population is greater than 
−10%, the non-inferiority of ceftobiprole to vancomycin plus aztreonam will be 
concluded.
If non-inferiority is declared at the one-sided significance level of 0.025, then superiority 
will be tested.
The primary efficacy analysis is based on the difference in the early clinical response 
rates between the two treatment groups. Analyses using risk ratio and odds ratio will also 
be performed.
In addition, the following sensitivity analyses will be performed for the primary outcome:

An unadjusted analysis, i.e., the 95% CI will not be adjusted for the stratification 
factors of geographic region (North America and Europe) and ABSSSI type

Patients with missing outcome values in both treatment groups will be excluded.
Subgroup analyses will be conducted for the primary efficacy outcome in the 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 ABSSSI type (wound, cellulitis, major abscess), 
underlying medical conditions (diabetes mellitus, illicit drug use), baseline fever status, 
antibacterial medications prior to study drug, concomitant antibacterial medication, use of 
anti-inflammatory medications, and performance of surgical interventions.
8.7.2
Analysis of secondary endpoints
The main secondary endpoint is the investigator-assessed clinical success at the TOC 
visit according to the following definition: complete or nearly complete resolution of 
baseline signs and symptoms of the primary infection, such that no further antibacterial 
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A patient meeting this definition cannot be classified as a clinical success if any of the 
following criteria are met:
1. Death from any cause prior to TOC
2. Additional antibacterial therapy received for treatment of the primary lesion 
3. Initiation of a non-study antibacterial treatment of another infection, unless the 
antibacterial agent lacks efficacy in the treatment of ABSSSI
4. Requirement for an unplanned surgical procedure for the ABSSSI after start of 
therapy, (other than debridement at bedside or local bedside wound care), with the 
exception of cellulitis where there is a conversion into an abscess within 48 h of study 
treatment initiation, or, for post-surgery patients, when an extension of the original 
incision is indicated.
5. Indeterminate assessment at TOC for any reason, including but not limited to:
(a) missing TOC visit
(b) lost to follow-up
(c) patient withdrew consent
(d) missing data in relation to signs and symptoms of the ABSSSI
(e) discontinuation from the study due to the need for hemodialysis
This main secondary endpoint will be specified in a separate SAP as the primary endpoint 
for the EMA, with non-inferiority assessed by the two-sided 95% CI of the 
between-group difference (ceftobiprole minus vancomycin plus aztreonam) using a 10% 
non-inferiority margin in the co-primary ITT and CE populations.
In addition, the following sensitivity analyses will be performed for the main secondary
endpoint:

An unadjusted analysis, i.e., the 95% CI will not be adjusted for the stratification 
factors of geographic region (North America and Europe) and ABSSSI type

Patients with missing outcome values in both treatment groups will be excluded.
Subgroup analyses will be conducted for the primary efficacy outcome in the 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 ABSSSI type (wound, cellulitis, major abscess), 
underlying medical conditions (diabetes mellitus, illicit drug use), baseline fever status, 
antibacterial medications prior to study drug, concomitant antibacterial medication, use of 
anti-inflammatory medications, and performance of surgical interventions.
In addition, the following secondary endpoints will be analysed using the same statistical
methods as for the primary endpoint:
1. Early clinical response based on percentage reduction in lesion size at 48–72 h after 
first treatment (CE population).
2. Clinical response defined as ≥ 80% decrease in lesion area at the EOT visit, and 
≥90% decrease in lesion area at the TOC visit (ITT population), with improvement of 
local signs of the infection in patients surviving up to the respective visit with no use 
of any concomitant systemic antibacterial treatment
or topical antibacterial
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(other than debridement at bedside or local bedside wound care), with the exception 
of cellulitis where there is a conversion into an abscess within 48 h of study treatment 
initiation, or, for post-surgery patients, when an extension of the original incision is 
indicated.
3. Sustained reduction in lesion size, defined as ≥ 20% decrease in lesion area 48–72 h 
after start of treatment (primary endpoint), that is sustained at the EOT and TOC 
visits (ITT population).
4. Investigator-assessed clinical success evaluated at 48–72 h after first treatment and
the EOT visit, and sustained clinical success at the LFU visit (ITT and CE 
populations).
Clinical success at the EOT visit is defined by the same criteria as for the main 
secondary endpoint, with an indeterminate assessment to include a missing EOT visit. 
Sustained clinical success requires that all criteria listed for the main secondary 
endpoint are met and there were no new signs or symptoms of the ABSSSI between 
the TOC and LFU visits.
5. ACM through Day 28 (±2 days) (ITT population).
A time to event analysis using the Kaplan-Meier method will also be performed for 
ACM.
6. Microbiological response at Day 3, Day 5, and at the EOT, TOC and LFU visits in 
the mITT and ME populations, based on post-therapy cultures obtained from the 
primary infection site at the respective time points, using the following definitions:
(a) Eradication: No growth of the baseline pathogen(s), based on post-therapy 
cultures obtained from the primary infection site at the respective time points.
(b) Presumed eradication: No post-therapy culture due to lack of culturable material, 
accompanied by investigator-assessed clinical success. 
(c) Persistence: Evidence of continued growth of the baseline pathogen
(d) Presumed persistence: No post-therapy culture due to lack of culturable material, 
accompanied by the absence of investigator-assessed clinical success. 
(e) Superinfection: Emergence of a new pathogen(s) at the primary site of infection, 
accompanied by the absence of investigator-assessed clinical success. 
(f) Relapse or recurrence: Pre-therapy pathogen isolated between the EOT and TOC 
visits, or between the TOC and LFU visits, after a pathogen response of 
‘eradication’ or ‘presumed eradication’ at the EOT or TOC visits.
In addition, the absolute and percentage change in lesion area size will be analysed, and 
various percentage reductions from baseline (e.g., ≥10%, ≥20%, ≥30% at 48–72 h after 
start of treatment; ≥50%, ≥80%, ≥90%, ≥95% at TOC) will be summarized by 
treatment group in the mITT and CE populations.
Furthermore, an analysis will be performed to assess the concordance between early 
clinical response (primary endpoint) and clinical response at the EOT and TOC visits 
(Other secondary endpoint 2).
Patients’ self-assessment pain severity will be measured using a VAS (0–100 mm) and 
Wong-Baker FACES® Pain Rating Scale, with the change from baseline calculated and 


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summarized at various time points. Differences between treatment groups will be 
determined using an ANCOVA, with treatment group as a factor, and type of ABSSSI 
and baseline pain levels as covariates. Pain levels will be assessed using a 6-point 
numeric rating scale (NRS). The pain scores will be summarized by treatment group in 
the ITT and CE populations at each of the following visits: Screening, 48–72 h after start 
of treatments, EOT, and TOC.
Resource utilization (such as length of hospital stay, duration and dosage of IV
administration, concomitant medication, diagnostic tests performed, surgery performed, 
and minor non-surgical procedures) will be summarized by treatment group.
Additional analyses may be conducted at the sponsor’s discretion; the details of such 
analyses will be described in the SAPs.
8.8
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.
Summary tables of AEs will be provided (see Section 7.1.1).
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. AEs will be summarized separately for those events
starting prior to the TOC visit, and for those occurring from the TOC visit to the LFU 
visit. 
Non-treatment-emergent AEs 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.
8.9
Pharmacokinetics
Plasma concentration data will be analyzed at each time point and will be presented as 
individual concentrations and with descriptive statistics (mean, standard deviation [SD], 
coefficient of variation [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 on the PK parameters of demographic and baseline 
factors such as age, weight, sex, race, and renal function 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.


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8.10
Blinded interim analysis
One blinded interim analysis for sample size re-estimation will be conducted based solely 
on pooled information across the two treatment arms when early clinical response data 
are available for 60% of the patients planned to be randomized (approximately 404 
patients). No statistical adjustment is required. The interim analysis will involve a sample 
size re-estimation to assess whether the initial sample size estimate is adequate for 
evaluating the primary endpoint of the study. 
For safety monitoring, the DSMB will be utilised periodically throughout the study.
Blinded interim safety assessments will be performed twice in each year after enrollment 
of the first patient. 
Details will be provided in the DSMB Charter. 
Investigators, sponsor employees, and others who are involved in the conduct and the 
analyses of the study (with the exception of the unblinded pharmacist or delegate) will 
remain blinded to the treatment codes and interim analysis results until all monitoring 
decisions have been made, and the database has been locked for final analysis.


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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 Conference on 
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. 
Should the investigator wish to assign the study records to another party, or move them to 
another location, the sponsor must be notified in advance.


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If the investigator cannot guarantee 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 (blinded and unblinded) 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 (blinded and unblinded) must be written after each monitoring visit, 
per site and per visit. These monitoring reports (blinded and unblinded) must be reviewed 
and approved by the respective supervisors (blinded and unblinded) of the Monitors.
Monitoring instructions are provided in the Clinical Monitoring Plan.
9.3
Audits and inspections
The study may be audited at any time, with appropriate notification, by qualified 
personnel from the sponsor or its designees, to assess compliance with the protocol, GCP, 
and regulatory requirements. These audits may also be conducted for quality assurance 
purposes, to ensure that complete and accurate data are submitted, and that all AEs are 
being identified and reported in compliance with the protocol and applicable regulations. 
The study may also be inspected by regulatory authority inspectors, after appropriate 
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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 multicenter studies only in their entirety, and not as individual center data. 
Authorship is to be determined by mutual agreement.
The results of this study will be made available, e.g., submitted for publication and/or 
presentation at scientific meetings, in a timely manner. All manuscripts or abstracts must
be submitted to the sponsor prior to publication or presentation, allowing the sponsor to 
protect proprietary information, and to provide comments based on information from 
other studies that may not yet be available to an investigator. 


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10
ETHICS AND GOOD CLINICAL PRACTICE
10.1
Good Clinical Practice
The study must be conducted in compliance with this protocol, ICH 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 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 post-treatment phase 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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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 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-008 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 31 March 2016 was submitted to the US FDA for special 
protocol assessment (SPA).

Protocol Version 2.0 dated 13 October 2016 was submitted to the UK Medicines & 
Healthcare products Regulatory Agency (MHRA) for scientific advice.

Protocol Version 3.0 dated 15 February 2017 was submitted to the US FDA for SPA
amendment.

Protocol Version 4.0 dated 12 April 2017 was used for regulatory and IEC/IRB 
approval for commencement of this clinical study.
Since commencement of the study, the following protocol amendments and updated 
versions have been issued:

Protocol Amendment 1 produced Protocol Version 5.0 dated 31 May 2017.

Protocol Amendment 2 produced Protocol Version 6.0 dated 11 July 2018 (current 
version).


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12
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comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the 
treatment of patients with complicated skin and skin-structure infections. Clin Infect 
Dis. 2008; 46: 647–55.
(Noel 2008b) Noel GJ, Strauss RS, Amsler K, et al. Results of a double-blind, 
randomized trial of ceftobiprole treatment of complicated skin and skin structure 
infections caused by gram-positive bacteria. Antimicrob Agents Chemother. 2008; 
52: 37–44.
(Pollack 2015) Pollack CV Jr, Amin A, Ford WT Jr, et al. Acute Bacterial Skin and Skin 
Structure Infections (ABSSSI): Practice Guidelines for Management and Care 
Transitions in the Emergency Department and Hospital. J Emerg Med. 2015; 48:
508–19
(Prokocimer 2013) Prokocimer P, De Anda C, Fang E, et al. Tedizolid phosphate vs
linezolid for treatment of acute bacterial skin and skin structure infections: the 
ESTABLISH-1 randomized trial. JAMA. 2013; 309: 559–569.
(Queenan 2005) Queenan AM and Bush K. Johnson & Johnson Pharmaceutical Res. and 
Dev. L.L.C. Ceftobiprole: Effect on AmpC β-Lactamase Induction and Resistance 
Frequency in Gram-Negative Bacteria. ICAAC 2005; Poster Abstract C1-55.
(Queenan 2007) Queenan AM, Shang W, Kania M, et al. Interactions of ceftobiprole with 
beta-lactamases from molecular classes A to D. Antimicrob Agents Chemother 
2007; 51: 3089–95.
(Queenan 2010) Queenan AM, Shang W, Bush K, et al. Differential selection of single-
step AmpC or efflux mutants of Pseudomonas aeruginosa by using cefepime,
ceftazidime, or ceftobiprole. Antimicrob Agents Chemother 2010; 54: 4092–7. 
(Rouse 2007) Rouse MS, Steckelberg JM, and Patel R. In vitro activity of ceftobiprole, 
daptomycin, linezolid, and vancomycin against methicillin-resistant staphylococci 
associated with endocarditis and bone and joint infection. Diagn Microbiol Infect 
Dis 2007; 58: 363–5. 
(Rybak 2009) Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring 
of vancomycin in adult patients: a consensus review of the American Society of 
Health-System Pharmacists, the Infectious Diseases Society of America, and the 
Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009; 
66: 82–98.
(Xydalba EPAR) EMA Summary of the European Assessment Report for Xydalba, 
available 
at 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/ 
human/medicines/002840/human_med_001848.jsp&mid=WC0b01ac058001d124.


