A Phase 1, Single-center, Open-label, Non-randomized, Fixed-sequence, Drug-drug Interaction Study to Assess the Effect of Repeated Doses of Intravenous Ceftobiprole on the Pharmacokinetics of Oral Pitavastatin (OATP1B Substrate) and on Plasma Levels of Coproporphyrin I (OATP1B Biomarker) in Healthy Subjects
Phase: PHASE1
Conditions: Drug-drug Interaction Study
Sponsor: Basilea Pharmaceutica

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CLINICAL STUDY PROTOCOL
A PHASE 1, SINGLE-CENTER, OPEN-LABEL, NON-RANDOMIZED, 
FIXED-SEQUENCE, DRUG-DRUG INTERACTION STUDY TO ASSESS THE EFFECT 
OF REPEATED DOSES OF INTRAVENOUS CEFTOBIPROLE ON THE 
PHARMACOKINETICS OF ORAL PITAVASTATIN (OATP1B SUBSTRATE) AND ON 
PLASMA LEVELS OF COPROPORPHYRIN I (OATP1B BIOMARKER) IN HEALTHY 
SUBJECTS
CONFIDENTIAL
Sponsor code: BPR-CP-101
ICON code: 0680-0062
EU CT number: 2024-518592-60-00
Ceftobiprole OATP1B interaction study
Investigational product:
Ceftobiprole medocaril sodium
Clinical phase:
Phase 1 study
Indication to be studied:
Not applicable
Sponsor:
Basilea Pharmaceutica International Ltd, Allschwil
Hegenheimermattweg 167b
4123 Allschwil
Switzerland
Contract Research
ICON Early Clinical & Bioanalytical Solutions
Organization 
Van Swietenlaan 6
9728 NZ Groningen
The Netherlands
Version 1.0, 30-Sep-2024
This study will be performed in compliance with the principles of Good Clinical Practice.
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CUNPCA*. SILEY PROTOCOL 
030(1) 
______________ 
_______ 
- 
Weioil.O.30-Sip-2024 
SPONSOR AUTHORIZATiON OF CUNICAL STUDY PROTOCOL 
The Sponsor and the Co'tract Resea:ch Ogantzatcn agree to conduct the study as ousned vi ttWs 
dinical study protocoL Any modlcalion ol m. dmscal study protocol must be agreed upon by m. 
Sponsor and the Conbact Research Organizabon and must be documented in wrifr.g. 
Soonsor. Basilea Pharmaceutica International Ltd. Alschwd 
T1T1 
TEM.02701 9.0 ENscbvs Da 
06 .kvi 2023 
- 
Page 2014$ 
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SPONSOR A UTHORIZATION OF CLINICAL STUDY PROTOCOL
The Sponsor and the Contract Research Organization agree to conduct the study as outlined in this 
clinical study protocol. Any modification of the clinical study protocol must be agreed upon by the 
Sponsor and the Contract Research Organization and must be documented in writing.
Name/Position:
Date:
Signature:
Sponsor: Basilea Pharmaceutica International Ltd, Allschwil
PPD

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AUTHORIZATION OF CLINICAL STUDY PROTOCOL BY CONTRACT 
RESEARCH ORGANIZATION
The Sponsor and the Contract Research Organization agree to conduct the study as outlined in this 
clinical study protocol. Any modification of the clinical study protocol must be agreed upon by the 
Sponsor and the Contract Research Organization and must be documented in writing.
Name/Position:
Date:
Signature:
Contract Research Organization: ICON Early Clinical & Bioanalytical Solutions
Jart Oosterhaven, MD, PhD
……………………
………………………
Principal Investigator
Pharmaceutical Research Associates Group BV, an ICON company

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SERIOUS ADVERSE EVENT CONTACT INFORMATION
In the event of a serious adverse event (see Appendix 8.2), the Principal Investigator or designee 
must send a report within 24 hours of notification to:
Sponsor’s Pharmacovigilance Service Provider
PrimeVigilance Limited
The Surrey Research Park
1 Occam Court Guildford
Surrey GU2 7HJ, UK
Email: Basilea@primevigilance.com
Copy: drug.safety@basilea.com

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SYNOPSIS
Study Title
A PHASE 1, SINGLE-CENTER, OPEN-LABEL, NON-RANDOMIZED, FIXED-SEQUENCE, DRUG-DRUG 
INTERACTION STUDY TO ASSESS THE EFFECT OF REPEATED DOSES OF INTRAVENOUS 
CEFTOBIPROLE ON THE PHARMACOKINETICS OF ORAL PITAVASTATIN (OATP1B SUBSTRATE) AND 
ON PLASMA LEVELS OF COPROPORPHYRIN I (OATP1B BIOMARKER) IN HEALTHY SUBJECTS
Short Study Title
Ceftobiprole OATP1B interaction study
Study Codes
Sponsor code
: BPR-CP-101
ICON code
: 0680-0062
EU CT number
: TBD
Sponsor
Basilea Pharmaceutica International Ltd, Allschwil, Hegenheimermattweg 167b, 4123 Allschwil, Switzerland
Contract Research Organization 
ICON Early Clinical & Bioanalytical Solutions, Van Swietenlaan 6, 9728 NZ Groningen, The Netherlands
Objectives and Endpoints
Objectives
Endpoints
Primary
Primary

To assess the pharmacokinetics (PK) of a 
single oral dose of pitavastatin administered 
without and with intravenous (iv) ceftobiprole 
in healthy subjects.

Plasma PK parameters of pitavastatin including
Cmax, tmax, kel, t1/2, AUC0-t, AUC0-inf, CL/F, and 
Vz/F, as appropriate.
Secondary
Secondary

To assess the pharmacodynamic (PD) effect 
of iv ceftobiprole on the diurnal plasma level 
profile of coproporphyrin I (CP-I) in healthy 
subjects.

Plasma exposure parameters of CP-I, including 
AUEC0-25.5h, Cmax, tmax, Ctrough, and C25.5h.

To describe the systemic exposure of iv 
ceftobiprole without and with oral 
administration of pitavastatin in healthy 
subjects.

Plasma exposure parameters of ceftobiprole, 
including Ctrough, Cmax, tmax, kel, t1/2, AUC0-8h, CL, 
and Vz, as appropriate.

To assess the single-dose plasma PK of the 
pitavastatin metabolite pitavastatin lactone 
after a single oral dose of pitavastatin, 
administered without and with iv ceftobiprole 
in healthy subjects.

Plasma PK parameters of pitavastatin lactone 
including Cmax, tmax, kel, t1/2, AUC0-t, AUC0-inf, as 
appropriate.

Ratios of Cmax, AUC0-t, and AUC0-inf of pitavastatin 
lactone over parent drug.

To assess the safety and tolerability of 
ceftobiprole without and with administration of 
a single oral dose of pitavastatin in healthy 
subjects.

Type, frequency, severity, timing, and 
relationship to study drug of any adverse events 
(AEs).

Abnormalities and changes vs. baseline in
clinical laboratory, vital signs, and 12-lead 
electrocardiogram (ECG) parameters, as 
appropriate.

L 
'•• 
Period I 
Period 2 
I 
1
1 
Pitavastatin 2 mg, fasted 
Pitavastatin 2 mg, fasted 
Adniissioi 
Ceftobiprole 500 mg q8h, fasted 
conditions in the morning only 
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Design and Treatments
This will be a Phase 1, single-center, open-label, non-randomized, fixed-sequence, drug-drug interaction 
study in healthy male or female subjects to assess if there is an inhibitory effect of ceftobiprole on the hepatic 
organic anion-transporting polypeptide 1B (OATP1B) activity. Pitavastatin will be used as an OATP1B 
substrate in this study. The PK of oral pitavastatin will be assessed when administered alone and when 
administered together with iv ceftobiprole in a study design including two treatment periods. In addition, the 
PD effect of repeated doses of iv ceftobiprole on the diurnal plasma levels of coproporphyrin I (CP-I) will be 
assessed in this study as CP-I is an endogenous biomarker for hepatic OATPB1 activity.
The following treatments are planned to be administered in two periods: Period 1 (from Day −1 to Day 3): 
‘pitavastatin single dose’; and Period 2 (from Day 4 to Day 8): ‘pitavastatin single dose + ceftobiprole q8h’:

On Day 1, a single oral dose of 2 mg pitavastatin will be administered in the morning under fasted 
conditions.

From Day 4 to Day 7, 500 mg ceftobiprole (as the prodrug ceftobiprole medocaril sodium)1 will be 
administered as a 2-hour iv dose every 8 hours (q8h) under fasted conditions in the morning, and 
irrespective of timing of food intake further on the day.

On Day 6, a single oral dose of 2 mg pitavastatin will be coadministered with ceftobiprole 30 minutes 
prior to the end of the first iv dose of 500 mg ceftobiprole under fasted conditions.
A schematic overview of the study design is provided in Figure 1.
Figure 1
Study design
Study Schedule
Screening:
Between Day −21 and Day −3
Admission:
Day -2
Treatment period:
Period 1 (from Day −1 to Day 3): ‘pitavastatin single dose’
Period 2 (from Day 4 to Day 8): ‘pitavastatin single dose + ceftobiprole q8h’
Discharge:
Day 8
Follow-up/Early Termination: Day 15 ± 2 days/at the time of Early Termination
Duration of Participation
Up to 38 days
Subjects
A total of 12 healthy male or female subjects.
                                               
1 Unless referring specifically to the prodrug, the term ‘ceftobiprole’ is used throughout the remainder of this protocol, and all doses are 
of ceftobiprole equivalents. 500 mg of ceftobiprole is dosed as 667 mg of ceftobiprole medocaril sodium.