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13
APPENDICES
Appendix 1
List of antibiotics meeting the criterion of a half-life ≤ 12 hours
Half-life ≤ 12 hours
Half-life > 12 hours
Single dose permitted within > 3 days 
before randomization
Not permitted within 14 days 
before first infusion of study drug
Amikacin
Delafloxacin
Azithromycin
Amoxicillin
Dicloxacillin
Dalbavancin
Amoxicillin/Clavulanic acid
Doripenem
Doxycycline
Ampicillin
Ertapenem
Linezolid
Ampicillin/Sulbactam
Erythromycin
Minocycline
Cefaclor
Fosfomycin
Oritavancin
Cefadroxil
Gemifloxacin
Tigecycline
Cefamandole
Gentamicin
Teicoplanin
Cefazolin
Imipenem/cilastatin
Cefdinir
Levofloxacine
Cefditoren pivoxil
Loracarbef
Cefepime
Meropenem
Cefixime
Meropenem/vaborbactam
Cefoperazone
Metronidazole
Cefotaxime
Mezlocillin
Cefotetan
Moxifloxacin
Cefoxitin
Nafcillin
Cefpodoxime proxetil
Ofloxacin
Cefprozil
Oxacillin
Ceftaroline fosamil
Penicillin G
Ceftazidime
Penicillin V
Ceftazidime/avibactam
Piperacillin
Ceftibuten
Piperacillin/tazobactam
Ceftizoxime
Polymixin B
Ceftolozane/tazobactam
Quinupristin/dalfopristin
Cetriaxone
Rifampin
Cefuroxime
Tedizolid
Cephalexin
Telavancin
Chloramphenicol
Telithromycin
Ciprofloxacin
Tetracycline
Ciprofloxacin extended release
Ticarcillin
Clarithromycin
Ticarcillin/clavulanate
Clarithromycin XL
Tobramycin
Clindamycin
Trimethoprim
Colistimethate sodium
Trimethoprim-sulfamethoxazole
Daptomycin
Vancomycin
Note: PO vancomycin, fidaxomicin and nitrofurantoin are considered as non-systemic antibiotics and may be used 
within the 7 days prior to first study-drug infusion.


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Appendix 2
Criteria for evaluating relationship between adverse events and study 
treatment
NOT RELATED
This category is applicable to an AE that meets the following three criteria:
1. It does not follow a reasonable temporal sequence from administration of the 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.
Note: If an event neither follows a plausible temporal relationship nor a known pattern of 
response but there is no alternative explanation for the event, this will usually be judged a 
possibly related event. 


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PROBABLE 
This category is applicable to an AE that is considered, with a high degree of certainty, to 
be related to the 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.


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Appendix 3
Investigator’s protocol signature page
BASILEA 
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE
Protocol 
BPR-CS-008 Version 6.0
Basilea Product:
Ceftobiprole medocaril
Protocol Title:
A randomized, double-blind, multicenter study to establish the safety 
and efficacy of ceftobiprole medocaril compared with vancomycin plus 
aztreonam in the treatment of acute bacterial skin and skin structure 
infections
Basilea Pharmaceutica International Ltd
Approval Date:
11 July 2018
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 Conference on Harmonisation (ICH) guidelines for good clinical 
practice (GCP), including the EU Clinical Trial Directive 2001/20/EC and specifically, obtain 
approval from the 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

SAP_001.pdf: 
Confidential 
Basilea Pharmaceutica International Ltd. 
Protocol BPR-CS-008 
A randomized, double-blind, multicenter study to establish the safety and 
efficacy of ceftobiprole medocaril compared with vancomycin plus aztreonam 
in the treatment of acute bacterial skin and skin structure infections 
25JUL2019 
Statistical Analysis Plan 
Version 3.0 
Prepared by: 
PPD on Behalf of 
Basilea Pharmaceutica International Ltd. 
Grenzacherstrasse 487 
CH-4058 Basel/Switzerland  
NCT03137173 


Basilea Pharmaceutica International Ltd 
Statistical Analysis Plan, Version 3.0 
Protocol BPR-CS-008 
Date Issued: 25JUL2019 
II
TABLE OF CONTENTS 
1.
INTRODUCTION ............................................................................................................ 7
2.
OBJECTIVES ................................................................................................................... 7
2.1. PRIMARY OBJECTIVE ........................................................................................................... 7 
2.2. SECONDARY OBJECTIVES .................................................................................................... 7 
2.2.1. 
Main secondary objective ........................................................................................ 7 
2.2.2. 
Other secondary objectives ..................................................................................... 7 
3.
INVESTIGATIONAL PLAN .......................................................................................... 8
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 8 
3.2. STUDY ENDPOINTS ............................................................................................................. 9 
3.2.1. 
Primary Endpoint .................................................................................................... 9 
3.2.2. 
Main Secondary Endpoint ..................................................................................... 11 
3.2.3. 
Other Secondary Endpoints ................................................................................... 12 
3.3. TREATMENTS .................................................................................................................... 14 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ............................................................................... 14 
3.4.1. 
Ceftobiprole ........................................................................................................... 15 
3.4.2. 
Vancomycin ........................................................................................................... 15 
3.4.3. 
Aztreonam .............................................................................................................. 17 
4.
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 18
4.1. SAMPLE SIZE .................................................................................................................... 18 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 19 
4.3. ANALYSIS POPULATIONS .................................................................................................. 20 
4.3.1. 
Intent-to-Treat (ITT) Population ........................................................................... 20 
4.3.2. 
Microbiological Intent-to-Treat (mITT) Population ............................................. 20 
4.3.3. 
Clinically Evaluable (CE) Population ................................................................... 20 
4.3.4. 
Microbiologically Evaluable (ME) Population ..................................................... 21 
4.3.5. 
Safety Population ................................................................................................... 21 
4.3.6. 
Pharmacokinetic (PK) Population ........................................................................ 21 
4.4. OTHER IMPORTANT CONSIDERATIONS .............................................................................. 21 
4.4.1. 
Definition of Baseline ............................................................................................ 21 
4.4.2. 
Study Day Calculation and Visit Windows ............................................................ 21 
4.4.3. 
Missing and Partial Data ...................................................................................... 22 
4.4.4. 
Pre-specified Subgroups ........................................................................................ 22 
4.4.5. 
Duration (e.g., for Adverse Events) ....................................................................... 23 
4.4.6. 
Coding Dictionaries .............................................................................................. 23 
5.
SUBJECT DISPOSITION ............................................................................................. 24
5.1. DISPOSITION ..................................................................................................................... 24 
5.2. PROTOCOL DEVIATIONS ................................................................................................... 25 
6.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 25
6.1. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................................................... 25 
6.2. FEMALE REPRODUCTIVE SYSTEM ..................................................................................... 26 


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6.3. MEDICAL/SURGICAL HISTORY ......................................................................................... 26 
6.3.1. 
General Medical/Surgical History ........................................................................ 26 
6.3.2. 
Disease-Specific History ........................................................................................ 26 
6.4. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 27 
7.
TREATMENTS AND MEDICATIONS ....................................................................... 27
7.1. PRIOR AND CONCOMITANT MEDICATIONS/NON-DRUG PROCEDURES .............................. 27 
7.1.1. 
Prior and Concomitant Medications ..................................................................... 27 
7.1.2. 
Prior and Concomitant Non-Drug Procedures ..................................................... 28 
7.2. STUDY TREATMENTS ........................................................................................................ 28 
7.2.1. 
Extent of Exposure ................................................................................................. 28 
8.
EFFICACY ANALYSIS................................................................................................. 29
8.1. PRIMARY EFFICACY ANALYSIS ......................................................................................... 29 
8.1.1. 
Main Analysis ........................................................................................................ 29 
8.1.2. 
Sensitivity Analyses................................................................................................ 30 
8.2. SECONDARY EFFICACY ANALYSIS .................................................................................... 31 
8.2.1. 
Main Analysis ........................................................................................................ 31 
8.2.2. 
Sensitivity Analyses................................................................................................ 32 
8.3. OTHER SECONDARY EFFICACY ANALYSIS ........................................................................ 33 
8.3.1. 
Clinical Response Defined as ≥80% Decrease in Lesion Area at the EOT Visit, 
≥90% Decrease in Lesion Area at the TOC visit, and Clinical Success Achieved as per 
Secondary Endpoint Criteria Satisfied at EOT and TOC ...................................................... 33 
8.3.2. 
Sustained Reduction in Lesion Size at the EOT and TOC Visits ........................... 33 
8.3.3. 
Investigator-assessed clinical success evaluated at 48–72 h after first treatment 
and the EOT visit, and sustained clinical success at the LFU visit. ...................................... 33 
8.3.4. 
Microbiology ......................................................................................................... 34 
8.3.4.1. 
Microbiological Responses, Eradication Rate and Time to Eradication .............. 34 
8.3.4.2. 
Microbiological Evaluations and Pathogen Identification ................................... 34 
8.3.5. 
All-Cause Mortality (ACM) ................................................................................... 35 
8.3.6. 
Patient-Reported Pain ........................................................................................... 36 
8.3.7. 
Health Economic Outcome Measures ................................................................... 36 
8.3.8. 
Lesion Area ............................................................................................................ 36 
8.3.9. 
Infection Site Assessment ....................................................................................... 37 
9.
SAFETY ANALYSIS ..................................................................................................... 38
9.1. ADVERSE EVENTS ............................................................................................................. 38 
9.1.1. 
Incidence of Adverse Events .................................................................................. 38 
9.1.2. 
Relationship of Adverse Events to Study Drug ...................................................... 39 
9.1.3. 
Severity of Adverse Event ...................................................................................... 39 
9.1.4. 
Adverse Events Leading to Treatment Discontinuation ........................................ 39 
9.1.5. 
Outcome of Adverse Event ..................................................................................... 39 
9.2. DEATH .............................................................................................................................. 39 
9.3. CLINICAL LABORATORY EVALUATIONS ........................................................................... 40 
9.3.1. 
Hematology ............................................................................................................ 41 
9.3.2. 
Blood Chemistry .................................................................................................... 41 
9.3.3. 
Urine (dipstick Analysis) ....................................................................................... 42 


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9.3.4. 
Coagulation ........................................................................................................... 42 
9.3.5. 
Reticulocytes, haptoglobin and Coombs test ......................................................... 42 
9.3.6. 
Creatinine clearance ............................................................................................. 42 
9.3.7. 
Vancomycin Trough Level ..................................................................................... 42 
9.3.8. 
Pregnancy Test ...................................................................................................... 43 
9.4. VITAL SIGNS MEASUREMENTS ......................................................................................... 43 
9.5. PHYSICAL EXAMINATION ................................................................................................. 44 
10. 
PHARMACOKINETICS ............................................................................................... 44 
11. 
INTERIM ANALYSIS ................................................................................................... 44 
12. 
CHANGES IN THE PLANNED ANALYSIS FROM PROTOCOL ......................... 45 
13. 
REFERENCES ................................................................................................................ 46 
14. 
APPENDICES ................................................................................................................. 47 
14.1. 
IMPUTATION ALGORITHM FOR PARTIAL AND MISSING DATES AND TIME ..................... 47 
14.2. 
LIST OF CLINICAL CENTRAL LABORATORY TESTS ........................................................ 49 
 
 


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List of Abbreviations 
ABSSSI 
Acute Bacterial Skin and Skin Structure Infection 
ACM 
All-Cause Mortality 
AE 
Adverse Event 
AIC 
Akaike’s Information Criterion 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
AP 
Alkaline Phosphatase 
AR(1) 
Auto-Regressive 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
CE 
Clinically Evaluable 
CSH 
Heterogeneous Compound Symmetry 
CI 
Confidence Interval 
CLCR 
Creatinine Clearance 
CLSI 
Clinical and Laboratory Standards Institute 
CMH 
Cochran-Mantel-Haenszel 
CS 
Compound Symmetry 
CV 
Coefficient of Variation 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EOT 
End-Of-Treatment 
EU 
European Union 
EUCAST 
European Committee on Antimicrobial Susceptibility Testing 
FDA 
United States Food and Drug Administration 
GGT 
Gamma-Glutamyl Transferase 
h 
Hour(s) 
ICH 
International Conference on Harmonization 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web Response System 
K-M 
Kaplan-Meier 
LFT 
Liver Function Test 
LFU 
Last Follow-Up (visit) 
ME 
Microbiologically Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
mITT 
Microbiological Intent-To-Treat 
MMRM 
Mixed-Model Repeated Measures 
MRSA 
Methicillin-Resistant Staphylococcus aureus 
MSSA 
Methicillin-Susceptible Staphylococcus aureus 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PT 
Preferred term 


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QD 
Once Daily 
QW 
Once Weekly 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
T > MIC 
Time Drug Concentration is above the MIC 
US 
United States 
VTT 
Vancomycin Trough Testing 
WHO 
World Health Organization 
WBC 
White Blood Cell 
 


Basilea Pharmaceutica International Ltd 
 
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Date Issued: 25JUL2019 
 
7
1. Introduction 
BPR-CS-008 is a phase 3 randomized, double-blind, active-controlled, parallel-group, 
multicenter study in adult hospitalized patients with ABSSSIs to establish the safety and 
efficacy of ceftobiprole medocaril compared with vancomycin plus aztreonam in the 
treatment of acute bacterial skin and skin structure infections. 
 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analysis of clinical data collected in the study. This plan should be read in 
conjunction with the Final Study Protocol Version 6.0 (Amendment 2.0) – 11 July 2018, 
and the electronic case report forms (eCRFs) Version 9.0 – 09 May 2019. All analyses will 
be conducted using SAS® Version 9.3 or higher. 
2. Objectives 
2.1. 
Primary objective 
To demonstrate the non-inferiority of ceftobiprole to vancomycin plus aztreonam in 
patients with ABSSSIs with respect to early clinical response based on percentage 
reduction in lesion size at 48–72 h after first treatment in the ITT population. 
2.2. 
Secondary objectives 
2.2.1. 
Main secondary objective 
To demonstrate the non-inferiority of ceftobiprole to vancomycin plus aztreonam in 
patients with ABSSSIs, with respect to investigator-assessed clinical success at the test-of-
cure (TOC) visit 15–22 days after randomization, in the co-primary ITT and Clinically 
Evaluable (CE) populations. 
 