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Main Criteria for Inclusion
Sex:
Male or female
Age:
18 years to 65 years, inclusive, at Screening
Body mass index:
18.0 to 30.0 kg/m2, inclusive, at Screening
Study Drug
Active Medication
Active substance:
Ceftobiprole
Mechanism of action:
Beta-lactam antibiotic with bactericidal activity
Approved in the US for the 
treatment of:

Adult patients with Staphylococcus aureus bloodstream infections 
(bacteremia) (SAB), including those with right-sided infective endocarditis 

Adult patients with acute bacterial skin and skin structure infections 
(ABSSSI) 

Adult and pediatric patients (3 months to less than 18 years old) with 
community-acquired bacterial pneumonia (CABP)
Approved in the EU for the 
treatment of:
The following infections in adults, term neonates, infants, children and 
adolescents:

Hospital-acquired pneumonia, excluding ventilator-associated pneumonia

Community-acquired pneumonia
Dosage form:
Single dose vial containing lyophilized powder for reconstitution for iv infusion
Strength:
500 mg of ceftobiprole (as 667 mg of ceftobiprole medocaril sodium) per vial
Manufacturer:
Sourced by Sponsor
OATP1B probe substrate
Active substance:
Pitavastatin
Mechanism of action:
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
Approved for:
Hyperlipidemia; hypercholesterolemia
Dosage form:
Oral tablet
Strength:
2 mg
Manufacturer:
Sourced by Sponsor
Assessments
Pharmacokinetics:
Blood sampling for pitavastatin, its metabolite pitavastatin lactone, and 
ceftobiprole concentrations in plasma
Pharmacodynamics:
Blood sampling for diurnal CP-I levels in plasma
Safety:
AEs, clinical laboratory, vital signs, 12-lead ECG

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Statistical Methods
Sample size calculation:
This is an exploratory study where no prospective calculations of statistical 
power have been made. The sample size is based on obtaining adequate PK, 
PD, safety, and tolerability, data to achieve the objectives of the study.
Safety:
Descriptive statistics.
Pharmacokinetics:
Individual PK parameters will be estimated using non-compartmental analysis, 
as follows:

Pitavastatin and pitavastatin lactone on Day 1 and Day 6: Cmax, tmax, kel, t1/2, 
AUC0-t, AUCinf, CL/F (pitavastatin only), Vz/F (pitavastatin only), as 
appropriate; ratios of Cmax, AUC0-t, and AUC0-inf of pitavastatin lactone over 
parent drug; AUC and Cmax ratio Day 6/Day 1 for pitavastatin and 
pitavastatin lactone

Ceftobiprole on Day 5 and Day 6: Ctrough, Cmax, tmax, kel, t1/2, AUC0-8h, CL, 
and Vz, as appropriate
Descriptive statistics for all plasma concentrations and PK parameters.
A mixed-effects model with subject as a random effect and treatment as a 
fixed effect will be performed on the following natural logarithm 
(ln)-transformed PK parameters of pitavastatin and pitavastatin lactone: Cmax, 
AUC0-t, and AUC0-inf. The ratio of geometric least squares means, expressed 
as test (coadministration of pitavastatin + ceftobiprole)/reference (pitavastatin 
alone), and corresponding 90% confidence intervals (CIs) will be presented. 
Pharmacodynamics:
Individual PD parameters will be estimated, as follows:

AUEC0-25.5h, Cmax, tmax, Ctrough, and C25.5h on Days −1 to 1 and Days 5 to 6; 
Cmax, AUEC0-25.5h, Ctrough and C25.5h ratio between Days 5 to 6/Days −1 to 1, 
and shift (if any) of tmax on Days 5 to 6 versus Days −1 to 1.
Descriptive statistics for CP-I plasma levels and PD parameters.
A mixed-effects model with subject as a random effect and treatment as a 
fixed effect will be performed on the following natural logarithm (ln)-
transformed PK parameters of CP-I: Cmax, and AUEC0-25.5h. The ratio of 
geometric least squares means, expressed as test (during administration of 
ceftobiprole/reference (CP-I baseline), and corresponding 90% CIs will be 
presented.

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Table 1 Schedule of Assessments
Phase
Screening
Treatment period
Follow-up / Early termination
Study day
−21 to −3
−2
−1
1
2
3
4
5
6
7
8
15 ± 2 days
Ambulatory visit
X
X
Admission
X
Confinement
X
X
X
X
X
X
X
X
X
X
Discharge
X
Informed consent
X
Medical history
X
Demographics
X
Physical examinationa
X
Bodyweight, height, and BMI calculation
X
Serology (HBsAg, anti-HCV, anti-HIV 1 and 2)
X
Drug and alcohol screen
X
X
Pregnancy test (females only)
X
X
X
12-lead ECGb,d
X
X
X
X
X
Vital signsc,d
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratorye
X
X
X
X
X
X
Eligibility check
X
X
Inclusionf
X
Study drug administration (pitavastatin)g
X
X
Study drug administration (ceftobiprole medocaril sodium)h
X
X
X
X     
PK blood sampling for pitavastatin and metabolitei,d
X
X
X
X
X
X
PK blood sampling for ceftobiprolej,d
X
X
X
X
PD blood sampling for CP-Ik
X
X
X
X
Previous and concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
For abbreviations and footnotes, see next page.

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AE=adverse event; BMI=body mass index; CP-I=coproporphyrin I; ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; HCV= hepatitis C virus; HIV= human immunodeficiency virus; ICF=informed 
consent form; LH=luteinizing hormone; PD=pharmacodynamic(s); PK=pharmacokinetic(s)
a.
Complete physical examinations will be conducted at Screening. Symptom-driven physical examinations may be conducted at any time, per the Investigator’s discretion.
b.
12-lead ECG: at Screening, on Day -2, on Days 4 and 6 (prior to terminating the first 2-hour infusion of ceftobiprole on those days), and at Follow-up/Early Termination. 12-lead ECGs will be obtained 
after at least 5 minutes of rest in a supine position. ECGs may be repeated at the discretion of the Investigator to rule out erroneous readings.
c.
Vital signs (blood pressure [systolic and diastolic], pulse, respiratory rate, and body temperature): at Screening, on Days −2 and −1, on Day 1 (predose and 2 hours postdose of pitavastatin), on Days 
4 and 6 (prior to the start of the first ceftobiprole infusion and prior to terminating the first 2-hour infusion of ceftobiprole on those days), in the morning of Days 2, 3, 5, 7 and 8 (predose when applicable), 
and at Follow-up/Early Termination. All parameters will be obtained after at least 5 minutes of rest in a supine position. Note: Table 2 provides the vital signs time points relative to Day 1 pitavastatin 
administration.
d.
If multiple assessments are scheduled at the same timepoint, procedures should be performed in the following order: ECGs, vital sign measurements, PK blood sampling for pitavastatin and ceftobiprole, 
and blood sampling for PD markers. Note that PK blood sampling should be kept as close as possible to the specified timepoint.
e.
Clinical laboratory tests (including clinical chemistry, hematology, and urinalysis) at Screening, on Day −2, in the mornings of Days 2, 5, and 7, and at Follow-up/Early Termination. Results of the tests 
on Day −2 must be reviewed prior to inclusion. A fasting period of at least 4 hours is required before obtaining clinical laboratory blood samples at all time points.
f.
Inclusion of subjects will be done at predose on Day 1. This implies that beside other screening assessments, reserve subjects will have blood sampling for OATP1B activity marker CP-I in plasma on 
Day -1 (see footnote k).
g.
OATP1B probe drug (pitavastatin) will be administered orally on Days 1 and 6 under fasted conditions (i.e., after an overnight fast [no foods and drinks, except water] of at least 10 hours). Drug intake 
will take place with approximately 240 mL of noncarbonated water. Water intake (except for the water to be given to swallow the tablet) will not be allowed from at least 1 hour prior to dosing until 1 
hour after dosing. After dosing, fasting is required until a scheduled lunch at 4 hours postdose. On Day 6, OATP1B probe drug will be administered within 30 minutes prior to end of the first 2-hour 
ceftobiprole infusion on Day 6.
h.
Study drug (ceftobiprole medocaril sodium) will be administered q8h, by 2-hour infusion, on Days 4 to 7. The first infusion on each of Days 4 to 7 will be after an overnight fast. Water intake will be ad 
libitum, and food intake will be according to the clinic meal planning.
i.
Blood sampling for PK of pitavastatin and its metabolite pitavastatin lactone in plasma on Day 1 (before pitavastatin dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours after pitavastatin 
dosing), Day 2 (24 and 36 hours after pitavastatin dosing), and Day 3 (48 hours after pitavastatin dosing), and on Day 6 (before pitavastatin dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 
12 hours after pitavastatin dosing), Day 7 (24 hours and 36 after pitavastatin dosing), and Day 8 (48 hours after pitavastatin dosing). Note: Table 2 provides the PK sampling time points relative to Day 
1 pitavastatin administration.
j.
Blood sampling for ceftobiprole PK in plasma on Day 4: predose and 2 hours (immediately after infusion stop) after start of the first infusion on Day 4; on Day 5: predose and 1, 2 (immediately after 
infusion stop), 4, 6, and 8 hours (predose prior to the second infusion on Day 5) after start of the first infusion on Day 5; on Day 6 (predose), and 1, 2 (immediately after infusion stop), 4, 6, and 8 hours 
(predose for the second infusion on Day 6) after start of the first infusion on Day 6, and on Day 7 (predose, prior to the first infusion on Day 7). Note: Table 2 provides the PK sampling time points 
relative to Day 1 pitavastatin administration.
k.
Blood sampling for OATP1B activity marker CP-I in plasma: on Day 5 prior to the start of the first ceftobiprole infusion in the morning, at 2, 4, 6, and 8 hours after the start of the first ceftobiprole infusion
on Day 5 (8-hour sample just prior to the start of the second ceftobiprole infusion), at 16 hours after the start of the first ceftobiprole infusion on Day 5 (just prior to the start of the third ceftobiprole 
infusion on Day 5), and prior to pitavastatin dosing on Day 6 (approximately 25.5 hours after the start of the first ceftobiprole infusion on Day 5) (total of 7 samples). On Day −1 and Day 1, a total of 7 
samples will be taken at the corresponding clock times as are planned for Day 5 and Day 6. Note: Table 2 provides the sampling time points relative to Day 1 pitavastatin administration.

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Table 2 Detailed Schedule of Administration of Pitavastatin and Ceftobiprole, and 
Assessments With Time Points Relative to Day 1 Pitavastatin Dosing
Day
Time Point
With Day 1 
Pitavastatin 
Dosing as 
Baseline 
(hours)
Dose
PK of 
Pitavastatin 
and Metabolite
Ceftobiprole 
PK
CP-I Bood 
Sampling
12-Lead 
ECG
Vital Signs
Screening
X
X
−2
X
X
−1
−25.5
X
X
−23.5
X
−21.5
X
−19.5
X
−17.5
X
−9.5
X
1
Predose 
Pitavastatin
X
X
X
0
Day 1 
Pitavastatin 
Dosing
0.25
X
0.5
X
0.75
X
1
X
1.5
X
2
X
X
2.5
X
3
X
4
X
6
X
8
X
10
X
12
X
2
24
X
X
36
X
3
48
X
X
4
Predose 
Ceftobiprole
X
X
70.5
Start Day 4 
First 
Ceftobiprole 
Infusion
72.5
End Day 4 
First 
Ceftobiprole 
Infusion
X 
(Immediately 
After Stopping 
Day 4 First 
Ceftobiprole 
Infusion)
X (Prior to 
Stopping 
Day 4 First 
Ceftobiprole 
Infusion)
X (Prior to 
Stopping 
Day 4 First 
Ceftobiprole 
Infusion)
78.5
Start Day 4 
Second 
Ceftobiprole 
Infusion

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Day
Time Point
With Day 1 
Pitavastatin 
Dosing as 
Baseline 
(hours)
Dose
PK of 
Pitavastatin 
and Metabolite
Ceftobiprole 
PK
CP-I Bood 
Sampling
12-Lead 
ECG
Vital Signs
80.5
End Day 4 
Second 
Ceftobiprole 
Infusion
86.5
Start Day 4 
Third 
Ceftobiprole 
Infusion
88.5
End Day 4 
Third 
Ceftobiprole 
Infusion
5
Predose 
Ceftobiprole
X
X (Prior to 
Starting Day 5 
First 
Ceftobiprole 
Infusion)
X (Prior to 
Starting 
Day 5 First 
Ceftobiprole 
Infusion)
94.5
Start Day 5 
First 
Ceftobiprole 
Infusion
95.5
X
96.5
End Day 5 
First 
Ceftobiprole 
Infusion
X 
(Immediately 
After Stopping 
Day 5 First 
Ceftobiprole 
Infusion)
X
98.5
X
X
100.5
X
X
Predose 
Ceftobiprole
X (Prior to 
Starting Day 5 
Second 
Ceftobiprole 
Infusion)
X (Prior to 
Starting Day 5 
Second 
Ceftobiprole 
Infusion)
102.5
Start Day 5 
Second 
Ceftobiprole 
Infusion
104.5
End Day 5 
Second 
Ceftobiprole 
Infusion
Predose 
Ceftobiprole
X (Prior to 
Starting Day 5 
Third 
Ceftobiprole 
Infusion)
110.5
Start Day 5 
Third 
Ceftobiprole 
Infusion

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Day
Time Point
With Day 1 
Pitavastatin 
Dosing as 
Baseline 
(hours)
Dose
PK of 
Pitavastatin 
and Metabolite
Ceftobiprole 
PK
CP-I Bood 
Sampling
12-Lead 
ECG
Vital Signs
112.5
End Day 5 
Third 
Ceftobiprole 
Infusion
6
Predose 
Ceftobiprole
X (Prior to 
Starting Day 6 
First 
Ceftobiprole 
Infusion)
X (Prior to 
Starting Day 
6 First 
Ceftobiprole 
Infusion)
118.5
Start Day 6 
First 
Ceftobiprole 
Infusion
119.5
X
Predose 
Pitavastatin
X
X (Prior to 
Day 6 
Pitavastatin 
Dosing)
120
Day 6 
Pitavastatin 
Dosing
120.25
X
120.5
End Day 6 
First 
Ceftobiprole 
Infusion
X
X 
(Immediately 
After Stopping 
Day 6 First 
Ceftobiprole 
Infusion)
X (Prior to 
Stopping 
Day 6 First 
Ceftobiprole 
Infusion)
X (Prior to 
Stopping 
Day 6 First 
Ceftobiprole 
Infusion)
120.75
X
121
X
121.5
X
122
X
122.5
X
X
123
X
124
X
124.5
X
126
X
Predose 
Ceftobiprole
X (Prior to 
Starting Day 6 
Second 
Ceftobiprole 
Infusion)
126.5
Start Day 6 
Second 
Ceftobiprole 
Infusion
128
X
128.5
End Day 6 
Second 
Ceftobiprole 
Infusion
130
X

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Day
Time Point
With Day 1 
Pitavastatin 
Dosing as 
Baseline 
(hours)
Dose
PK of 
Pitavastatin 
and Metabolite
Ceftobiprole 
PK
CP-I Bood 
Sampling
12-Lead 
ECG
Vital Signs
132
X
134.5
Start Day 6 
Third 
Ceftobiprole 
Infusion
136.5
End Day 6 
Third 
Ceftobiprole 
Infusion
7
Predose 
Ceftobiprole
X (Prior to 
Starting Day 7 
First 
Ceftobiprole 
Infusion)
X (Prior to 
Starting 
Day 7 First 
Ceftobiprole 
Infusion)
142.5
Start Day 7 
First 
Ceftobiprole 
Infusion
144
X
144.5
End Day 7 
First 
Ceftobiprole 
Infusion
156
X
150.5
Start Day 7 
Second 
Ceftobiprole 
Infusion
152.5
End Day 7 
Second 
Ceftobiprole 
Infusion
158.5
Start Day 7 
Third 
Ceftobiprole 
Infusion
160.5
End Day 7 
Third 
Ceftobiprole 
Infusion
8
168
X
X
Follow-
up/Early 
Termination
X
X
CP-I=coproporphyrin I; ECG=electrocardiogram; PK=pharmacokinetic(s)

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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
SPONSOR AUTHORIZATION OF CLINICAL STUDY PROTOCOL ..............................................2
AUTHORIZATION OF CLINICAL STUDY PROTOCOL BY CONTRACT RESEARCH 
ORGANIZATION.....................................................................................................................3
SERIOUS ADVERSE EVENT CONTACT INFORMATION.............................................................4
SYNOPSIS .....................................................................................................................................5
TABLE OF CONTENTS ...............................................................................................................15
LIST OF TABLES.........................................................................................................................17
LIST OF FIGURES .......................................................................................................................17
LIST OF ABBREVIATIONS..........................................................................................................18
1.
INTRODUCTION ...................................................................................................................19
1.1
Background.................................................................................................................19
1.1.1
Overview of the Ceftobiprole Clinical Program .............................................19
1.1.1.1
Pharmacokinetics, Product Metabolism, and Tissue Distribution 
in Humans ........................................................................................19
1.1.1.2
Pharmacokinetics/Pharmacodynamics and Target Attainment ...19
1.2
Risk-benefit Assessment and Risk Mitigation ..........................................................20
1.3
Study Rationale...........................................................................................................20
2.
OBJECTIVES AND ENDPOINTS..........................................................................................22
3.
INVESTIGATIONAL PLAN ...................................................................................................23
3.1
Overall Study Design and Plan ..................................................................................23
3.1.1
Type of Study...................................................................................................23
3.1.2
Screening Period .............................................................................................23
3.1.3
Treatment Periods ...........................................................................................23
3.1.4
Follow-up / Early Termination.........................................................................24
3.1.5
Start and End of Study and Duration of the Study........................................24
3.2
Discussion of Study Design.......................................................................................24
3.2.1
Other.................................................................................................................24
3.3
Selection of Study Population....................................................................................25
3.3.1
Inclusion Criteria .............................................................................................25
3.3.2
Exclusion Criteria ............................................................................................26
3.3.3
Removal of Subjects from Assessment.........................................................27
3.3.3.1
Stopping Rules for Individual Subjects..........................................27
3.4
Treatments...................................................................................................................28
3.4.1
Treatments Administered................................................................................28
3.4.2
Identity of Investigational Products ...............................................................28
3.4.3
Method of Assigning Subjects to Treatment Groups....................................29
3.4.4
Selection of Doses in the Study .....................................................................29
3.4.5
Timing of Doses in the Study..........................................................................30

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3.4.6
Meals During the Study...................................................................................30
3.4.7
Blinding............................................................................................................30
3.4.8
Concomitant Medication and Other Restrictions During the Study.............30
3.4.9
Treatment Compliance ....................................................................................31
3.5
Pharmacokinetic, Pharmacodynamic, and Safety Assessments.............................31
3.5.1
Pharmacokinetic, Pharmacodynamic, and Safety Assessments, and 
Schedule of Assessments ..............................................................................31
3.5.1.1
Pharmacokinetic Assessments ......................................................31
3.5.1.1.1
Blood Sampling .............................................................31
3.5.1.2
Pharmacodynamic Assessments ...................................................32
3.5.1.3
Safety and Tolerability Assessments.............................................32
3.5.1.3.1
Adverse Events..............................................................32
3.5.1.3.2
Clinical Laboratory ........................................................33
3.5.1.3.3
Vital Signs......................................................................34
3.5.1.3.4
Electrocardiogram.........................................................34
3.5.1.3.5
Physical Examination....................................................34
3.5.1.4
Total of Blood Volume.....................................................................34
3.5.2
Appropriateness of Assessments ..................................................................34
3.5.2.1
Timing of Assessments...................................................................34
3.5.3
Drug Concentration Measurements ...............................................................35
3.5.4
Retention of Blood Samples ...........................................................................35
3.6
Statistical Procedures and Determination of Sample Size.......................................35
3.6.1
Analysis Sets ...................................................................................................35
3.6.1.1
Safety Set .........................................................................................35
3.6.1.2
Pharmacokinetic Set........................................................................35
3.6.1.3
Pharmacodynamic Set ....................................................................35
3.6.2
Statistical and Analytical Plan for Pharmacokinetic, Pharmacodynamic, and 
Safety Evaluation.............................................................................................35
3.6.2.1
Pharmacokinetic Evaluation ...........................................................36
3.6.2.2
Pharmacodynamic Evaluation ........................................................37
3.6.2.3
Evaluation of Safety and Tolerability..............................................38
3.6.2.3.1
Adverse Events..............................................................38
3.6.2.3.2
Clinical Laboratory ........................................................38
3.6.2.3.3
Vital Signs and Electrocardiograms.............................38
3.6.2.3.4
Physical Examination....................................................38
3.6.3
Determination of Sample Size.........................................................................39
3.7
Data Quality Assurance..............................................................................................39
4.
ETHICS .................................................................................................................................40
4.1
Ethical Conduct of the Study .....................................................................................40