Note: The primary and the main secondary objectives will be region-specific. The above 
primary and main secondary objectives are for submission to the United States Food and 
Drug Administration (US FDA); in the European Union (EU), the above main secondary 
objective will be the primary objective, and the primary objective listed above will be the 
main secondary objective. This SAP will be used for submission to the FDA and the 
European Medicines Agency (EMA). 
2.2.2. 
Other secondary objectives 
To compare ceftobiprole with vancomycin plus aztreonam with respect to: 
• Early clinical response based on percentage reduction in lesion size at 48–72 h after 
first treatment (CE population). 
• Clinical response based on percentage reduction in lesion size at the end-of-treatment 
(EOT) and TOC visits (ITT and CE populations). 


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• Sustained reduction in lesion size at the EOT and TOC visits (ITT and CE 
populations). 
• Investigator-assessed clinical success evaluated at 48–72 h after first treatment and the 
EOT visit, and sustained clinical success at the last follow-up (LFU) visit (ITT and CE 
populations). 
• All-cause mortality through Day 28 (ITT and CE populations). 
• Microbiological response at Day 3, Day 5, and the EOT, TOC and LFU visits (mITT 
and ME populations). 
• Change in patient-reported pain from baseline at all visits except the Day 28 visit (ITT 
and CE populations). 
• Health economic outcome measures (ITT and CE populations). 
• Safety: incidence, type, severity and relationship to study medication of adverse events 
and changes in laboratory tests (hematology and blood chemistry, including 
haptoglobin, urinalysis, Coombs test) (Safety population). 
• To assess the pharmacokinetics (PK) of ceftobiprole (PK population). 
3. Investigational Plan 
3.1. 
Overall Study Design and Plan 
This is a randomized, double-blind, active-controlled, parallel-group, multicenter study in 
adult hospitalized patients to establish the safety and efficacy of ceftobiprole medocaril 
compared with vancomycin plus aztreonam in the treatment of ABSSSIs. Randomization 
will be stratified by study site and type of ABSSSI (with major cutaneous abscess 
comprising ≤30% of the ITT population). 
 
Approximately 674 patients will be randomized in a 1:1 ratio to ceftobiprole or the 
comparator regimen. It is anticipated that the study will be performed at approximately 
80 centers in North America and Europe. 


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Table 1   Summary of treatment and follow-up schedule
 
 
The study comprises three phases: 
1. Pre-treatment: Screening and baseline, duration up to 24 h. 
2. Active treatment: Randomization to at least 5 days and up to 10 days, of study drug 
administration with IV ceftobiprole, or IV vancomycin plus aztreonam. Study 
treatment may be extended up to 14 days if in the investigator’s opinion this is 
required, and the extension is approved by the sponsor’s medical monitor. 
3. Post-treatment: 
• an EOT visit within 24 h after last treatment 
• a TOC visit 15–22 days after randomization 
• an LFU visit 28–35 days after last treatment 
 
The total duration of the study for each patient is approximately 5–7 weeks. 
 
In addition, at 28 days after randomization, survival status (Alive; Dead; Lost to Follow-
up) is to be verified for evaluation of all-cause mortality (ACM). Survival status (by 
telephone or visit) must be obtained at Day 28 (±2 days). 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
The study is designed to determine whether ceftobiprole is non-inferior to vancomycin plus 
aztreonam for the primary endpoint of early clinical response based on percentage reduction 
from baseline in lesion size at 48–72 h after first study-drug administration. 
 
Early clinical response 48–72 h after start of treatment based on the patient meeting all of 
the following criteria: 


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1. ≥20% reduction from baseline in the area (length × width of erythema, edema, or 
induration) of the primary lesion. Derived surface area as calculated in the eCRF 
will be used for the analysis. 
2. Survival for ≥72 h from the time of administration of the first dose of study drug. 
3. No use of concomitant systemic antibacterial treatments, or topical antibacterial 
administration on the primary lesion before or on the latest lesion measurement done 
within 48–72 h after the first dose of study drug. 
4. No additional unplanned surgical procedure for the ABSSSI after start of therapy 
and before or on the latest lesion measurement done within 48–72 h after the first 
dose of study drug (other than debridement at bedside or local bedside wound care), 
with the exception of cellulitis where there is a conversion into an abscess within 
48 h of study treatment initiation, or, for post-surgery patients, when an extension of 
the original incision is indicated. 
 
Patients with missing data relevant for the assessment of the primary endpoint will be 
considered as non-responders for the primary analysis. 
 
Actual elapsed time (rather than calendar day) will be used to measure the time from first 
dose of study drug to the 48–72 h early-response assessment. In case assessment time is 
missing, time will be imputed to 12:00. 
 
The primary endpoint is to be assessed in the ITT population. 
 
Standardized measurement of the lesion area (i.e., erythema, edema, or induration, 
whichever is largest) is to be performed with a flexible plastic ruler or tape measure, by 
multiplying the longest length of the lesion by the widest width perpendicular to that 
length. 
 
In addition, a measurement of the maximum width of erythema or edema/induration from 
the edge of the wound (surgical or traumatic) or abscess will be recorded. If abscess, the 
measurement should be taken from the end of the fluctuance before drainage or from the 
edge of the drainage site after drainage. 
 
Measurements are to be performed at Screening (within the 6 h prior to first dose of study 
drug); twice on Days 2, 3, and 4; and once on Day 8, EOT, and the TOC and LFU visits. 
 
On days when two measurements are obtained, the measurements are to be taken at least 
8 h apart. 
 
A digital photograph (primary ABSSSI lesion) will be obtained at Screening, at the early 
clinical response assessment (48–72 h after first treatment), and at the EOT and TOC 
visits, for each patient, and will be used for documentation purposes and as source data. 
Digital photography will not be used for the measurement of the ABSSSI lesion size area; 


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the determination of the ABSSSI lesion size area will be solely based on the ruler 
measurements. 
 
This will be the main secondary endpoint for EMA submission. 
3.2.2. 
Main Secondary Endpoint 
Investigator-assessed clinical success at the TOC visit 15–22 days after randomization. 
The TOC visit should be performed at least 5 days after EOT. 
 
Clinical success will be assessed by the investigator using a four-point scale relative to the 
baseline assessment: cured, improved, stable, or worsened. In case of worsened (e.g., 
bacteremia, osteomyelitis, amputation), signs and symptoms need to be documented as 
AEs. 
 
Clinical success is defined as complete (cured) or nearly complete (improved) resolution of 
baseline signs and symptoms of the primary infection, such that no further antibacterial 
treatment is needed. 
 
A patient meeting this definition cannot be classified as a clinical success if any of the 
following criteria are met: 
1. Death from any cause prior to TOC. 
2. Additional antibacterial therapy received for treatment of the primary lesion prior to 
TOC. 
3. Initiation of non-study antibacterial treatment of another infection, unless the 
antibacterial agent lacks efficacy in the treatment of ABSSSI prior to TOC. 
4. Requirement for an unplanned surgical procedure for the ABSSSI after start of 
therapy and prior to TOC, (other than debridement at bedside or local bedside 
wound care), with the exception of cellulitis where there is a conversion into an 
abscess within 48 h of study treatment initiation, or, for post-surgery patients, when 
an extension of the original incision is indicated. 
5. Indeterminate assessment at TOC for any reason, including but not limited to: 
a. missing TOC visit 
b. lost to follow-up 
c. patient withdrew consent 
d. missing data in relation to signs and symptoms of the ABSSSI 
e. discontinuation from the study due to the need for hemodialysis 
 
The main secondary endpoint is to be assessed in the ITT and CE populations. 
 
This will be the primary endpoint for EMA submission. 


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3.2.3. 
Other Secondary Endpoints 
1. Early clinical response based on percentage reduction in lesion size at 48–72 h after 
first treatment in the CE population, using the same definition for response as for the 
primary endpoint. 
2. Clinical response (see Section 3.2.1) defined as ≥80% decrease in lesion area at the 
EOT visit, and ≥90% decrease in lesion area at the TOC visit (ITT and CE 
populations), with improvement of local signs of the infection, i.e., achieving 
clinical success (as discussed in Section 3.2.2) at the respective visit. 
3. Sustained reduction in lesion size at the EOT and TOC visits (ITT and CE 
populations). 
Sustained reduction in lesion size is defined as ≥ 20% decrease in lesion area 48–
72 h after start of treatment (primary endpoint) that is sustained at the EOT and 
TOC visits. Reduction in lesion size is sustained at a specific time point if criteria 2, 
3 and 4 detailed in Section 3.2.1 are also satisfied for that specific time point. 
4. Investigator-assessed clinical success evaluated at 48–72 h after first treatment and 
the EOT visit, and sustained clinical success at the LFU visit (ITT and CE 
populations). 
Clinical success at the 48–72 h after first treatment and EOT visit are defined by the 
same criteria as for the main secondary endpoint, with an indeterminate assessment 
to include a missing visit at the 48–72 h after first treatment and EOT visit. 
Clinical success at LFU visit is defined by the same criteria as for the main 
secondary endpoint, with an indeterminate assessment to include a missing LFU 
visit. 
Sustained clinical success requires that all criteria listed for the main secondary 
endpoint are met at TOC and LFU visits. 
5. ACM at Day 28 (ITT and CE populations) 
Assessment of survival status at Day 28 
6. Microbiological response as assessed by the investigator at Day 3, Day 5, and the 
EOT, TOC and LFU visits (mITT and ME populations). 
Eradication: No growth of the baseline pathogen(s) based on post-therapy cultures 
obtained from the primary infection site at the respective time points. 
Presumed eradication: No post-therapy culture due to lack of culturable material, 
accompanied by investigator-assessed clinical success. 
Persistence: Evidence of continued growth of the baseline pathogen. 
Presumed persistence: No post-therapy culture due to lack of culturable material, 
accompanied by the absence of investigator-assessed clinical success. 
Superinfection: Emergence of a new pathogen(s) at the primary site of infection, 
accompanied by the absence of an investigator-assessed clinical success. 
Relapse or recurrence: Pre-therapy pathogen isolated between the EOT and TOC 
visits, or between the TOC and LFU visits, after a pathogen response of 
‘eradication’ or ‘presumed eradication’ at the EOT or TOC visits. 


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Non-evaluable:  No pathogen isolated at baseline (either no sample obtained for 
culture or culture had no growth at baseline). 
7. Change from baseline in patient-reported pain (ITT and CE populations) 
Time points: all visits, (with exception of Day 28) 
Patient-reported pain, assessed at baseline and throughout the study, using a visual 
analogue scale (VAS) with a 100 mm line, on which the 0 point indicates ‘no pain’ 
and the 100 mm point indicates ‘worst pain ever’, and a Wong-Baker FACES® Pain 
Rating Scale. 
 
 
 
8. Health economic outcome measures (ITT and CE populations) 
Time point: From start of study medication until the LFU visit 
Resource requirements and health economic data will be derived from study-specific 
data, or collected ancillary to study conduct, to perform health economics analyses. 
These analyses will aim to enable economic comparisons of ceftobiprole with 
vancomycin and aztreonam. 
9. Safety (Safety Population) 
Time point: First dose of study drug until LFU 
Adverse events, laboratory tests (including hematology, blood chemistry, and 
haptoglobin), Coomb’s test, vital signs, physical examination, and concomitant 
medications. 
10. Pharmacokinetics (PK Population) 
Time points: Day 4 
Plasma levels of ceftobiprole. 
Sparse PK sampling 


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o Day 4: predose, 2 h (end of infusion), 4 to 6 h 
Rich PK sampling 
o Day 4: predose, 2 h (end of infusion), 3 h, 4 h, 6 h and 8 h 
3.3. 
Treatments 
After randomization and during active treatment, patients will receive ceftobiprole and 
placebo or vancomycin and aztreonam according to the schedule outlined in Table 2. The 
two intravenous treatment regimens to be administered are: 
• Ceftobiprole 500 mg q8h (with dose adjustment for renal impairment). 
• Vancomycin 1000 mg (or 15 mg/kg) q12h plus aztreonam 1000 mg q12h (both with 
dose adjustment for renal impairment). Vancomycin dose adjustments for obese and 
hypermetabolic patients are according to local standards of care. 
 
Table 2   Study-drug administration 
 
* Or 15 mg/kg vancomycin: the decision to use vancomycin at a fixed or weight-based dose is to be made by the 
investigator on the basis of the site’s standard of care, and needs to be communicated prior to randomization to the 
unblinded pharmacist or delegate. If VTT is performed, the vancomycin dose may be adjusted according to trough 
levels. 
** The requirement for aztreonam therapy will be reassessed at the 72-h study visit. 
NA, not applicable. 
 