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4.2
Independent Ethics Committee..................................................................................40
4.3
Subject Information and Consent ..............................................................................41
4.4
Privacy.........................................................................................................................41
5.
STUDY ADMINISTRATIVE STRUCTURE.............................................................................42
5.1
Distribution of Activities.............................................................................................42
5.1.1
Study Drug .......................................................................................................42
5.1.2
Electronic Case Report Form Design.............................................................42
5.1.3
Data Management............................................................................................42
5.1.4
Statistics ..........................................................................................................42
5.1.5
Clinical Study Report Writing .........................................................................42
5.2
Documentation............................................................................................................42
5.2.1
Archiving..........................................................................................................42
5.2.2
Recording of Data in Source Documents and Electronic Case Report Forms
..........................................................................................................................42
6.
CONFIDENTIALITY AND PUBLICATION POLICY...............................................................43
7.
REFERENCES ......................................................................................................................44
8.
APPENDICES .......................................................................................................................45
8.1
Drug Accountability....................................................................................................45
8.2
Adverse Events and Serious Adverse Events Evaluation and Reporting...............45
8.2.1
Adverse Events................................................................................................45
8.2.2
Serious Adverse Events..................................................................................47
8.2.3
Suspected Unexpected Serious Adverse Reactions.....................................48
8.2.4
Follow-up of Adverse Events..........................................................................48
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................................9
Table 2
Detailed Schedule of Administration of Pitavastatin and Ceftobiprole, and Assessments 
With Time Points Relative to Day 1 Pitavastatin Dosing................................................11
Table 3
Pharmacokinetic Parameters ........................................................................................37
Table 4
Pharmacodynamic Parameters .....................................................................................38
LIST OF FIGURES
Figure 1
Study Design.................................................................................................................23

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LIST OF ABBREVIATIONS
ABSSSI
acute bacterial skin and skin structure infections
AE
adverse event 
BCRP
breast cancer resistance protein
BMI
body mass index
CABP
community-acquired bacterial pneumonia
CFU
colony forming unit
CI
confidence interval
CHMP
Committee for Medicinal Products for Human Use 
CP-I
coproporphyrin I
CSP
clinical study protocol
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trial Information System 
CTR
Clinical Trial Regulation
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
concentration required to inhibit 50% of the activity
ICF
Informed Consent Form
ICH
International Council for Harmonisation 
IEC
Independent Ethics Committee
IRB
Institutional Review Board
iv
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MIC
minimum inhibitory concentration
OAT
organic anion transporter
OATP1B
organic anion-transporting polypeptide 1B
OATP1B1
organic anion-transporting polypeptide 1B1
OATP1B3
organic anion-transporting polypeptide 1B3
OCT
organic cation transporter
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
q8h
every 8 hours
S. aureus
Staphylococcus aureus
SAB
Staphylococcus aureus bacteremia
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
T>MIC
Time that drug concentration exceeds MIC
TEAE
treatment-emergent adverse event
tid
three times a day
WMA
World Medical Association
Note: Definitions of pharmacokinetic (PK) and/or pharmacodynamic (PD) parameters are provided in Section 3.6.2.

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1.
INTRODUCTION
1.1
Background
A detailed description of the pharmacology, PK, safety, and toxicology of ceftobiprole from 
nonclinical and clinical studies is provided in the Investigator’s Brochure (IB).1 Details most relevant 
for the current study are summarized below.
Ceftobiprole is a beta-lactam antibiotic with bactericidal activity against a broad spectrum of 
Gram-positive 
bacteria, 
including 
methicillin-resistant 
Staphylococcus 
species, 
vancomycin-resistant Staphylococcus aureus (S. aureus), and penicillin-resistant Streptococcus 
pneumoniae. Ceftobiprole also demonstrates in vitro activity against Gram-negative bacteria, 
including Pseudomonas aeruginosa. Ceftobiprole binds tightly to penicillin-binding proteins that are 
related to beta-lactam resistance in staphylococci and pneumococci.
1.1.1
Overview of the Ceftobiprole Clinical Program
The completed ceftobiprole clinical development program includes 20 Phase 1 studies, and the 
following five Phase 3 studies: 1) in pediatric patients aged 3 months to < 18 years with either 
hospital-acquired bacterial pneumonia (HABP) or community-acquired bacterial pneumonia (CABP) 
requiring hospitalization and treatment with intravenous (iv) antibiotics (N=138); 2) in patients with 
HABP (N=772); 3) in patients with CABP (N=632); 4) in patients with acute bacterial skin and skin 
structure infections (ABSSSIs) (N=676); and 5) in patients with S. aureus bloodstream infection 
(SAB) (N=389). (The number of patients refers to the Safety population in the respective studies).
1.1.1.1
Pharmacokinetics, Product Metabolism, and Tissue Distribution in Humans
The PK of ceftobiprole in adult subjects are predictable, linear, and time-independent across the 
dose range of 125 to 1000 mg, and variability is low (<30%). Steady-state drug concentrations are
attained on the first day of dosing (3 times daily [tid]), and no appreciable accumulation is observed 
in subjects with normal renal function. The volume of distribution at steady-state of ceftobiprole is 
approximately 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 elimination half-life 
(t1/2) is 3 to 4 hours.
Ceftobiprole is eliminated primarily unchanged by renal excretion, with minimal metabolism to an 
open-ring metabolite, BAL1029, which accounts for approximately 4% of total exposure. The 
predominant mechanism responsible for elimination is glomerular filtration. The distribution of 
ceftobiprole in lung epithelial lining fluid, bone, muscle, and adipose tissue is similar to that of other 
cephalosporins. Following administration of 500 mg ceftobiprole tid 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.
1.1.1.2
Pharmacokinetics/Pharmacodynamics and Target Attainment
The probabilities of target attainment were obtained using a population PK/PD model developed for 
unbound ceftobiprole based on data from clinical studies of healthy subjects and patients.
Overall and for the recommended clinical dose regimen of ceftobiprole of 500 mg as a 2-hour 
iv infusion every 8 hours, percent probabilities of PK/PD target attainment on the first dosing day
based on free-drug plasma %T minimum inhibitory concentration (MIC) targets associated with net 
bacterial stasis (ABSSSI only) and with 1-log10 colony forming unit (CFU) reduction from baseline 

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(CABP only), weighted over the MIC distributions for the isolate collections evaluated, were >99.9% 
for S. aureus, 100% for Staphylococcus pneumoniae (CABP only), 100% for Streptococcus species 
(ABSSSI only), and approximately 87% Enterobacterales. In patients with S. aureus bacteremia, the 
highest MIC value at which percent probabilities of PK/PD target attainment on Days 1 and 10 
approached or exceeded 90% based on nonclinical ceftobiprole free-drug plasma % time that drug 
concentration exceeds MIC (T>MIC) targets associated with net bacterial stasis and a 1-log10 CFU 
reduction from baseline for S. aureus was at least 4 μg/mL (the MIC value inhibiting 100% of 
methicillin-resistant S. aureus and all S. aureus isolates). Overall and for the recommended clinical 
dose regimen of ceftobiprole of 500 mg as a 2-hour iv infusion every 6 hours for the first 8 days and 
every 8 hours from Day 9, percent probabilities of PK/PD target attainment on Days 1 and 10 based 
on free-drug plasma %T>MIC targets associated with net bacterial stasis and a 1-log10 CFU 
reduction from baseline for S. aureus, weighted over the MIC distributions for the 13,715 S. aureus
isolates collected from centers in the US from 2016 to 2020, were >99.9%.
1.2
Risk-benefit Assessment and Risk Mitigation
Up to 22 Jan 2024, the estimated overall cumulative exposure to ceftobiprole in clinical studies 
supportive of the currently approved indications is 1779 subjects/patients, comprising 1606 adult 
subjects (including 305 healthy subjects) and 173 pediatric patients. The observed safety profile is 
consistent with that of the cephalosporin class as a whole. Based on clinical Phase 3 studies in 
adults, the most common adverse reactions occurring in ≥1% of patients treated with ceftobiprole 
were nausea, diarrhea, vomiting, headache, hyponatremia, phlebitis, dysgeusia,
alanine
aminotransferase increased, and rash.
Important identified risks include hepatic enzymes increased, hyponatremia, hypersensitivity 
reactions including anaphylactic reactions, and convulsions.
The additional identified risks of nausea and vomiting, and Clostridium difficile colitis (including 
pseudomembranous colitis) are of low frequency, considered manageable, reversible, and therefore 
without significant impact on the benefit-risk of ceftobiprole. Section 6 of the IB serves as the 
Reference Safety Information for ceftobiprole.
There is no expected clinical benefit for the healthy subjects who will participate in this study. The 
information obtained in this study can be used to provide an indication for a possible effect of 
ceftobiprole on blood concentrations of drugs eliminated by OATP1B1 and OATP1B3.
Overall, on the basis of the available nonclinical and clinical data, and prior knowledge, the 
risk-benefit profile of ceftobiprole is judged acceptable for the proposed clinical study.
1.3
Study Rationale
In vitro studies demonstrated that ceftobiprole is an inhibitor of the hepatocyte uptake transporters
organic anion-transporting polypeptide 1B1 (OATP1B1) and organic anion-transporting polypeptide 
1B3 (OATP1B3) with IC50s of 67.6 µM and 44.1 µM, respectively, but is not an inhibitor of 
P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), multidrug resistance mutation 1, 
multidrug resistance-associated protein 2, organic anion transporter (OAT) 1 and 3, organic cation 
transporter (OCT) 1 and 2. Since the concentration required to inhibit 50% of the activity (IC50) values 
of OATP1B1 and OATP1B3 inhibition are in the order of magnitude of systemic ceftobiprole levels 
after efficacious clinical dose levels, ceftobiprole may increase concentrations of drugs eliminated 
by OATP1B1 and OATP1B3, such as statins (pitavastatin, pravastatin, and rosuvastatin), glyburide, 

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and bosentan. Ceftobiprole is potentially a weak substrate of the renal tubule cells uptake 
transporters OAT1 and OCT2.
This study has therefore been designed to determine whether ceftobiprole impacts the single dose 
PK of the OATP1B1 and OATP1B3 substrate pitavastatin.2 Further to the evaluation of ceftobiprole 
dosing on the levels of pitavastatin as organic anion-transporting polypeptide 1B (OATP1B) probe 
drug, this study will evaluate the effects of ceftobiprole on the systemic levels of coproporphyrin-1 
(CP-I) as endogenous marker for OATP1B activity.

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2.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Primary
To assess the PK of a single oral dose of 
pitavastatin, administered without and with 
iv ceftobiprole in healthy subjects.
Plasma PK parameters of pitavastatin 
including Cmax, tmax, kel, t1/2, AUC0-t, AUC0-inf, 
CL/F, and Vz/F, as appropriate.
Secondary
Secondary
To assess the PD effect of iv ceftobiprole 
on the diurnal plasma level profile of CP-I
in healthy subjects.
Plasma exposure parameters of CP-I, 
including AUEC0-25.5h, Cmax, tmax, Ctrough, and 
C25.5h.
To describe the systemic exposure of iv 
ceftobiprole 
without 
and 
with 
oral 
administration of pitavastatin in healthy 
subjects.
Plasma exposure parameters of ceftobiprole, 
including Ctrough, Cmax, tmax, kel, t1/2, AUC0-8h, 
CL, and Vz, as appropriate.
To assess the single-dose plasma PK of 
the pitavastatin metabolite pitavastatin 
lactone after a single oral dose of 
pitavastatin, administered without and with 
iv ceftobiprole in healthy subjects.
Plasma PK parameters of pitavastatin 
lactone including Cmax, tmax, kel, t1/2, AUC0-t, 
AUC0-inf, as appropriate.
Ratios of Cmax, AUC0-t, and AUC0-inf of 
pitavastatin lactone over parent drug.
To assess the safety and tolerability of 
ceftobiprole 
without 
and 
with 
administration of a single oral dose of 
pitavastatin in healthy subjects.
Type, frequency, 
severity, 
timing, and 
relationship to study drug of any adverse 
events (AEs).
Abnormalities and changes vs. baseline in
clinical laboratory, vital signs, and 12-lead 
electrocardiogram (ECG) parameters, as 
appropriate.

Period I 
Period 2 
Pitavastatin 2 mg, fasted 
Pitavastatin 2 mg, fasted 
Admission 
Ceftobiprole 500 mg q8h, fasted 
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3.
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
3.1.1
Type of Study
This will be a Phase 1, single-center, open-label, non-randomized, fixed-sequence, drug-drug 
interaction study in healthy male or female subjects to assess if there is an inhibitory effect of 
ceftobiprole on the hepatic OATP1B activity. Pitavastatin will be used as an OATP1B substrate in 
this study. The PK of oral pitavastatin will be assessed when administered alone and when 
administered together with intravenous (iv) ceftobiprole in a study design including two treatment 
periods. In addition, the PD effect of repeated doses of iv ceftobiprole on the diurnal plasma levels 
of CP-I will be assessed in this study as CP-I is an endogenous biomarker for hepatic OATPB1 
activity.
The treatments planned in this study are described in Section 3.4.1. 
A schematic overview of the study design is provided in Figure 1.
Figure 1
Study Design
CP-I=coproporphyrin 1; PK=pharmacokinetics; q8h=every 8 hours
3.1.2
Screening Period
Subjects will report to the medical screening facility/clinical site for the eligibility screening 
(see Section 3.3 for inclusion and exclusion criteria) within 3 weeks prior to the first drug 
administration. 
Subjects will sign the study specific Informed Consent Form (ICF) prior to any study-specific 
screening procedures being performed. The written informed consent will be obtained for all 
subjects, regardless of their eligibility for the study; the signed ICFs will be retained and archived at 
the ICON and a copy will be provided to the subject.
Eligibility screening will consist of the assessments as presented in the schedule of assessments 
(Table 1).
3.1.3
Treatment Periods
Subjects will be admitted to the clinical research center on Day −2, which is 2 days prior to Day 1, 
the day of the first drug administration, and 1 day prior to characterization of the CP-I baseline profile 
on Day −1. They will be discharged on Day 8 after completion of the assessments.

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The study design will comprise two treatment periods, with Period 1 for pitavastatin alone (from 
Day −1 to Day 3), and Period 2 for pitavastatin + ceftobiprole (from Day 4 to Day 8).
Assessments during the treatment periods will be performed as presented in the schedule of 
assessments (Table 1).
Inclusion of subjects will be done at predose on Day 1. This implies that reserve subjects will have 
blood sampling for OATP1B activity marker CP-I in plasma on Day −1.
3.1.4
Follow-up / Early Termination
The follow-up assessments will be performed 5 to 9 days after discharge on Day 8 (Day 15 ± 2 days) 
or 5 to 9 days after the time of Early Termination. 
Assessments during Follow-up/Early Termination will be performed as presented in the schedule of 
assessments (Table 1).
3.1.5
Start and End of Study and Duration of the Study
The start of the study is defined as the date on which the first subject provides informed consent.
A subject is considered to have completed the study if he/she has completed all study visits. 
The end of the study is defined as the date of the last visit or last procedure of the last subject in the 
study.
The total duration of the study from Screening until Follow-up for subjects will be up to 38 days.
3.2
Discussion of Study Design
The fixed-sequence design was chosen to allow each subject to serve as his/her own control with 
respect to pitavastatin PK characteristics with and without ceftobiprole coadministration. 
A washout period of 5 days between the days of pitavastatin administration is considered sufficient 
in view of the elimination half-life of pitavastatin (approximately 12 hours).
Strong OATP1B inhibitors are known to increase the CP-I blood concentrations. Therefore, changes 
in plasma CP-I concentrations can be used as a sensitive and selective endogenous biomarker for 
OATP1B activity and provide an indication for a possible drug-drug interaction, with the note that 
CP-I appears informative by its own merit, without apparent need for, or advantage of, adding further 
markers like coproporhyrin-III (CP-III).3,4,5 In the present study OATP1B activity will be assessed by 
comparing baseline CP-I levels to CP-I levels after multiple doses of ceftobiprole.
3.2.1
Other
For this exploratory study, no prospective calculations of statistical power have been made. The 
sample size has been based on the desire to obtain adequate PK, PD, safety, and tolerability, data 
to achieve the objectives of the study.
The intended sample size of 12 subjects is considered adequate to fully address the primary 
objective of the study, given the precedence of earlier studies with pitavastatin as probe substrate. 
Prueksaritanont and colleagues (2014) demonstrated in a sample of eight subjects the notable 
increase of pitavastatin exposure by a single dose of rifampin.2 In samples of six subjects with mild 
liver cirrhosis and six subjects with moderate liver cirrhosis, Hui and colleagues (2015) demonstrated 
an unambiguous difference in pitavastatin exposure in relation to liver function, after a single oral 
dose of 2 mg of pitavastatin.6

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Healthy subjects have been chosen as the study population due to the study design and the low risk 
of clinically significant toxicity at anticipated exposure levels. Additionally, the short duration of 
exposure will not be able to provide clear therapeutic benefit and justify patients discontinuing 
current therapies. Moreover, use of healthy subjects as opposed to patients will allow a clearer 
interpretation of the study results, as there will be no confounding factors resulting from changes in 
disease state and/or concomitant medications.
The Investigator will take all the usual precautions necessary for studies at an early stage in the 
development of a new drug.
3.3
Selection of Study Population
A total of 12 healthy male or female subjects are planned to be included in the study. 
3.3.1
Inclusion Criteria
Note: Restrictions that apply to the period after admission are described in Section 3.4.8, except 
when they concern a statement of willingness.
The following inclusion criteria must be met for a subject to be eligible for inclusion in the study:
1. Sex: male or female
2. Age: 18 years to 65 years, inclusive, at Screening.
3. Body mass index (BMI): 18.0 to 30.0 kg/m2, inclusive, at Screening.
4. Good physical and mental health on the basis of medical history, physical examination, clinical 
laboratory, ECG, and vital signs at Screening and admission to the clinical research center, as 
assessed by the Investigator.
5. Normal renal function (creatinine clearance ≥90 mL/min as determined by the Cockcroft-Gault 
equation) at Screening and admission to the clinical research center.
6. Females can be of nonchildbearing potential or of childbearing potential:
a) Female participants of nonchildbearing potential: defined as either surgically sterilized or 
physiologically incapable of becoming pregnant, or at least 1 year postmenopausal 
(amenorrhea duration of 12 consecutive months). All female participants should have a 
negative serum pregnancy test at Screening and admission to the clinical research center.
b) Female participants of childbearing potential must not be pregnant or lactating and should 
have a negative serum pregnancy test at Screening and admission to the clinical research 
center. Additionally, they must agree not to donate ova, not to attempt to become pregnant, 
and, if engaging in sexual intercourse with a fertile male partner, must agree to use 
adequate contraception from at least 4 weeks prior to the first administration of the study 
drug until after discharge from the clinical research center. Adequate contraception is 
defined as using hormonal contraceptives or an intrauterine device combined with at least 
one of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total 
abstinence from heterosexual intercourse, in accordance with the lifestyle of the participant, 
is also acceptable.
7. Male subjects, if not surgically sterilized, must agree to use adequate contraception and not
donate sperm from admission to the clinical research center until after discharge from the 
clinical research center. Adequate contraception for the male subject (and his female partner, 
if she is of childbearing potential) is defined as using hormonal contraceptives or an intrauterine 
device combined with at least one of the following forms of contraception: a diaphragm, a 