On each treatment day, study-drug administration should be no more than ± 2 h from the 
scheduled time point. 
3.4. 
Dose Adjustment/Modifications 
The vancomycin dose may be adjusted by the unblinded pharmacist or delegate in 
accordance with the local standard of care. 
 
The total daily volume of study-drug infusions is 1200 mL for study participants with 
CLCR ≥70 mL/min, 950 mL for patients with CLCR of 50 – <70 mL/min, 700 mL for 
patients with CLCR of 30 to <50 mL/min and 450 mL for patients with CLCR of 
<30 mL/min (see Table 3). 


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Table 3   Dosing and dose adjustment for ceftobiprole and vancomycin/aztreonam based on CLCR
 
3.4.1. 
Ceftobiprole 
Ceftobiprole 500 mg is to be administered every 8 h as a 2-h IV infusion. 
• For patients with mild renal impairment (i.e., CLCR 50 – 80 mL/min), no dosage 
adjustment is necessary. 
• For patients with moderate renal impairment (CLCR 30 – <50 mL/min), the 
recommended dose of ceftobiprole is 500 mg q12h, as a 2-h IV infusion. 
• For patients with severe renal impairment (CLCR <30 mL/min), the recommended 
dose of ceftobiprole is 250 mg q12h, as a 2-h IV infusion. 
 
A patient who develops the need for hemodialysis must be discontinued from the study 
before hemodialysis commences. 
3.4.2. 
Vancomycin 
The IV vancomycin dose for adults with a CLCR >100 mL/min is either fixed 1000 mg, or 
weight-based at 15 mg/kg every 12 h, administered as a 2-h IV infusion. The dosage 
regimen to be used for vancomycin at the study site must be agreed by the investigator and 
unblinded pharmacist (or delegate) prior to randomization. 
 
If dose adjustments are made based on CLCR values, the following recommendations 
apply: 


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• CLCR 70–100 mL/min: vancomycin 750 mg is to be administered as a 2-h IV 
infusion q12h (or a total daily dose of 15 × the CLCR in mL/min distributed q12h), 
from study Day 1 until EOT. 
• CLCR 30 – <70 mL/min: vancomycin 1000 mg, or 15 × the CLCR in mL/min, is to be 
administered as a 2-h IV infusion q24h, from study Day 1 until EOT. 
• CLCR <30 mL/min: vancomycin 500 mg, or 15 × CLCR in mL/min, is to be 
administered as a 2-h IV infusion q24h, from study Day 1 until EOT. 
 
A patient who develops the need for hemodialysis must be discontinued from the study 
before hemodialysis commences. 
 
Dose adjustment in morbidly obese and hypermetabolic patients 
 
If dictated by local standards of care, adjustments to the dose of vancomycin are permitted, 
for example in obese and hypermetabolic patients; adjustments to dosing in the morbidly 
obese (e.g., BMI >35) are encouraged if consistent with local standards of care. 
 
For doses that exceed 1.2 g of vancomycin (i.e., >10 mg/min), care should be taken to 
adjust (prolong) the infusion time appropriately, or to consider a change in the dosing 
interval. 
 
If adjustments to dosing for obese or hypermetabolic patients are standard at a site, the 
infusion rate and volume must be adjusted for all such patients at that site prior to first 
study drug administration, including those randomized to ceftobiprole who are receiving 
placebo-vancomycin. 
 
Every effort should be made to maintain the blind if changes in the vancomycin infusion 
duration (i.e., >2-h infusion duration) or dosing schedule from twice daily to three times 
daily that are implemented during the study (after administration of first study drug 
administration), e.g., based on a change in renal function or based on vancomycin trough 
levels. 
 
Vancomycin trough level determination in all patients prior to the fourth vancomycin 
dose (central laboratory) 
 
A vancomycin trough level for central laboratory assessment is to be obtained 
approximately 30 min before administration of the fourth dose of vancomycin (i.e., on 
Day 2 for patients who receive vancomycin on a q12h schedule, and on Day 4 for patients 
who receive vancomycin on a q24h schedule). The central laboratory results will not be 
communicated to the study site. 
 
 


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Vancomycin trough level determination using local laboratories 
 
When locally available, the vancomycin dosage may be adjusted by the unblinded 
pharmacist or delegate based on vancomycin trough testing (VTT), to maintain steady-state 
trough levels of 10–15 mg/L; adjustments are to be managed according to local standards 
at each site. 
 
In study sites which use vancomycin trough level monitoring to guide vancomycin dosing 
using a local laboratory, a blood sample for local laboratory testing of the vancomycin 
trough level should be obtained in addition to the central laboratory blood sample before 
administration of the fourth dose of vancomycin. Additional local laboratory testing of 
vancomycin trough levels should be obtained according to institutional practices at the 
respective study site. 
 
If the local practice at a site is to take blood samples for VTT, for blinding purposes these 
must be drawn from all patients at the site, regardless of study-drug treatment. The 
unblinded local laboratory technician must only provide the results of this testing to the 
unblinded pharmacist or delegate for patients randomized to vancomycin. If the patient is 
randomized to ceftobiprole, the local laboratory unblinded technician must discard samples 
and not report a vancomycin trough level. 
 
Local VTT results will be entered in the unblinded eCRF by the unblinded pharmacist or 
delegate, together with the vancomycin dose. 
3.4.3. 
Aztreonam 
Aztreonam 1000 mg is to be administered as a 0.5-h IV infusion q12h. If CLCR is 
<30 mL/min (i.e., severe renal impairment), the aztreonam dosage regimen may be 
adjusted by the unblinded pharmacist or delegate. 
 
The requirement for aztreonam therapy will be reassessed at the 72-h study visit. 
 
Prolonged serum levels of aztreonam may occur in patients with transient or persistent 
renal impairment. Accordingly, for patients with estimated CLCR ≥10 and <30 mL/min, 
after an initial usual dose of 1000 mg, the maintenance dose of aztreonam should be 
reduced to 500 mg. 
 
A patient who develops the need for hemodialysis must be discontinued from the study 
before hemodialysis commences. 
 
 


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4. General Statistical Considerations 
Continuous data will be described using descriptive statistics (i.e., n, mean, standard 
deviation (SD), median, minimum, and maximum). Categorical data will be described 
using the patient count and percentage in each category. Non-zero percentages will be 
rounded to one decimal place, except 100% will be displayed without any decimal places. 
For the summary statistics of all numerical variables unless otherwise specified, minimum 
and maximum will be displayed to the same level of precision as reported up to a 
maximum of 3 decimal places. Mean and median will be displayed to one level of 
precision greater than the data collected up to a maximum of 3 decimal places. Standard 
deviation / standard error will be displayed to two levels of precision greater than the data 
collected up to a maximum of 3 decimal places. 
 
All comparisons will be for ceftobiprole versus vancomycin plus aztreonam. For between-
group comparisons, a two-sided 95% CI for the difference in outcome rates between the 
two treatment groups will be derived, unless otherwise specified. A two-sided test will be 
used at a Type I error rate of 0.05 for comparison between the ceftobiprole group and the 
vancomycin plus aztreonam group. All other statistical analyses will be performed using a 
two-sided hypothesis test at the overall 5% level of significance. No adjustment for Type I 
error will be made for multiple comparisons. 
 
P-values will be rounded to four decimal places. If a p-value is less than 0.0001 it will be 
reported as “<0.0001.” If a p-value is greater than 0.9999 it will be reported as “>0.9999.” 
Data will be displayed in all listings sorted by treatment group. 
 
When count data are presented, the percentage will be suppressed when the count is zero in 
order to draw attention to the non-zero counts. A row denoted “Missing” will be included 
in count tabulations where specified on the shells to account for dropouts and missing 
values. The denominator for all percentages will be the number of patients in that treatment 
within the population of interest, unless otherwise specified. 
4.1. 
Sample Size 
The study is designed to determine whether ceftobiprole is non-inferior to vancomycin 
plus aztreonam for the outcome measure of early clinical response at 48–72 h after start of 
treatment, defined as 
1. a ≥20% reduction from baseline in the area (longest length × perpendicular width of 
erythema, edema, or induration) of the primary lesion, 
2. survival for ≥72 h from the time of administration of the first dose of study drug,  
3. no use of concomitant systemic antibacterial treatment or topical antibacterial 
administration on the primary lesion, and 
4. no additional unplanned surgical procedure for the ABSSSI after start of therapy 
(other than debridement at bedside or local bedside wound care), with the exception 
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treatment initiation, or, for post-surgery patients, when an extension of the original 
incision is indicated. 
 
A sample size of 674 patients (337 per group) will provide at least 90% 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: πvancomycin/aztrenonam – πceftobiprole ≥ 0.10 versus 
HA: πvancomycin/aztrenonam – πceftobiprole < 0.10. 
 
Early clinical response rates of an at least 20% reduction in lesion area size (primary 
endpoint) and clinical cure rates at the TOC visit (main secondary endpoint) from recent 
Phase 3 studies in ABSSSI are summarized in tabular form in protocol Section 8.1. These 
clinical study data support an estimate of early clinical response rates of >80%. 
 
The sample size estimate is therefore based on: 
• a point estimate for early clinical response of 80% in each treatment group in the 
ITT and CE population. 
• one-sided alpha level of 0.025. 
• non-inferiority margin of 10 percentage points for the between-group difference of 
the primary endpoint. 
 
Based on these assumptions, randomization of 337 patients per treatment group (total 674 
patients) would provide >90% power to demonstrate the non-inferiority of ceftobiprole 
compared to vancomycin plus aztreonam. Patients with cutaneous abscesses will comprise 
≤30% of those randomized. 
 
With randomization of 337 patients per treatment group, the statistical power at a one-
sided alpha level of 0.025 is 90% (ITT population) and 97% (CE population) for the key 
secondary endpoint, assuming that 85% of the ITT population is in the CE population 
using the same non-inferiority margin. 
4.2. 
Randomization, Stratification, and Blinding 
Eligible 
patients 
will 
be 
randomized 
in 
a 
1:1 
ratio 
to 
ceftobiprole 
or 
vancomycin/aztreonam, based on a computer-generated randomization schedule. The 
unblinded pharmacist or delegate will contact the IWRS to obtain the study treatment 
assignment, and dispense blinded therapy accordingly. The IWRS will associate that 
patient with the next available treatment in the appropriate stratum on randomization. 
 
Randomization will be stratified at baseline, using block randomization, by: 
• Study site 


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• Type of ABSSSI (cellulitis/erysipelas, major cutaneous abscess, or wound 
infection). Actual values (rather than IWRS strata values) will be used in all efficacy 
analysis. 
 
Patients with a major cutaneous abscess must comprise ≤30% of the ITT population. 
 
Detailed randomization instructions are provided in the IWRS manual. 
 
The unblinded pharmacist or delegate will provide blinded and properly labeled study 
medication only to investigational staff. Only the unblinded pharmacist or delegate at the 
site, will have access to treatment codes via IWRS. Investigators, other site staff, sponsor 
employees, and others involved in the conduct of the study (with the exception of the 
above) will remain blinded to the treatment codes until the database has been locked for 
final analysis. 
 
Individual treatment codes for each randomized patient will be available to investigators 
from the IWRS. The treatment code should only be broken in medical emergencies. It is 
advisable to contact the medical monitor prior to breaking the blind. The investigator will 
record the reason for unblinding in the patient’s records/source documents. 
4.3. 
Analysis Populations 
4.3.1. 
Intent-to-Treat (ITT) Population 
The ITT population will include all randomized patients. All patients in the ITT population 
will be analyzed according to the treatment they were randomized to receive and not 
according to what they actually received, if different.  
4.3.2. 
Microbiological Intent-to-Treat (mITT) Population 
The mITT population will be the subset of patients in the ITT population who have had 
causative (infecting) pathogens identified by the central microbiology laboratory from skin 
lesion and blood cultures (local laboratory identification results will only be used if no 
causative (infecting) pathogen is identified by the central laboratory). 
 
Patients with no pathogen isolated at baseline (microbiologically non-evaluable) will be 
excluded from the mITT population.  
4.3.3. 
Clinically Evaluable (CE) Population 
The CE population will be the subset of patients in the ITT population who have complied 
with important aspects of the study until TOC visit, i.e., with no major protocol deviations 
(e.g., a completed response outcome assessment, and no concomitant systemic antibacterial 
treatment or topical antibacterial applied to the primary lesion). Major protocol deviations 
will be identified prior to the database lock and study unblinding.  


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4.3.4. 
Microbiologically Evaluable (ME) Population 
The ME population will be the subset of patients in the mITT population who are also in 
the CE population. Analysis at each timepoint will be performed on patients with available 
response at that timepoint (excluding those with a microbiological response of ‘Not 
Evaluable’ or missing). 
4.3.5. 
Safety Population 
The Safety population will include all randomized patients who received at least one dose 
of study drug. Patients in the safety population will be analyzed according to the first study 
drug actually received. 
4.3.6. 
Pharmacokinetic (PK) Population 
The PK population will include all patients who receive at least one dose of ceftobiprole 
and have at least one plasma concentration measurement obtained by the appropriate 
methodology. 
4.4. 
Other Important Considerations 
4.4.1. 
Definition of Baseline 
Baseline for safety and efficacy is the last available value prior to or on the first dose of 
study drug date and time. In case the time of the first dose of study drug and/or the time of the 
assessment is unknown, assessments done the day of the dose of first study drug will be 
considered as baseline, unless otherwise specified. No data known to be collected post first 
study drug date will be used in determining the baseline value, unless otherwise specified. 
 