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cervical cap, or a condom. Total abstinence from heterosexual intercourse, in accordance with 
the lifestyle of the subject, is also acceptable. 
8. All prescribed medication must have been stopped at least 30 days prior to admission to the 
clinical research center. An exception is made for hormonal contraceptives, which may be used 
throughout the study.
9. All over-the-counter medication, vitamin preparations and other food supplements, or herbal 
medications (e.g., St. John’s wort) must have been stopped at least 14 days prior to admission 
to the clinical research center. An exception is made for paracetamol that is allowed up to 
admission to the clinical research center (up to 2 g/day for no more than 3 consecutive days).
10. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to Screening and 
admission to the clinical research center.
11. Ability and willingness to abstain from methylxanthine-containing beverages or food (coffee, 
tea, cola, chocolate, energy drinks) from 48 hours (2 days) prior to admission to the clinical 
research center.
12. Willing and able to sign the inform consent form.
3.3.2
Exclusion Criteria
Note: Restrictions that apply to the period after admission are described in Section 3.4.8, except 
when they concern a statement of willingness.
A subject who meets any of the following exclusion criteria will not be eligible for inclusion in the 
study:
1. Employee of ICON or the Sponsor.
2. History of relevant drug and/or food allergies, particularly to antibiotics.
3. Subject received a known potent inhibitor of OATP1B activity (e.g., cyclosporin A or rifampin) 
within 30 days prior to admission to the clinical research center. 
4. Subject received a potential inducer of OATP1B activity (e.g., carbamazepine) within 30 days 
prior to admission to the clinical research center.
5. Subject has signs of, or frequently recurring, fungal infections.
6. Subject has a history of seizures.
7. Subject has a history of frequent diarrhea.
8. Smoking more than 5 cigarettes, 1 cigar, or 1 pipe daily; the use of tobacco products in the 
48 hours (2 days) prior to admission to the clinical research center is not allowed.
9. History of alcohol abuse or drug addiction (including soft drugs like cannabis products) within 
12 months prior to Screening.
10. Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals approximately 
250 mL of beer, 100 mL of wine, or 35 mL of spirits).
11. Positive drug and/or alcohol screen (opiates, methadone, cocaine, amphetamines, 
methamphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, tricyclic 
antidepressants, and alcohol) at Screening or at admission to the clinical research center.
12. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, or 
human immunodeficiency virus (HIV) 1 and 2 antibodies at Screening.
13. Participation in a drug study within 30 days prior to the first pitavastatin administration on Day 1 
of the current study. Participation in four or more other drug studies in the 12 months prior to 
the first pitavastatin administration on Day 1 of the current study.

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14. Donation or loss of more than 450 mL of blood within 60 days prior to the first pitavastatin 
administration on Day 1 of the current study. Donation or loss of more than 1.5 liters of blood 
(for male subjects)/more than 1.0 liters of blood (for female subjects) in the 10 months prior to 
the first pitavastatin administration on Day 1 of the current study.
15. Significant and/or acute illness within 5 days prior to the first pitavastatin administration on 
Day 1 that may impact safety assessments, in the opinion of the Investigator.
16. Unsuitable veins for iv infusion or blood sampling.
Subjects should refrain from consumption of any foods containing poppy seeds within 48 hours prior 
to Screening and admission to the clinical research center to avoid false positive drug screen results. 
In addition, they should refrain from strenuous exercise within 96 hours prior to Screening and 
admission as this could result in abnormal clinical laboratory values. If subjects indicate that they 
have violated these restrictions, but this does not lead to deviating laboratory values, subjects can 
still be eligible for participation at the Investigator’s discretion.
3.3.3
Removal of Subjects from Assessment
Participation in the study is voluntary. A subject has the right to withdraw from the study at any time 
for any reason.
The Investigator has the right to terminate participation of a subject for any of the following reasons: 
difficulties in obtaining blood samples, violation of the protocol, severe AEs or serious adverse 
events (SAEs), or for any other reason relating to the subject's safety or integrity of the study data.
If a subject is withdrawn from the study, the Sponsor and/or study monitor will be informed 
immediately. If there is a medical reason for withdrawal, the subject will remain under the supervision 
of the Investigator until satisfactory health has returned.
After signing informed consent, subjects who drop out or withdraw for any reason without completing 
all screening evaluations successfully as well as subjects who drop out or withdraw prior to the first 
dose of study drug will be considered screening failures.
A subject who is withdrawn or voluntarily withdraws from the study for any reason, whether related 
to the study drug or not, after having received the first dose of study drug, will be considered an 
early-termination subject. If a subject is withdrawn for a reason related to the study drug, according 
to the judgment of the Investigator, the early-termination subject will not be replaced. If a subject 
does not complete the study for a reason not related to the study drug, the early-termination subject 
may be replaced after mutual agreement between the Sponsor and ICON.
The decision regarding the replacement of subjects will be documented.
ICON will make every effort to ensure that early-termination subjects who have received study drug 
complete the early-termination assessments/safety follow-up assessments.
3.3.3.1
Stopping Rules for Individual Subjects
Dosing of a subject will be stopped at any time during the study if any of the following circumstances 
occurs: 

A drug-related serious adverse reaction (i.e., an SAE considered at least possibly related to the 
study drug administration). 

A drug-related severe adverse reaction (i.e., severe nonserious AEs considered at least possibly 
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
Other findings that, at the discretion of the Investigator and/or Sponsor’s Medical Monitor, 
indicate that further dosing should be stopped.
3.4
Treatments
3.4.1
Treatments Administered
The following treatments are planned to be administered in two periods: Period 1 (from Day −1 to 
Day 3): ‘pitavastatin single dose’; and Period 2 (from Day 4 to Day 8): ‘pitavastatin single dose + 
ceftobiprole q8h’:

On Day 1, a single oral dose of 2 mg pitavastatin will be administered in the morning under 
fasted conditions.

From Day 4 to Day 7, 500 mg ceftobiprole (as the prodrug ceftobiprole medocaril sodium)2 will 
be administered as a 2-hour iv dose every 8 hours (q8h) under fasted conditions in the morning, 
and irrespective of timing of food intake further on the day.

On Day 6, a single oral dose of 2 mg pitavastatin will be coadministered with ceftobiprole 
30 minutes prior to the end of the first iv dose of 500 mg ceftobiprole under fasted conditions.
3.4.2
Identity of Investigational Products
Active Medication
Active substance:
Ceftobiprole
Mechanism of action:
Beta-lactam antibiotic with bactericidal activity
Approved in the US 
for the treatment of:
Adult patients with SAB, including those with right-sided infective 
endocarditis
Adult patients with ABSSSI 
Adult and pediatric patients (3 months to less than 18 years old) with 
CABP
Approved in the EU 
for the treatment of:
The following infections in adults, term neonates, infants, children and 
adolescents:
Hospital-acquired pneumonia, excluding ventilator-associated 
pneumonia
Community-acquired pneumonia
Dosage form:
Single dose vial containing lyophilized powder for reconstitution and iv 
infusion
Strength:
500 mg of ceftobiprole (as 667 mg of ceftobiprole medocaril sodium) per 
vial.
Manufacturer:
Sourced by Sponsor.
                                               
2 Unless referring specifically to the prodrug, the term ‘ceftobiprole’ is used throughout the remainder of this protocol, and all doses are 
of ceftobiprole equivalents. 500 mg of ceftobiprole is dosed as 667 mg of ceftobiprole medocaril sodium.

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OATP1B probe substrate
Active substance:
Pitavastatin
Mechanism of action:
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
Approved for:
Hyperlipidemia; hypercholesterolemia
Dosage form:
Oral tablet
Strength:
2 mg
Manufacturer:
Sourced by Sponsor
Details of study drug preparation by the ICON Pharmacy are described in the Pharmacy Preparation 
Record prepared by the ICON Pharmacy. 
The active medication and the probe substrate are commercially obtained by Sponsor. 
For details concerning drug storage and drug accountability, see Appendix 8.1.
3.4.3
Method of Assigning Subjects to Treatment Groups
All subjects signing informed consent will be assigned a subject number in Electronic Data Capture 
(EDC). After signing informed consent, subjects who drop out or withdraw for any reason without 
completing all screening evaluations successfully, as well as subjects who drop out or withdraw prior 
to the first dose of study drug, will be considered screening failures. A minimal set of screen failure 
information will be collected: demography, screen failure details, eligibility criteria, and any SAE.
On Day 1, subjects eligible for treatment will be assigned an enrollment number (01–12). In the event 
that a subject would need to be replaced (see Section 3.3.3), the replacement subject will receive 
the enrollment number of the subject to be replaced, increased by 100 (e.g., 101 replacement 
number for enrollment number 01), and will be administered the same treatments in the same order.
3.4.4
Selection of Doses in the Study
The selected dose of ceftobiprole of 500 mg administered as a 2-hour iv infusion q8h is the 
recommended dose of ceftobiprole for adult patients with ABSSSI, for adult and pediatric patients 
with CABP, and as maintenance dose in adult patients with SAB. This regimen results in systemic 
ceftobiprole exposure that is well in the ranges of IC50 values for OATP1B inhibition, and thereby 
considered appropriate for the objectives of the present study. A more intense dosing regimen with 
dosing every 6 hours as in the early phase of SAB treatment is therefore not proposed for the current 
study.
Based on the safety profile of multiple iv doses (tid) seen in previous studies, 500 mg tid (total 
1,500 mg/day) is considered a safe dose in this study.1
Regarding pitavastatin as OATP1B probe drug, a dose of 2 mg is proposed for the present study, 
considering its successful use when discriminating pitavastatin exposures in small samples of 
subjects with mild and moderate liver impairment (Hui et al. 2004).6 The 2-mg dose level is expected 
to provide a more complete characterization of the full PK profile of pitavastatin, compared to the 
1-mg dose level deployed previously by Prueksaritanont et al. (2014) to assess the OATP1B 
inhibiting effect of rifampin.2 The 2-mg dose remains in the range of linearity of pitavastatin PK.7 The 
intended single 2-mg dose provides a more than 30-fold safety margin versus the 64-mg dose 
evaluated clinically previously in a repeated dosing setting8, and is therefore expected to be a safe 
single dose, also in case of a major interaction.

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3.4.5
Timing of Doses in the Study
On Day 1 and Day 6, pitavastatin will be administered to subjects between 08:00 and 12:00 hours 
in the morning under fasted conditions. Subjects will fast overnight for at least 10 hours following a 
light supper. 
The study drug will be swallowed together with approximately 240 mL water (room temperature). 
The study drug should not be chewed. 
On Days 4 to Day 7, ceftobiprole will be administered as a 2-hour iv infusion 3 times a day every 
8 hours (q8h). The morning dose will be administered following an overnight fast of at least 10 hours.
On Day 6, a single oral dose of pitavastatin will be coadministered the morning with a single iv dose 
of dose of ceftobiprole under fasted conditions. Pitavastatin will be administered 30 minutes prior to 
the end of the 2-hour ceftobiprole infusion.
On Days 1 and 6 only, fasting will continue for a period of 4 hours after administration of pitavastatin, 
i.e., until scheduled lunch. On Days 4, 5 and 7, a non-standardized breakfast will be given 1 hour 
after the end of the first ceftobiprole infusion of that day. 
During fasting, no fluids are allowed except water, with the following exception. On Days 1 and 6, 
water is not allowed from 1 hour before administration of pitavastatin until 1 hour after administration 
of pitavastatin (apart from the water taken with the dose as described above).

On Days 4 to 7, water is not allowed from 1 hour before the start of the first ceftobiprole infusion 
until 1 hour after the end of the first ceftobiprole infusion.
When not fasting, noncaffeinated fluids are allowed ad libitum.
On PK days (Day 1, Day 5, and Day 6) dosing for each individual subject will be at around the same 
time (±15 minutes) on each dosing day. On other (non-PK) days, a margin of ±30 minutes is allowed.
3.4.6
Meals During the Study
A fasting period of at least 4 hours is required before obtaining clinical laboratory blood samples at 
all time points.
With the exception of the restrictions with respect to methylxanthine- and alcohol-containing 
beverages or food as described in Section 3.4.8, and what has been described in Section 3.4.5, 
there are no special requirements related to food and beverage intake. When not fasting, meals and 
snacks (such as decaffeinated coffee, herbal tea, fruit, biscuits) will be provided according to the 
clinical site Standard Operating Procedures (SOPs). A light supper will be provided on the evening 
before those days where fasting is required until lunch time. 
3.4.7
Blinding
This is an open-label study.
3.4.8
Concomitant Medication and Other Restrictions During the Study
Note: Restrictions that apply to the period before admission are described in Section 3.3.1 and 
Section 3.3.2.
The use of all prescribed medication is not allowed from admission to the clinical research center 
until Follow-up. An exception is made for hormonal contraceptives, which are allowed throughout 
the study. The use of all over-the-counter medication, vitamin preparations and other food 

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supplements, or herbal medications (e.g., St. John’s wort) is not allowed from admission to the 
clinical research center until Follow-up. An exception is made for paracetamol: from admission 
onwards, the Investigator may permit a limited amount of paracetamol for the treatment of headache 
or any other pain (up to 2 g/day for no more than 3 consecutive days). Other medication to treat AEs 
may only be prescribed if deemed necessary by the Investigator. If medication is used, the name of 
the drug, the dose, and dosage regimen will be recorded in the eCRF. 
The use of methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy 
drinks), and grapefruit (juice) and tobacco products is not allowed during the stay in the clinical 
research center.
The use of alcohol is not allowed during the stay in the clinical research center and within 48 hours 
prior to Follow-up.
Strenuous exercise is not allowed from admission to the clinical research center until Follow-up. 
Male subjects, if not surgically sterilized, are required to use adequate contraception (see description 
below) and not donate sperm from admission to the clinical research center until after discharge 
from the clinical research center.
Female subjects of childbearing potential with a fertile male sexual partner are required to use 
adequate contraception (see description below) from at least 4 weeks prior to first administration of 
the study drug until after discharge from the clinical research center.
Adequate contraception is defined as using hormonal contraceptives or an intrauterine device 
combined with at least one of the following forms of contraception: a diaphragm, a cervical cap, or 
a condom. Total abstinence from heterosexual intercourse, in accordance with the lifestyle of the 
subject, is also acceptable.
Subjects must not donate blood during the study until the follow-up visit (other than the blood 
sampling planned for this study).
3.4.9
Treatment Compliance
Study drug will be administered in the clinical research center. To ensure treatment compliance, 
administration of the study drug will be supervised by the Investigator or authorized designee. 
Compliance will be further confirmed by bioanalytical assessment of pitavastatin and ceftobiprole in 
plasma samples (see Section 3.5.3).
The exact times of study drug administration and the number of units administered must be recorded 
in the eCRF. 
3.5
Pharmacokinetic, Pharmacodynamic, and Safety Assessments
3.5.1
Pharmacokinetic, Pharmacodynamic, and Safety Assessments, and Schedule of 
Assessments
A schedule of assessments is presented in Table 1.
3.5.1.1
Pharmacokinetic Assessments
3.5.1.1.1
Blood Sampling
At the time points defined in the Schedule of Assessments, blood samples will be taken for the 
analysis of pitavastatin, the metabolite pitavastatin lactone, and ceftobiprole in plasma samples. The 

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blood samples will be taken via an indwelling iv catheter or by direct venipuncture. The exact times 
of blood sampling will be recorded in the eCRF. Ceftobiprole PK samples should not be taken from 
the ceftobiprole iv infusion line and should be taken from the opposite arm during ceftobiprole 
infusion.
Details on sample processing, storage, and shipping will be described in the laboratory manual 
prepared by ICON.
Plasma samples may (in the future) also be used for research purposes such as evaluation of the 
activity of ceftobiprole, identification of exploratory biomarkers that are predictive of activity, or other 
exploratory evaluations that may help characterize the molecular mechanisms of ceftobiprole.
3.5.1.2
Pharmacodynamic Assessments
At the time points defined in the schedule of assessments, blood samples will be taken for the 
analysis of plasma CP-I levels.
Inclusion of subjects will be done at predose on Day 1. This implies that reserve subjects will have 
blood sampling for OATP1B activity marker CP-I in plasma on Day −1.
3.5.1.3
Safety and Tolerability Assessments
Safety and tolerability assessments will consist of AEs, clinical laboratory, vital signs, 12-lead ECG, 
and physical examination. Assessments will be performed in accordance with the schedule of 
assessments.
3.5.1.3.1
Adverse Events
The time period for actively eliciting and collecting AEs and SAEs (‘active collection period’) for each 
subject begins from the time the subject provides informed consent, which is obtained before 
undergoing any study-related procedure and/or receiving study intervention), up to and including 
Follow-up.
Any clinically significant observations, as determined by the Investigator, in the results of clinical 
laboratory tests, 12-lead ECGs, vital signs measurements, or physical examinations will be recorded 
as AEs.
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the first 
administration of the study drug, or any event already present that worsens in either severity or 
frequency following exposure to the study drug. 
An AE that occurs prior to the first administration of the study drug will be considered a 
pre-treatment AE. 
At several time points before and after drug administration, subjects will be asked non-leading 
questions to determine the occurrence of AEs. Subjects will be asked in general terms about any 
AEs at regular intervals during the study. In addition, all AEs reported spontaneously during the 
course of the study will be recorded. All AEs will be recorded in the eCRF as reported terms. 
The severity of the AEs will be graded in accordance with the Common Terminology Criteria for 
Adverse Events (CTCAE v5.0); the relationship between the AEs and the study drug will be indicated 
as related or not related. Details on grading the severity of AEs and assessing the relationship to 
study treatment are given in Appendix 8.2.

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For subjects who are screening failures, the active collection period ends when screening failure 
status is determined.
If a subject withdraws from the study and also withdraws consent for the collection of future 
information, the active collection period ends when consent is withdrawn.
If a subject either permanently or temporarily discontinues participation in the study because of an 
AE or SAE, the event must be recorded in the eCRF, and if an SAE, reported using the SAE Report 
Form.
Investigators are not required to actively seek information on AEs or SAEs after the subject has 
concluded study participation. However, if the Investigator learns of any SAE, including a death, at 
any time after a subject has completed the study, and considers the event to be reasonably related 
to the study drug, the Investigator must promptly report the SAE to the Sponsor using the SAE 
Report Form.
Any pregnancy of either a subject or a partner of a male subject must be monitored, until Follow-up 
if warranted.
3.5.1.3.2
Clinical Laboratory 
Blood and urine samples for clinical laboratory assessments will be collected, analyzed, and 
processed according to the clinical site SOPs.
The following parameters will be measured:

Clinical chemistry (serum quantitatively):
total bilirubin, alkaline phosphatase, gamma glutamyl transferase, aspartate aminotransferase, 
alanine aminotransferase, lactate dehydrogenase creatinine, creatine kinase, urea, total 
protein, glucose, inorganic phosphate, sodium, potassium, calcium, and chloride.
Creatinine clearance will be calculated using the Cockcroft-Gault equation at screening and 
admission to the clinical research center.

Hematology (blood quantitatively):
leukocytes, erythrocytes, hemoglobin, hematocrit, thrombocytes, absolute partial automated 
differentiation (lymphocytes, monocytes, eosinophils, basophils, and neutrophils), mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration. 
Manual differential white blood cell count or red blood cell differentiation will only be performed 
if there is an abnormality in the blood cell count in accordance with the clinical site SOPs.

Urinalysis (urine qualitatively):
specific gravity, pH, hemoglobin, leukocytes, nitrite, protein, glucose, bilirubin, ketones, and 
urobilinogen. 
Urine sediment examinations will only be performed if there is an abnormality in urinalysis in 
accordance with the clinical site SOPs.

Serology:
HbsAg, HCV antibodies, and HIV 1 and 2 antibodies.

Drug and alcohol screen (urine or serum qualitatively):
Urine: opiates, methadone, cocaine, amphetamines, methamphetamines (including ecstasy), 
cannabinoids, barbiturates, benzodiazepines, and alcohol.
Serum: tricyclic antidepressants. 