For microbiological analysis, the identification of baseline pathogen(s) is based on all 
isolates collected from screening until 24 hours after first dose. 
4.4.2. 
Study Day Calculation and Visit Windows 
Visit windowing approaches will not be used for this study. Visit based summaries will 
include scheduled assessments only. If more than the specified number of measurements 
has been taken in a scheduled visit, the latest recorded values will be used in visit 
summaries, unless otherwise stated. All scheduled and unscheduled post-baseline 
assessments will be used for derivation of minimum and maximum post-baseline values. If 
more than one assessment has the same maximum value, then the record with earliest 
occurrence will be selected as the maximum assessment. If more than one assessment has 
the same minimum value, then the record with earliest occurrence will be selected as the 
minimum assessment. All available data will be listed. 
 
Analysis of the primary endpoint 48–72 h early-response analyses will be solely based 
upon actual elapsed time since first dose of study drug as discussed in Section 3.2.1 of this 
SAP. If multiple lesion measurements are taken within 48–72 h after the first dose of study 
drug, the last lesion measurement within this period will be used. 


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Likewise, analysis of Day 28 survival status and time until death will be based upon actual 
elapsed time since randomization as discussed in Section 8.3.6 of this SAP. 
 
The following conventions will be used to calculate analysis study day: 
• Day 1 is the day of first study drug administration. Day -1 is the day before Day 1. 
No Day 0 is defined for this study. 
• Prior to Day 1, the algorithm is: 
Study Day = visit/examination date – date of first study drug administration. 
• For Day 1 and subsequent days, the algorithm is: 
Study Day = visit/examination date – date of first study drug administration + 1. 
 
Summary data such as adverse events and concomitant medications will not be reported by 
visit. Tables which report abnormalities (e.g., clinically notable abnormalities, laboratory 
shift tables) will include all assessments. 
4.4.3. 
Missing and Partial Data 
Patients with missing data relevant for an assessment will be considered non-responders 
for the response analysis of that assessment. 
 
For partial dates, the algorithms for imputation will vary depending upon the parameter; 
the details can be found in Appendix 14.1 Imputation Algorithm for Partial and Missing 
Dates and Times. 
4.4.4. 
Pre-specified Subgroups 
Subgroup analyses will be performed for the primary and main secondary efficacy 
endpoints where applicable. For each specific subgroup, if there are not enough patients 
(i.e., <5% ITT population), the corresponding analyses will not be performed. 
 
The subgroups analyses by causative (infecting) pathogen(s), minimal inhibitory 
concentration(s) and positive baseline blood culture will be determined in the mITT and 
ME populations. 
 
Subgroup analyses will include the following factors:  
• Age (years) (18–34 , 35–64, 65–74, ≥75) 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• Geographic region (North America, Europe) 
• Causative (infecting) pathogen(s) and susceptibility phenotype of causative 
(infecting) pathogen(s) (e.g., MRSA, MSSA) overall and by baseline ABSSSI type. 


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Any group that has less than 10 organisms will not be included in the subgroup 
analyses. 
• Study drug(s) minimal inhibitory concentration(s) for causative (infecting) 
pathogen(s) 
• Positive baseline blood culture, overall and by causative (infecting) pathogen 
• Baseline ABSSSI type (cellulitis/erysipelas, major cutaneous abscess, wound 
infection) (actual values) 
• Diabetes mellitus (Yes, No) 
• Illicit drug use (Current, Previous, Never) 
• Injection drug use (Current, Previous, Never) 
• Baseline creatinine clearance (mL/min) range (<30, 30 – <50, 50–80, >80) 
• Baseline white blood cell (WBC) count [Normal (4.0 × 109/L ≤ WBC ≤ 10.0 × 
109/L), Abnormal (WBC < 4.0 × 109/L or WBC ˃ 10.0 × 109/L)] 
• Baseline fever status (Fever [>38 °C / 100.4 °F, measured orally, >38.5 °C / 
101.3 °F measured tympanically, >37.5 °C / 99.5 °F measured by the axillary 
method, or >39 °C / 102.2 °F measured rectally], No Fever [Formulae applicable to 
‘Fever’ inverted, i.e., using ≤ in place of  >]) 
• Baseline >10% immature neutrophils (band forms) (Yes, No) 
4.4.5. 
Duration (e.g., for Adverse Events) 
If date and time are collected, then duration is calculated as event end date and time minus 
event onset date and time. Duration will be displayed as days and fraction of days or as 
hours and fractions of hours depending on which appears most appropriate. Unit is days or 
hours. 
 
If only date is collected, then duration is calculated as event end date minus event onset 
date + 1. Unit is days. 
4.4.6. 
Coding Dictionaries 
Adverse events, medical history and prior and concomitant Non-drug treatment procedures 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
22.0 or later. 
 
Previous and concomitant treatments will be coded with the World Health Organization 
Drug Dictionary Enhanced (WHO DDE) dated 01SEP2018 or later.  


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5. Subject Disposition 
5.1. 
Disposition 
A summary of the analysis sets includes the number and percentage of patients for the 
following categories: patients screened, patients who failed screening and the reasons for 
screen failure, patients in the ITT population, patients randomized but never dosed, 
patients in the Safety population, patients in the mITT population, patients in the CE 
population, patients in the ME population, patients in the PK population. All percentages 
will be based on the number of patients randomized. 
 
A summary of the patients excluded from mITT/CE population and the reasons for 
exclusion will be presented. This summary will include the number and percentage of 
patients for the following categories: patients excluded from the mITT population and 
reasons, and patients excluded from the CE population and reasons. Percentages for 
exclusion reasons will be based on the number of patients excluded from the specific 
analysis set being summarized. Patients could be excluded from an analysis set for more 
than one reason. 
 
Patient disposition will be summarized for ITT and CE populations. A disposition of 
patients includes the number and percentage of patients for the following categories: 
patients who completed the study, patients who did not complete the study with reasons, 
patients who completed the study treatment, patients who discontinued study treatment 
early with reasons for discontinuation, patients who completed the EOT visit, patients did 
not complete the EOT visit with overall reasons, patients who completed the TOC visit, 
patients who did not complete the TOC visit with overall reasons, patients who completed 
the LFU visit, patients who did not complete the LFU visit with overall reasons. All 
percentages will be based on the number of patients randomized. 
 
The reason for study discontinuation, the reason for study treatment discontinuation and 
the overall reason the patient did not complete the EOT/TOC/LFU visit may include any of 
the following: adverse event, abnormal laboratory value, abnormal test procedure result, 
intercurrent illness, death, protocol deviation, lost to follow-up, administrative or logistical 
reasons, lack of efficacy, hemodialysis, pregnancy, investigator decision, withdrawal by 
patient, unblinding of treatment assignment or other. 
 
Patient disposition data will also be presented in a listing. 
 
A plot of time to early discontinuation of study drug and a summary will be provided using 
Kaplan-Meier. Time to study drug discontinuation is defined as the time from date and 
time of randomization to date and time of study drug discontinuation. Patients who 
completed study treatment will be censored at the last point of known study drug 
administration. If the patient is not given study drug then the time to discontinuation will 
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For patients with primary ABSSSI diagnosis change between screening and anytime 
thereafter during the study, the number and percentage of patients with change in diagnosis 
category (Wound Infection, Cellulitis, and Major Abscess) will be reported and the number 
of days until new diagnosis will also be presented using descriptive statistics. The number 
of days until new primary ABSSSI diagnosis is defined as the number of days from 
randomization until the date of new diagnosis.  
 
A summary of enrollment will be provided for each geographical region, country and site 
for all randomized patients. 
5.2. 
Protocol Deviations 
Deviations from the protocol will be recorded appropriately. The protocol deviations will 
be categorized as significant and non-significant deviations. The significant deviations will 
be further classified as major and minor. The final list of protocol deviations will be 
documented prior to unblinding the study data, and patients with major protocol deviations 
will be identified as part of the data review meeting (DRM) process, prior to database lock. 
 
Major protocol deviations will be presented in a summary table by protocol deviation 
category for ITT Population. All the significant deviations will be presented in a listing. 
6. Demographics and Baseline Characteristics 
6.1. 
Demographics and Baseline Characteristics 
The demographics and baseline characteristics will be presented in tables using descriptive 
statistics. The demographic characteristics consist of: 
• Age (from eCRF)  
• Age category (years) (<18, 18–34, 35–64, 65–74, ≥75) 
• Sex (integrated from IWRS) (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other) 
• Geographic region (North America, Europe) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• Baseline Weight 
• Baseline Height 
• Baseline Body Mass Index (BMI) 
• Diabetes mellitus (Yes, No) 
• Illicit drug use (Current, Previous, Never) 
• Injection drug use (Current, Previous, Never) 
• Baseline creatinine clearance (mL/min) (<30, 30 – <50, 50–80, >80) 


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• Baseline fever (Fever [>38 °C / 100.4 °F, measured orally, >38.5 °C / 101.3 °F 
measured tympanically, > 37.5 °C / 99.5 °F measured by the axillary method, or 
>39 °C / 102.2 °F measured rectally], No Fever [Formulae applicable to ‘Fever’ 
inverted, i.e., using ≤ in place of  >]) 
• Baseline WBC count [Normal (4.0 × 109/L ≤ WBC ≤ 10.0 × 109/L), Abnormal 
(WBC < 4.0 × 109/L or WBC ˃ 10.0 × 109/L)] 
• Baseline >10% immature neutrophils (band forms) (Yes, No) 
• Systemic Antibacterial medications prior to study drug (Yes, No) 
• Topical Antibacterial medications prior to study drug (Yes, No) 
• Concomitant antibacterial medications (Metronidazole) 
 
A patient’s age in years is recorded directly on the eCRF (integrated from IWRS). Age will 
be summarized using descriptive statistics and will be listed. 
 
Demographics will be presented for ITT and CE analysis populations.  
 
Demographics and baseline characteristics data will also be listed. 
6.2. 
Female Reproductive System 
Female reproductive system at screening will be presented for the ITT population and will 
consist of fertility status, number of months if post-menopausal, and method of birth 
control. Pregnancy test at screening will also be presented. 
6.3. 
Medical/Surgical History 
6.3.1. 
General Medical/Surgical History 
The number and percentage of patients with any Medical history other than primary 
ABSSSI history will be summarized overall and for each system organ class and preferred 
term. Percentages will be calculated based on number of patients in the ITT population. 
 
Patient medical/surgical history data including specific details will be presented in a 
listing. 
6.3.2. 
Disease-Specific History 
The following medical/surgical history parameters related to primary ABSSSI will be 
summarized for the ITT population using descriptive statistics: 
• Recent surgical procedure that resulted in the primary ABSSSI 
• Days since most recent surgical procedure 
• Recent trauma that resulted in the primary ABSSSI 
• Days since most recent trauma 


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• Infection Site Assessment (erythema, induration, localized warmth, pain on 
palpation, tenderness on palpation, swelling, edema, fluctuance, incision required, 
incision performed, drainage required, drainage performed, purulent drainage, and 
seropurulent drainage) 
• Description of Primary ABSSSI (days since symptoms onset, time since 
measurements, longest length, widest width perpendicular to the longest length, 
calculated surface area, measurement taken (before drainage vs. after drainage), 
days since most recent drainage, and maximum width of erythema or 
edema/induration from the edge of the wound or abscess) 
• Location of primary ABSSSI (abdominal skin, arm, axilla, back, buttock, chest, 
face, foot, hand, inguinal region, leg, neck, scalp, shoulder) 
• Microbiological causative (infecting) pathogen(s) isolated at baseline. 
 
Incomplete symptom onset dates will be imputed as detailed Appendix 14.1. 
 
Details of ABSSSI surgical procedures anticipated during the study and/or planned at 
baseline will also be listed. 
6.4. 
Inclusion and Exclusion Criteria 
The details of Inclusion and Exclusion criteria are listed in Section 4.2 and 4.3 of the 
protocol. All inclusion/exclusion information on ITT patients will be included in a by-
patient listing. For patients who did not satisfy these criteria, the criteria numbers will be 
listed with the deviation. 
7. Treatments and Medications 
7.1. 
Prior and Concomitant Medications/Non-Drug Procedures 
7.1.1. 
Prior and Concomitant Medications 
All medications taken other than the study medications during the study (including 30 days 
prior to Screening) must be documented on the appropriate section of the eCRF. 
 
Prior non-antibiotic medications are defined as medications with a stop date occurring 
before the first dose date. Concomitant non-antibiotic medications are defined as 
medications that are ongoing on the first dose date, or with a start date missing or 
occurring on or after the first dose date. The number and percentage of patients who 
receive prior and concomitant non-antibiotic medication will be summarized separately by 
drug class and preferred name. 
 
Prior antibiotic medications are defined as medications with a stop date and time occurring 
before the first dose date and time. Concomitant antibiotic medications are defined as 
medications that are ongoing on the first dose date and time, or with a start date and time 
missing or occurring on or after the first dose date and time. The number and percentage of 


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patients who receive prior and concomitant antibiotic medication will be summarized 
separately by drug class and preferred name. 
 
At each level of summarization, a patient is counted once if he/she reports one or more 
medications at that level. Drug class will correspond to the Anatomical Therapeutic 
Classification (ATC) Level 4 term. All prior medications and concomitant medications 
will be summarized for the ITT population. 
 
The imputation algorithm for partial and missing medication dates is provided in Appendix 
14.1. 
 
All prior and concomitant medications will be presented in a listing. 
7.1.2. 
Prior and Concomitant Non-Drug Procedures 
Prior non-drug procedures are defined as procedures with a stop date occurring before the 
first dose date. Concomitant non-drug procedures are defined as treatments that are 
ongoing on the first dose date, or with a start date missing or occurring on or after the first 
dose date. The number and percentage of patients who receive prior and concomitant non-
drug procedures will be summarized separately. All prior and concomitant non-drug 
procedures will be summarized for the ITT population. 
 
The imputation algorithm for partial and missing procedure dates is provided in Appendix 
14.1. 
 
All prior and concomitant non-drug procedures will be presented in a listing. 
7.2. 
Study Treatments 
7.2.1. 
Extent of Exposure 
Duration of exposure is defined as the total number of days a patient is exposed to any 
study drug and will be presented as the total number of days from the first dose date of 
study drug (Day 1) to the last dose date of study drug (date of last known study drug 
administration as recorded on the Study Completion/Termination page on the eCRF) i.e., 
(Date of last dose of study drug - Date of first dose of study drug) + 1. If the last dose date of 
study drug on the Study Completion/Termination page is missing, or if a patient is lost to 
follow-up, then the last infusion end date recorded on the Exposure page on the eCRF will 
be used. 
 
The duration of exposure to study drug by treatment group will be summarized for all 
patients in the Safety population and will be presented in a table by summary statistics. 
The duration of exposure will then be classified into one of the following categories: > 0–
< 5 days, 5–10 days, > 10–14 days, and > 14 days and will be presented as the number and 


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percentage of patients in each duration category. Percentages will be computed from the 
number of patients in the Safety population. 
 
Because study drug dose adjustment may occur during the study, the exposure to study 
drug will also be characterized by cumulative dose by treatment within each treatment 
group, which is defined as the sum of actual doses (mg) administered to a patient. The total 
cumulative dose (mg) will be summarized by descriptive summary statistics, by day and 
overall. 
 
Also, the number of actual doses by treatment group will be defined as the number of 
occasions the dose is administered on a given day. The total number of actual doses will be 
summarized by day, and overall. 
 
The overall compliance by treatment group will be summarized descriptively. For each 
patient, the compliance will be calculated as the total number of actual doses divided by 
the total number of planned doses, across the overall treatment period. The compliance will 
then be classified into one of the following categories: < 80%, 80 – 120 % and > 120 % 
and will be presented as the number and percentage of patients in each category. 
Percentages will be computed from the number of patients in the safety population. 
 
A summary of each patient’s exposure will be presented in a listing. 
8. Efficacy Analysis 
8.1. 
Primary Efficacy Analysis 
8.1.1. 
Main Analysis 
The main primary analysis will be based on the ITT population. 
 
The numbers and percentages of responders and non-responders will be determined in each 
treatment group. 
 
The weighted difference in percentage of responders at 48–72 h (ceftobiprole group minus 
the vancomycin plus aztreonam group), and the 95% CI for the weighted difference will be 
computed using CMH weights method adjusted for geographical region (North America 
and Europe), and actual type of ABSSSI. Estimates of the weighted risk ratio and weighted 
odds ratio will also be provided. 
 
A bar graph showing the proportions of patients with early clinical response will be 
produced. 
 
Test hypothesis for non-inferiority: 
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HA: π1 - π2 >-0.10 
 
Where, 
π1 = Proportion of patient with early clinical response for ceftobiprole group 
π2 = Proportion of patient with early clinical response for vancomycin plus 
aztreonam group 
 
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 (ceftobiprole minus vancomycin plus aztreonam) in the ITT population is 
greater than -10%, the non-inferiority of ceftobiprole to vancomycin plus aztreonam will 
be concluded. 
 
If non-inferiority is declared at the one-sided significance level of 0.025, then the 
difference will be tested for superiority. 
 
Test hypothesis for superiority: 
H0: π1 - π2 ≤ 0 
HA: π1 - π2 > 0 
 
Where, 
π1 = Proportion of patient with early clinical response for ceftobiprole group 
π2 = Proportion of patient with early clinical response for vancomycin plus 
aztreonam group 
 
Superiority will be declared if the lower limit of the two-sided 95% CI exceeds 0 (or 
equivalently p-value less than 0.05 using CMH test). 
 
The same analysis will be repeated on the CE population. 
 
Subgroup analyses listed in Section 4.4.4 will be conducted for the primary efficacy 
outcome in the ITT and CE populations. 
 
In addition to tabulating the subgroup analyses, a forest plot showing the weighted 
treatment differences with associated 95% CI and p-values, computed using CMH weights 
statistics controlling for stratum (geographical region and actual type of ABSSSI when 
applicable), will be produced. 
8.1.2. 
Sensitivity Analyses 
To assess the robustness of the primary efficacy analysis results, the following sensitivity 
analyses will be performed for the primary outcome in ITT and CE populations: 


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• An unadjusted analysis by unstratified Wald Statistic will be provided, i.e., statistic 
will not be adjusted for the geographic region (North America and Europe) and 
actual ABSSSI type. 
• Patients with missing surface area of primary lesion at baseline or 48–72 h will be 
excluded (Observed Cases analysis). 
• The insufficient number of patients per site not warranting the investigation of the 
treatment by site interaction effect, only the heterogeneity of treatment effect across 
geographic regions (North America and Europe) will be evaluated. To assess the 
geographic region effect, the interaction between treatment and geographic region 
will be evaluated using Gail-Simon test with significance level of 0.10. In case the 
interaction is found to be significant, then further analysis of the primary endpoint 
will be performed to assess where these regional differences lie. This may include 
further subgroup analysis by site. 
• Based on audit findings, a sensitivity analysis of the primary endpoint will be 
performed, excluding data from site 069. 
• A forest plot by site showing the weighted treatment differences with associated 
95% CI and p-values, computed using CMH weights statistics controlling actual 
type of ABSSSI will be produced.  
8.2. 
Secondary Efficacy Analysis 
8.2.1. 
Main Analysis 
The main secondary analysis will be based on the ITT and CE populations. 
 
The numbers and percentages of Success and No-Success will be determined in each 
treatment group at TOC visit. 
 
The weighted difference in percentage of clinical success at TOC visit (ceftobiprole group 
minus the vancomycin plus aztreonam group), and the 95% CI for the weighted difference 
will be computed using CMH weights method, adjusted for geographical region (North 
America and Europe), and actual type of ABSSSI. Estimates of the weighted risk ratio and 
weighted odds ratio will also be provided. 
 
A bar graph showing the proportions of patients with clinical success will be produced. 
 
Test hypothesis for non-inferiority: 
H0: π1 - π2 ≤ -0.10 
HA: π1 - π2 > -0.10 
 
Where, 
π1 = Proportion of patient with clinical success for ceftobiprole group 


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π2 = Proportion of patient with clinical success for vancomycin plus aztreonam 
group 
 
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 
clinical success rates (ceftobiprole minus vancomycin plus aztreonam) in the ITT and CE 
populations is greater than 10%, the non-inferiority of ceftobiprole to vancomycin plus 
aztreonam will be concluded. 
 
If non-inferiority is declared at the one-sided significance level of 0.025, then the 
difference will be tested for superiority. 
 
Test hypothesis for superiority: 
H0: π1 - π2 ≤ 0 
HA: π1 - π2 > 0 
Where, 
π1 = Proportion of patient with clinical success for ceftobiprole group 
π2 = Proportion of patient with clinical success for vancomycin plus aztreonam 
group 
 
Superiority will be declared if the lower limit of the two-sided 95% CI exceeds 0 (or 
equivalently p value less than 0.05 using CMH test). 
 
Subgroup analyses listed in Section 4.4.4 will be conducted for the primary efficacy 
outcome in the ITT and CE populations. 
8.2.2. 
Sensitivity Analyses 
In addition, the following sensitivity analyses will be performed for the main secondary 
endpoint: 
• An unadjusted analysis by unstratified Wald Statistic will be provided, i.e., statistic 
will not be adjusted for the geographic region (North America and Europe) and 
actual ABSSSI type. 
• Patients with missing investigator-assessed clinical success at the TOC visit will be 
excluded (Observed Cases analysis). 
• The insufficient number of patients per site not warranting the investigation of the 
treatment by site interaction effect, only the heterogeneity of treatment effect across 
geographic regions (North America and Europe) will be evaluated. To assess the 
geographic region effect, the interaction between treatment and geographic region 
will be evaluated using Gail-Simon test with significance level of 0.10. In case the 
interaction is found to be significant, then further analysis of the primary endpoint 
will be performed to assess where these regional differences lie. This may include 
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• Based on audit findings, a sensitivity analysis of the primary endpoint will be 
performed, excluding data from site 069. 
• A forest plot by site showing the weighted treatment differences with associated 
95% CI and p-values, computed using CMH weights statistics controlling for actual 
type of ABSSSI will be produced. 
• Analysis will be performed to assess the association between the primary endpoint, 
i.e., early clinical response at 48–72 h, and the secondary endpoint, i.e., clinical 
responses at the TOC visits controlling for treatment group using CMH. 
8.3. 
Other Secondary Efficacy Analysis 
8.3.1. 
Clinical Response Defined as ≥80% Decrease in Lesion Area at the EOT 
Visit, ≥90% Decrease in Lesion Area at the TOC visit, and Clinical 
Success Achieved as per Secondary Endpoint Criteria Satisfied at EOT 
and TOC 
The numbers and percentages of responders and non-responders will be determined in each 
treatment group at EOT, TOC, and EOT and TOC combined in the ITT and CE 
populations. 
 
The weighted difference in percentage of responders at EOT and TOC visits (ceftobiprole 
group minus the vancomycin plus aztreonam group), and the 95% CI for the weighted 
difference will be computed using CMH weights method adjusted for geographical region 
(North America and Europe), and actual type of ABSSSI. Estimates of the weighted risk 
ratio and weighted odds ratio as well as the p-value for CMH test will also be provided. 
8.3.2. 
Sustained Reduction in Lesion Size at the EOT and TOC Visits 
The numbers and percentages of responders and non-responders for sustained reduction in 
lesion size at EOT and TOC visits will be determined in each treatment group in the ITT 
and CE populations. 
 
The weighted difference in percentage of responders for sustained reduction in lesion size 
at EOT and TOC visits (ceftobiprole group minus the vancomycin plus aztreonam group), 
and the 95% CI for the weighted difference will be computed using CMH weights method 
adjusted for geographical region (North America and Europe), and actual type of ABSSSI. 
Estimates of the weighted risk ratio and weighted odds ratio as well as the p-value for 
CMH test will also be provided. 
8.3.3. 
Investigator-assessed clinical success evaluated at 48–72 h after first 
treatment and the EOT visit, and sustained clinical success at the LFU 
visit. 
The investigator-assessed the level of clinical success will be summarized at each given 
visit. Also, the weighted difference in percentage of clinical success (Cured + Improved) at 
each visit and the 95% CI for the weighted difference will be computed using CMH 


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weights method, adjusted for geographical region (North America and Europe), and actual 
type of ABSSSI. P-value for CMH test will also be provided. 
 
The numbers and percentages of responders and non-responders for sustained clinical 
success at TOC and LFU visits will be determined in each treatment group in the ITT and 
CE populations. 
 
The weighted difference in percentage of responders for sustained clinical success at TOC 
and LFU visits (ceftobiprole group minus the vancomycin plus aztreonam group), and the 
95% CI for the weighted difference will be computed using CMH weights method adjusted 
for geographical region (North America and Europe), and actual type of ABSSSI. 
Estimates of the weighted risk ratio and weighted odds ratio as well as the p-value for 
CMH test will also be provided. 
8.3.4. 
Microbiology 
8.3.4.1. 
Microbiological 
Responses, 
Eradication 
Rate 
and 
Time 
to 
Eradication 
Microbiological response (as defined in Section 3.2.3) at Day 3, Day 5, and the EOT, TOC 
and LFU visits will be determined in each treatment group in the mITT and ME 
populations. 
 
The numbers and percentages of responders and non-responders will be determined in each 
treatment group. Eradication and presumed eradication will be grouped together as 
responders. Patients with microbiological response persistence, presumed persistence, 
superinfection, relapse or recurrence, or patients with missing data will be considered non-
responders for the analysis. Proportion of patients achieving microbiological eradication or 
presumed eradication will be analyzed for each visit separately using the same statistical 
methods as for the primary endpoint. 
 
The time to microbiological [presumed] eradication will be compared using Kaplan-Meier 
(KM) estimates. An unstratified log rank test will be performed to assess the difference 
between treatment groups. KM plot of time to microbiological [presumed] eradication will 
also be presented. Time to [presumed] eradication is defined as the actual elapse time from 
date of randomization to date of the first [presumed] eradication. Patients without 
[presumed] eradication records will be censored at the date of the last microbiological 
assessment date. 
8.3.4.2. 
Microbiological Evaluations and Pathogen Identification 
Causative (infecting) pathogens will be identified by the central or local microbiology 
laboratory. Identification and susceptibility test results from the central microbiology 
laboratory will be used in the analyses. Local laboratory identification results will only be 
used if no central laboratory data are available. Causative (infecting) pathogens include but 


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are not limited to the following bacterial species: Enterobacter spp., Klebsiella 
pneumoniae, Staphylococcus aureus, Streptococcus viridans, Streptococcus pyogenes.  
 
The microbiological data will be summarized in the mITT and ME populations and 
analyzed as follows: 
• Association between the clinical success achieved as per secondary endpoint criteria 
satisfied at TOC and the Microbiological [presumed] eradication rate at the TOC 
visit controlling for treatment group using CMH. 
• Distribution of ceftobiprole and vancomycin MICs for pathogens isolated at 
baseline, including MIC50, MIC90 and MIC range, overall and by treatment group. 
MIC50 is the MIC value which inhibits 50% of pathogens isolated at baseline. 
MIC90 is the MIC value which inhibits 90% of pathogens isolated at baseline. 
MIC range is the minimum and maximum MIC values measured for pathogens 
isolated at baseline. 
Susceptibility interpretation results by Clinical and Laboratory Standards Institute 
(CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) 
criteria (Susceptible, Intermediate, Resistant) of pathogens isolated at baseline by 
tested drug, overall and by geographical region (North America, Europe). 
• Microbiological eradication rate at TOC visit by baseline causative (infecting) 
pathogen.  
• Patients with clinical and microbiological responses at TOC visit by baseline 
causative (infecting) pathogen. 
• Shift in ceftobiprole and vancomycin MIC results from baseline to TOC for baseline 
causative (infecting) pathogens in the ceftobiprole group. 
• Patients with baseline causative (infecting) pathogen classified as resistant 
(EUCAST and CLSI criteria), by region. 
8.3.5. 
All-Cause Mortality (ACM) 
The survival time between the two treatment groups will be compared using KM estimates 
for the ITT and CE populations. 
 
An unstratified log rank test will be performed to assess the difference between treatment 
groups which will include all available mortality data as of the date of data cut, not just 
mortality data up to mortality day 28. Survival rates (Event-Free Probability Estimates) at 
Day 28 will be estimated using K-M estimate. Associated two-sided 95% CI will be 
calculated using Greenwood formula. 
 
Time to death is defined as the actual elapse time from date of randomization to date of 
death. Patients without death records (alive or lost to follow-up) will be censored at the last 
point they were known to be alive. 
 


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A Kaplan-Meier plot of survival time will also be provided. 
8.3.6. 
Patient-Reported Pain 
The pain scores will be summarized by treatment group in the ITT and CE populations at 
each time point with exception of Day 28. 
 
The change from baseline will be calculated and summarized at all visits with exception of 
Day 28. 
 
The difference in mean change from baseline of VAS and Wong-Baker Pain scale between 
treatment groups will be estimated using a mixed-model repeated measures (MMRM) 
analysis. The MMRM design will model the result on the treatment groups, visit, actual 
type of ABSSSI, geographical region (North America and Europe) and pain levels at 
baseline as covariates, with subjects as a random effect. The interaction term between 
treatment group and visit will also be included to allow the treatment group difference to 
differ over time. The variance-covariance matrix will be assumed to be unstructured and 
the Kenward-Rogers method will be used to calculate the degrees of freedom. If there are 
convergence problems with the MMRM analysis, other covariance structures will be 
examined to resolve the convergence issue, i.e., other additional variance-covariance 
structures would be evaluated, including compound symmetry (CS), heterogeneous 
compound symmetry (CSH), and auto-regressive [AR(1)]. In this eventuality, the 
Akaike’s Information Criterion (AIC) will be used to determine the optimal variance-
covariance structure matrix for the primary comparisons. 
 
From this model, the Least Square (LS) mean treatment difference at each visit will be 
presented along with the 95% CI and the two-sided p-value for treatment effect at each 
visit. 
 
Line plots of means and SEs will be created to display the change from baseline over the 
entire study period. 
8.3.7. 
Health Economic Outcome Measures 
Information on health economics outcome measures from baseline to the LFU visit will be 
collected at the LFU visit to perform summarization for total length of stay in hospital, 
location of treatment within the healthcare system and reason for healthcare encounter. 
 
All the Health economic outcome measures will be summarized by treatment group in the 
ITT and CE populations. 
8.3.8. 
Lesion Area 
The absolute and percentage change in lesion area size will be summarized by the 
treatment group in the ITT and CE populations. 
 


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The mean difference in absolute and percent change from baseline in lesion area size 
between treatment groups will be estimated using a MMRM analysis. The MMRM design 
will model the result on the treatment groups, visit, actual type of ABSSSI, geographical 
region (North America and Europe) and pain levels at baseline as covariates, with subjects 
as a random effect. The interaction term between treatment group and visit will also be 
included to allow the treatment group difference to differ over time. The 
variance-covariance matrix will be assumed to be unstructured and the Kenward-Rogers 
method will be used to calculate the degrees of freedom. If there are convergence problems 
with the MMRM analysis, other covariance structures will be examined to resolve the 
convergence issue, i.e., other additional variance-covariance structures would be evaluated, 
including compound symmetry (CS), heterogeneous compound symmetry (CSH), and 
auto-regressive [AR(1)]. In this eventuality, the Akaike’s Information Criterion (AIC) will 
be used to determine the optimal variance-covariance structure matrix for the primary 
comparisons. 
 
From this model, the LS mean treatment difference at each visit will be presented along 
with the 95% CI and the two-sided p-value for treatment effect at each visit. 
 
The number and percentage of patients with percent reductions in lesion size area from 
baseline (e.g., ≥10%, ≥20%, ≥30%, ≥40%, ≥60% , ≥ 70% at 48–72 h after start of 
treatment; ≥40% ,≥ 50%,  ≥60% , ≥70% ,≥80%, ≥90%, ≥95% at TOC) will be summarized 
by treatment group in the mITT and CE populations. The weighted difference in 
percentage of patients with specific percent reductions in lesion size area (the ceftobiprole 
group minus the vancomycin plus aztreonam group), and the 95% CI for the weighted 
difference will be computed using CMH weights method adjusted for geographical region 
(North America and Europe), and actual type of ABSSSI. P-value for CMH test and 
estimates of the weighted risk ratio and weighted odds ratio will also be provided. 
 
Box plots will be provided to display the distribution of percent change in lesion size at 
each visit. In Addition, line plots of means and SEs will be created to display the absolute 
and percentage change in lesion area size over the entire study period. 
8.3.9. 
Infection Site Assessment 
The infection-site assessment including incision/drainage, erythema, heat/localized 
warmth, pain/tenderness to palpation, fluctuance, and swelling/induration will be 
summarized at each given visit. 
 
 


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9. Safety Analysis 
All analysis of safety will be conducted using the Safety population. Statistical hypothesis 
testing will not be performed on any safety results. 
9.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. 
 
A serious AE (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 
 
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. 
 
All AEs are defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of 
first dosing up to and including the scheduled LFU visit, and will be considered for the 
analysis purpose. Any event occurring prior to the first dosing will be recorded as medical 
history. For calculating inclusion in summary tables, incomplete onset dates will be 
imputed as detailed in Appendix 14.1. 
 
AEs will be tabulated, according to the Medical Dictionary for Regulatory Activities 
(MedDRA®), system organ class (SOC), and preferred term (PT). 
9.1.1. 
Incidence of Adverse Events 
The incidence of AEs and SAEs tables will include only one occurrence of a PT per 
patient. If a patient reports the same PT multiple times, then that PT will only be 
incremented by one since patient counts will be presented. As with the PT, if a patient 
reports multiple AEs within the same SOC, then that SOC will only be incremented by one 
since patient counts will be presented. For tables showing incidence by SOC and PT, SOC 
will be sorted in alphabetical order. Within each SOC, preferred terms will be sorted in 
descending order of frequency on total of all treatment groups. 
 
The incidence of all AEs and SAEs will be presented by SOC and PT and separately by PT 
only. 


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Dot and interval plot showing the largest difference in the proportion of AEs between the 
two treatment groups will be created. The plot will include risk differences and their 
corresponding 95% Confidence Intervals (CIs). All AEs, will be sorted by descending 
difference in proportion. 
 
All AEs will be listed. 
9.1.2. 
Relationship of Adverse Events to Study Drug 
A summary of treatment-related AEs and SAEs will also be presented in a table by SOC 
and PT. 
 
The relationships will be collected as the possibility that study drug caused the event. The 
possible relationships are “Not Related”, “Unlikely”, “Possible”, and “Probable”. A 
treatment-related AE is an AE with any relation to study drug other than “Not Related” or 
“Unlikely”. In the AE relationship table, if a patient reports multiple occurrences of the 
same AE, only the most closely related occurrence will be presented. AEs that are missing 
relationship will be presented in the summary table as “Unknown” but will be presented in 
the data listing with a missing relationship. 
9.1.3. 
Severity of Adverse Event 
A summary of AEs and SAEs by severity will be presented in a table. AEs will be 
classified by severity (mild, moderate and severe). In the AE severity table, if a patient 
reported multiple occurrences of the same AE, only the most severe will be presented. AEs 
that are missing severity will be presented on tables as “Unknown” but will be presented in 
the data listing with a missing severity. 
9.1.4. 
Adverse Events Leading to Treatment Discontinuation 
Summary tables of AEs leading to study drug discontinuation by primary SOC and 
preferred term by treatment arm will be provided. Treatment-related AEs leading to study 
drug discontinuation will be listed by patient. 
9.1.5. 
Outcome of Adverse Event  
AEs will be classified by outcome (Recovered or Resolved, Recovered or Resolved with 
Sequelae, Recovering or Resolving, Not Recovered or Not Resolved, Death Related to 
Adverse Event and Unknown). The outcomes will be listed by patients. 
9.2. 
Death 
The summary of treatment-related AEs where the answer to “Outcome” is “Death Related 
to Adverse Event” will also be presented. SOC will be sorted in alphabetical order.  Within 
each SOC, total AEs of preferred terms will be sorted in descending order of frequency on 
total of all treatment groups. 
 


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All patient deaths during this study will be collected and presented in a listing. The 
information that is presented includes days on study and AE with an outcome of “Death 
Related to Adverse Event”. 
9.3. 
Clinical Laboratory Evaluations 
Local safety laboratory parameters to be used to assess patient eligibility at Screening 
include hematology, blood chemistry, coagulation, blood glucose, and urinalysis. Central 
laboratory safety parameters will be carried out in accordance with the schedule of 
assessments in Section 5.1 of the protocol, will be used for analysis in the study.  
 
All summaries will be based on central laboratory data using the standard international (SI) 
units provided by the central laboratory; in case of missing baseline results from the central 
laboratory, the local laboratory data will be used. Implausible central laboratory results 
were flagged by the central laboratory; these results will not be tabulated but will be listed.  
 
Summary tables for central laboratory safety parameters including actual values and 
change from Baseline values will be presented for clinical laboratory tests with numeric 
values by visit. 
 
Central laboratory data will also be summarized using shift tables where appropriate. Each 
patient’s continuous laboratory safety parameter values will be flagged as “low”, “normal”,  
“high” or “missing” relative to the normal ranges of the central laboratory. Each patient’s 
categorical laboratory safety parameter values will be flagged as “abnormal” or “normal”. 
This categorical data will be summarized in shift tables comparing the minimum post-
baseline value, maximum post-baseline value and all other relevant post-baseline visits 
with those at the baseline visit. In addition, laboratory values outside derived marked 
reference range values (multiplying the lower and upper ranges using the Basilea standard 
marked factors) will be summarized. 
 
Laboratory results will be graded using the Division of AIDS (DAIDS) for Adverse Events 
Version 2.1. In case, if any laboratory parameter is not present in the grading criteria of 
DAIDS then Division of Microbiology and Infectious diseases (DMID) dated Nov 2007 
grading scale will be used. Local and central laboratory results will be graded separately 
(e.g. baseline from local laboratory will not be compared to post baseline central laboratory 
results). The central laboratory categorical data will be summarized in shift tables. 
 
Laboratory data collected at unscheduled visits will be included in listings and will 
contribute to tables of shifts from Baseline and in tables showing changes from Baseline to 
highest value and lowest value. Unscheduled lab results will not be windowed for the 
purposes of assigning a nominal visit. However, they will be included in calculations of 
highest/lowest values in selected laboratory parameters. 
 


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Laboratory values and their respective reference ranges will be reported to the same 
number of decimal places as provided by the laboratory. 
 
Differentials will be displayed in the laboratory output as absolute values. If the laboratory 
can provide only percentage values, these will be converted into absolute for reporting. 
9.3.1. 
Hematology 
The laboratory tests listed in the Appendix 14.2 will be included in hematology summary 
tables. 
 
All hematology data by patient will be presented in a listing. Patients with abnormalities as 
per normal ranges in hematology will be listed. 
9.3.2. 
Blood Chemistry 
The laboratory tests listed in the Appendix 14.2 will be included in clinical chemistry 
summary tables. 
 
All chemistry data by patient will be presented in a listing. Patients with abnormalities as 
per normal ranges in chemistry will be listed.  
The incidence of patients with abnormalities in ALT or AST will be summarized overall 
(highest post-baseline value) for each treatment group for the following categories: 
• ≤ 3 x ULN 
• > 3 to ≤ 5 x ULN 
• > 5 to ≤ 8 x ULN  
• > 8 to ≤ 10 x ULN 
• > 10 x ULN 
 
Also, the incidence of patients with abnormalities in ALT or AST associated to 
abnormalities in total bilirubin (TBILI) will also be summarized overall (highest post-
baseline value) for each treatment group for the following categories: 
• ALT or AST ≤ 3 ULN and BILI ≤ 2 ULN 
• ALT or AST > 3 ULN and BILI ≤ 2 ULN 
• ALT or AST ≤ 3 ULN and BILI > 2 ULN 
• ALT or AST > 3 ULN and BILI > 2 ULN 
 
Patients with at least one post-baseline ALT or AST that is ≥ 3 x ULN will be listed 
showing all liver function tests (LFTs), i.e., ALT, AST, bilirubin (total, direct & indirect), 
alkaline phosphatase, and GGT observed across all visits. 
 


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Evaluation of drug-induced serious hepatotoxicity (eDISH) plots of maximum ALT/AST 
values versus total bilirubin will be presented for assessment of potential Drug Induced 
Liver Injury (DILI). 
9.3.3. 
Urine (dipstick Analysis) 
The following local laboratory tests will be collected at screening for urine (dipstick 
analysis): blood, glucose, ketones, leukocytes, nitrite, pH, protein, specific gravity, 
bilirubin, and urobilinogen. Urine (dipstick analysis) results at screening will be listed only. 
9.3.4. 
Coagulation 
The following laboratory tests will be included: prothrombin time, international 
normalized Ratio, and activated partial thromboplastin time. All coagulation data by 
patient will be summarized and will be presented in a listing.  
9.3.5. 
Reticulocytes, haptoglobin and Coombs test 
Reticulocytes, haptoglobin and Coombs test will be assessed by central laboratory 
according to the schedule shown in Section 5.1 of the protocol. Reticulocytes, haptoglobin 
and Coombs test values will be summarized and will be presented in a listing. 
9.3.6. 
Creatinine clearance 
Creatinine clearance (CLCR) test will be assessed by local laboratory.  
 
Box plots will be provided to display the distribution of the CLCR level reported by sites at 
each visit. In addition, line plots of means and SEs will be created to display the actual 
value, change from baseline and percent change from baseline over the entire study period. 
 
The CLCR level reported by sites will be summarized and will be presented in a listing. 
9.3.7. 
Vancomycin Trough Level 
Vancomycin trough level (central laboratory assessment): a vancomycin trough level for 
central laboratory assessment is to be obtained approximately 30 minutes before 
administration of the fourth dose of vancomycin (i.e., on Day 2 for patients who receive 
vancomycin on a q12h schedule, and on Day 4 for patients who receive vancomycin on a 
q24h schedule). 
 
Vancomycin trough levels (local laboratory assessment): in study sites which use 
vancomycin trough level monitoring to guide vancomycin dosing and which perform 
vancomycin trough level testing using a local laboratory, an additional blood sample for 
local laboratory testing of the vancomycin trough level should also be obtained before 
administration of the fourth dose of vancomycin on Day 2 (vancomycin q12h schedule) or 
Day 4 (vancomycin q24 h schedule). If obtained, local laboratory testing of vancomycin 
trough levels should be obtained per institutional practices at the respective study site. 
 


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Vancomycin trough level results obtained from local and central laboratory will be listed. 
9.3.8. 
Pregnancy Test 
Pregnancy testing is to be performed for women of childbearing potential; at Screening a 
serum pregnancy test is to be obtained; at the LFU visit 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. If a pregnancy test result is 
positive, study drug must be discontinued, and the patient followed for safety, and 
assessment of the pregnancy outcome. 
 
Pregnancy test data will be summarized and will be presented in a listing. 
9.4. 
Vital Signs Measurements 
Vital signs include weight, respiratory rate, radial pulse rate, systolic blood pressure and 
diastolic blood pressure and are to be taken once at each study visit at a time point when 
temperature assessment is performed. Body temperature is to be measured twice daily 
(morning and evening) during the first 8 days of treatment, after which temperature 
measurements are to be taken once on each scheduled study visit day except Day 28. The 
same method of measuring temperature should be chosen within a site for all patients 
during course of the study. Pulse rates and blood pressures 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. A patient’s height must only be assessed during the 
Screening visit. 
 
Summary tables presenting observed values and changes from baseline will be presented 
for vital sign data, including weight (kg), systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), temperature (°C) morning and evening, pulse (bpm), and respiration 
(breaths/minute), by treatment group at each visit on a given timepoint in the safety 
population. Changes from baseline to each scheduled post-baseline visit will be presented. 
Change from baseline will only be calculated for patients having non-missing baseline and 
post-baseline measurements. The change from baseline in temperature will be calculated 
only if the baseline and post baseline measurements are done by same method. Summary 
table presenting minimum and maximum post-baseline values will also be provided. 
 
All vital sign data by patient will be presented in a listing. 
 
Box plots will be provided to display the distribution of vital signs results at each visit. In 
addition, line plots of means and SEs will be created to display the change from baseline 
over the entire study period. 
The following values should be used as default Marked Reference Ranges: 
• Diastolic Blood Pressure: < 60 or > 100 mmHg. 
• Systolic Blood Pressure: < 80 or > 180 mmHg. 


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• Pulse: < 40 or > 120 beats/min. 
• Temperature: < 36 0C / 96.8 °F 
• Temperature: > 38 °C / 100.4 °F measured orally. 
• Temperature: > 38.5 °C / 101.3 °F measured tympanically. 
• Temperature: > 37.5 °C / 99.5 °F measured by the axillary method. 
• Temperature: > 39 °C / 102.2 °F measured rectally. 
 
Each patient’s continuous vital signs results values will be flagged as “low”, “normal”, 
“high” or “missing” relative to the marked reference ranges. This categorical data will be 
summarized in shift tables comparing the changes from baseline value as Low/Normal to 
post-baseline value as High or baseline value as High/Normal to post-baseline value as 
Low. 
9.5. 
Physical Examination 
A complete physical examination will be performed at screening visit. Complete physical 
examination includes general appearance, skin, neck inclusive thyroids, eyes, nose, throat, 
cardiovascular system, thorax/lungs, abdomen, lymph nodes, extremities, nervous system, 
and mental status. A brief physical examination will be performed for visits: Day 3, EOT, 
TOC, and LFU. Brief physical examination is to be focused on any changes from baseline. 
 
A table will summarize physical examination results by treatment group and overall for the 
Safety population. Each visit captures the status of a body system and any finding 
associated with the body system as normal, abnormal, or not done. Physical examination 
results for all patients will be presented in a listing. 
10. Pharmacokinetics 
Plasma concentration data will be analyzed at each time point and will be presented as 
individual concentrations and with descriptive statistics (mean, standard deviation [SD], 
coefficient of variation [CV%], min, median and max). A retrospective population PK 
model will be developed as a separate study not performed by PPD. Pharmacokinetic 
analyses will be based on the population PK model and the effects on the PK parameters of 
demographic and baseline factors such as age, weight, sex, race, and renal function 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. 
11. Interim analysis 
The interim analysis was conducted involving a sample size re-estimation to 
1. assess whether the initial sample size estimate is adequate for evaluating the 
primary endpoint as defined in Section 8.1.1, and 
2. select a larger sample size, if warranted. 
 


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The interim analysis was blinded, i.e., conducted based solely on pooled information 
across the two treatment arms when early clinical response data were available for 60% of 
the patients planned to be randomized (approximately 404 patients). The number and 
percentage of responders and non-responders based on the primary endpoint mentioned in 
Section 8.1.1 and Clinical Success/No Success based on main secondary endpoint 
mentioned in Section 8.2.1 were provided. A summary table based on primary endpoint 
was provided on ITT population and tables based on secondary endpoint were provided on 
ITT and CE populations. 
 
The final decision for sample size re-estimation was based on the overall response rates for 
primary and secondary endpoints, and was at the Sponsor’s discretion. 
 
The interim analysis was performed in November 2018. Following the blinded review of 
the primary and secondary endpoints, it was decided to keep the sample size specified in 
the protocol unchanged. 
 
For safety monitoring, a DSMB will be utilized periodically throughout the study. Blinded 
interim safety assessments will be performed twice in each year after enrollment of the first 
patient. 
 
Details will be provided in the DSMB Charter. 
 
Note that investigators, sponsor employees, and others who are involved in the conduct 
and the analyses of the study (with the exception of the unblinded pharmacist or delegate) 
will remain blinded to the treatment codes and DSMB analysis results until all monitoring 
decisions have been made, and the database has been locked for final analysis.  
12. Changes in the Planned Analysis from Protocol 
• This SAP will be used for submission to the FDA and the EMA. No separate SAP 
will be written for EMA submission. In the EU, the main secondary objective listed 
in this SAP will be the primary objective, and the primary objective listed in this 
SAP will be the main secondary objective. 
• The other secondary endpoint related to sustained reduction in lesion size at the 
EOT and TOC visits and all-cause mortality through day 28 will also be analyzed 
for CE population. 
• The window of ±2 days was removed from the other secondary endpoint related to 
all- cause mortality through Day 28. 
• The CE Population definition was updated to include the condition till TOC visit 
• Other Secondary endpoint like patient-reported pain and lesion area will be analyzed 
using mixed-model repeated measures (MMRM) instead of ANCOVA as mentioned 
in protocol section 8.7.2. 


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13. References 
LaVange, L., Durham, T., and Koch, G., (2005). Randomization-based nonparametric 
methods for the analysis of multicentre trials. Statistical Methods in Medical Research 
Vol. 14, 281-301. 
O’Brien, P., and Fleming T. (1979). A multiple testing procedure for clinical trials. 
Biometrics Vol. 35, 549-556. 
Peduzzi, P., Henderson, W., Hartigan, P., and Lavori, P. (2002). Analysis of randomized 
controlled trials. Epidemiologic Reviews, Vol. 24, No. 1, 26-38. 
 
 


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14. Appendices 
14.1. 
Imputation Algorithm for Partial and Missing Dates and Time 
 
Incomplete Dates of Primary ABSSSI Symptom onset 
If day is missing, day will be set to 15th of the month. 
If month is missing, month and day will be set to July 1st. 
If either imputation above results in a date > informed consent, then impute it as the date of 
informed consent -1. 
Missing Time for Lesion Size Assessments 
In case assessment date is present but time is missing, time will be imputed to 12:00. 
 
Medications and Non-Drug Procedures 
 
Impute partial/missing start date with earliest possible date, and end date with latest 
possible date. 
 
If start date is completely missing in which the day, month, and year are all unknown, then 
the start date will not be imputed. 
 
For the partial start date, 
• If the year is present and the month and day are missing, set month and day to 
January 1st. 
• If the year and month are present and the day is missing and year and month are 
equal to year and month of first dose, set day to the first dose day.  
• If the year and month are present and the day is missing and year and month are not 
equal to year and month of first dose, set to 1st day of month. 
 
If the end date is completely missing, in which the day, month, and year are all unknown, 
then the end date will not be imputed. 
 
For the partial end date, 
• If the year is present and the month and day are missing, set month and day to 
December 31st. 
• If the year and month are present and the day is missing, set day to last day of the 
month. 
 


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Medications/Non-drug procedures with both missing start and end date after imputation 
will be considered as concomitant. 
 
Adverse Event  
If onset date is completely missing, onset date is set to date of first dose. 
 
If year is present and month and day are missing: 
 
If year = year of first dose, then set month and day to month and day of first dose 
 
If year < year of first dose, then set month and day to December 31st. 
 
If year > year of first dose, then set month and day to January 1st. 
 
If month and year are present and day is missing: 
 
If year = year of first dose and 
 
 
If month = month of first dose then set day to day of first dose 
 
 
If month < month of first dose then set day to last day of month 
 
 
If month > month of first dose then set day to first day of month 
 
If year < year of first dose then set day to last day of month 
 
If year > year of first dose then set day to first day of month 
 
 


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14.2. 
List of Clinical Central Laboratory Tests 
 
Hematology 
Blood Chemistry 
Basophils (10^9/L) 
Alanine Aminotransferase (U/L)  
Eosinophils (10^9/L) 
Albumin (g/L) 
Erythrocytes (10^12/L) 
Alkaline Phosphatase (U/L) 
Hematocrit (%) 
Aspartate Aminotransferase (U/L) 
Hemoglobin (g/L) 
Bilirubin (umol/L) 
Leukocytes (10^9/L) 
C Reactive Protein (nmol/L) 
Lymphocytes (10^9/L) 
Chloride (mmol/L) 
Monocytes (10^9/L) 
Creatinine (umol/L) 
Neutrophils (10^9/L) 
Direct Bilirubin (umol/L) 
Platelets (10^9/L) 
Gamma Glutamyl Transferase (U/L) 
Reticulocytes/Erythrocytes/Leukocytes (%) 
Glucose (mmol/L) 
Direct Coombs 
Glucose, Random (mmol/L) 
 
Indirect Bilirubin (umol/L) 
 
Lactate Dehydrogenase (U/L) 
 
Potassium (mmol/L) 
 
Protein (g/L) 
 
Sodium (mmol/L) 
 
Urate (mmol/L) 
 
Urea (mmol/L) 
 
Haptoglobin (g/L)