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
Pregnancy test (females only):
β-human chorionic gonadotropin in serum.
For screening and admission, clinical laboratory tests may be repeated once if in the judgment of 
the Investigator there is a reason to believe the initial results are inaccurate.
In the event of an unexplained or unexpected clinical laboratory test value, the test must be repeated 
as soon as possible and followed up until the results have returned to the normal range and/or an 
adequate explanation for the abnormality is found. The clinical laboratory will clearly mark all 
laboratory test values that are outside the normal range, and the Investigator will indicate which of 
these deviations are clinically significant. Clinically significant laboratory result deviations must be 
recorded as AEs, with the relationship to the treatment indicated (see also Appendix 8.2).
3.5.1.3.3
Vital Signs
Systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate should be 
recorded after the subject has been resting for at least 5 minutes in the supine position. These 
assessments should be made using an automated device whenever possible. 
For screening and admission, vital signs may be repeated once if in the judgment of the Investigator 
there is a reason to believe the initial results are inaccurate (e.g., white coat hypertension).
3.5.1.3.4
Electrocardiogram
A standard 12-lead ECG is to be recorded after the subject has been resting for at least 5 minutes 
in the supine position. The ECG will be recorded using an ECG machine equipped with 
computer-based interval measurements. The following ECG parameters will be recorded: heart rate, 
PR interval, QRS-duration, QT-interval, QTc-interval (Fridericia’s), and the interpretation of the ECG 
profile by the Investigator.
For screening and admission, ECG may be repeated once if in the judgment of the Investigator there 
is a reason to believe the initial results are inaccurate.
3.5.1.3.5
Physical Examination
Physical examination including body weight and height will be performed according to the clinical 
site SOPs. 
3.5.1.4
Total of Blood Volume
The total volume of blood drawn for a subject will not exceed 500 mL (except when extra blood 
samples need to be taken for safety reasons). 
3.5.2
Appropriateness of Assessments
The assessments that will be made in this study are standard and generally recognized as reliable, 
accurate, and relevant. 
3.5.2.1
Timing of Assessments 
For pitavastatin PK, predose samples will be obtained between waking up and dosing. Postdose 
samples up to 20 minutes postdose will be obtained with a time window of ±1 minute. Thereafter, 
postdose samples will be obtained with time margins of ±5% of the time that has passed since 
dosing.
For ceftobiprole PK, samples prior to the first infusion of a day will be obtained between waking up 
and the start of the iv infusion. For predose (trough) samples during multiple dosing, a 5% time 

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window since the last dose is allowed, but the sample must be taken before the next dose. Postdose 
samples up to 20 minutes after the start of the iv infusion will be obtained with a time window of ±1 
minute. Thereafter, postdose samples will be obtained with time margins of ±5% of the time that has 
passed since the start of the iv infusion.
For CP-I diurnal profiling on Days -1 to 1 and on Days 5 to 6, samples will be obtained within margins 
of ±15 minutes. On Day 5, the first sample will be obtained prior to the start of the iv infusion with 
ceftobiprole. On Days 1 and 6, the last CP-I sample will be collected prior to pitavastatin dosing.
For safety assessments, predose assessments will be performed between waking up and dosing /
the start of the iv infusion. For safety assessments up to 2.5 hours postdose/after the start of the iv 
infusion, a time window of ±15 minutes is allowed. Thereafter, serial postdose assessments 
(e.g., multiple assessments within any given day) must be performed with time margins of ±10% of 
the time that has passed since (last) dosing/the start of the iv infusion.
When assessments are planned for the same scheme time, the order of the assessments should be 
arranged in such a way that PK and PD blood sampling will be done after the ECG and vital signs 
recordings have been conducted, with PK blood sampling exactly on time.
3.5.3
Drug Concentration Measurements
The analysis of pitavastatin, metabolite pitavastatin lactone, ceftobiprole, and CP-I in plasma 
samples will be performed using validated liquid chromatography-mass spectrometry/mass 
spectrometry methods. 
3.5.4
Retention of Blood Samples
Blood and urine samples remaining after clinical laboratory assessments have been performed can 
be used by ICON to develop and test methods. ICON will process these samples anonymously.  
Blood samples remaining after PK and/or PD assessments have been performed will be stored by
the Sponsor for research related to this clinical study. The samples will be stored for a maximum 
period of 12 months, after which they will be destroyed.
3.6
Statistical Procedures and Determination of Sample Size
3.6.1
Analysis Sets
3.6.1.1
Safety Set
All subjects who have received at least one dose of study drug.
3.6.1.2
Pharmacokinetic Set
All subjects who have received at least one dose of study drug and provided sufficient bioanalytical 
assessment results to calculate reliable estimates of the PK parameters.
3.6.1.3
Pharmacodynamic Set
All subjects for whom the PD data are considered to be sufficient and interpretable.
3.6.2
Statistical and Analytical Plan for Pharmacokinetic, Pharmacodynamic, and Safety 
Evaluation
A Statistical Analysis Plan (SAP) will be generated by Basilea and finalized prior to database lock. 
Full details of the analysis to be performed will be included in the SAP.

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Any deviation from the SAP will be reported in the section “Changes in Planned Analysis” in the 
clinical study report (CSR).
3.6.2.1
Pharmacokinetic Evaluation
PK endpoints will be the plasma PK parameters of pitavastatin, pitavastatin lactone, and
ceftobiprole. The PK parameters to be determined or calculated using noncompartmental analysis 
from the plasma concentration-time data for pitavastatin, pitavastatin lactone, and ceftobiprole
include, but are not limited to, the parameters as given in Table 3. A complete list of PK parameters 
and analyses will be provided in the SAP.

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Table 3
Pharmacokinetic Parameters
Parameter Description
Pitavastatin
Pitavastatin 
lactone
Ceftobiprole
Ctrough
Trough plasma concentration
X
Cmax
Maximum observed plasma concentration
X
X
X
tmax
Time to attain maximum observed plasma concentration
X
X
X
AUC0-t
Area under the plasma concentration-time curve up to 
time t, where t is the last point with concentrations above 
the lower limit of quantification (LLOQ) 
X
X
AUC0-8h
Area under the plasma concentration-time curve up to 8 
hours after the start of the first ceftobiprole infusion of the 
day (prior to the second infusion of the day)
X
AUC0-inf
Area under the plasma concentration-time curve from 
time 0 to infinity calculated as: AUC0-inf=AUC0-t+Clast/kel,
where Clast is the last measurable plasma concentration 
X
X
kel
Terminal elimination rate constant
X
X
X
t1/2
Terminal elimination half-life, calculated as 0.693/kel
X
X
X
CL
Clearance
X
CL/F
Apparent oral clearance, calculated as dose/AUC0-inf
X
Vz
Volume of distribution at terminal phase 
X
Vz/F
Apparent volume of distribution at terminal phase 
X
In addition, ratios of Cmax, AUC0-t, and AUC0-inf of pitavastatin lactone over parent drug will be 
calculated.
Also, the Day 6/Day 1 ratios will be calculated for AUC and Cmax for pitavastatin and pitavastatin 
lactone. 
The PK parameters and their statistical evaluation will be included in the CSR for this study.
All data will be summarized using descriptive statistics and will be listed and summarized in tabular 
and/or graphical form.
A mixed-effects model with subject as a random effect and treatment as a fixed effect will be 
performed on the following natural logarithm (ln)-transformed PK parameters of pitavastatin and
pitavastatin lactone: Cmax, AUC0-t, and AUC0-inf. The ratio of geometric least squares means, 
expressed as test (coadministration of pitavastatin + ceftobiprole)/reference (pitavastatin alone), and 
corresponding 90% confidence intervals (CIs) will be presented.
3.6.2.2
Pharmacodynamic Evaluation
PD endpoints will be the plasma exposure parameters of CP-I. The parameters to be determined or 
calculated from the plasma level-time data CP-I include, but are not limited to, the parameters as 
given in Table 4. A complete list of plasma exposure parameters and analysis will be provided in the 
SAP.

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Table 4
Pharmacodynamic Parameters
Parameter
Description
Cmax
Maximum observed plasma level
tmax
Time to attain maximum observed plasma level
Ctrough
Trough plasma level
C25.5h
Plasma level at 25.5 hours after the start of the first ceftobiprole infusion on Day 5 (prior to 
pitavastatin dosing on Day 6) or at the corresponding clock time on Day 1
AUEC0-25.5h
Area under the plasma level-time curve up to time 25.5 hours after the start of the first ceftobiprole 
infusion on Day 5 (prior to pitavastatin dosing on Day 6) or at the corresponding clock time on Day 1
In addition, Cmax, AUEC0-25.5h, Ctrough and C25.5h ratio between Days 5 to 6/Days -1 to 1, and shift (if 
any) of tmax on Days 5 to 6 versus Days -1 to 1 will be calculated.
The PD parameters and their statistical evaluation will be included in the CSR for this study.
All data will be summarized using descriptive statistics and will be listed and summarized in tabular 
and/or graphical form.
Statistical analysis will be performed on PD parameters to compare baseline CP-I plasma 
concentrations to CP-I plasma concentrations after multiple doses of ceftobiprole. A mixed-effects 
model with subject as a random effect and treatment as a fixed effect will be performed on the 
following natural logarithm (ln)-transformed PK parameters of CP-I: Cmax, and AUEC0-25.5h. The ratio 
of 
geometric 
least 
squares 
means, 
expressed 
as 
test 
(during 
administration 
of 
ceftobiprole)/reference (CP-I baseline), and corresponding 90% CIs will be presented. 
3.6.2.3
Evaluation of Safety and Tolerability
Safety and tolerability will be assessed through AEs, clinical laboratory, vital signs, ECGs, and 
physical examination findings.
3.6.2.3.1
Adverse Events
A listing of all individual AEs will be provided. Summary tables of TEAEs will be presented by System 
Organ Class based on the MedDRA terminology list (Preferred Terms): one containing the number 
of TEAEs (frequency of occurrence, number of subjects experiencing the event) by treatment and 
one containing the number of drug-related TEAEs (frequency of occurrence, number of subjects 
experiencing the event) per treatment. Additional tables of total counts by treatment and relationship 
and by treatment and severity will be given.
3.6.2.3.2
Clinical Laboratory
Clinical laboratory data will be listed accompanied by an indication if the parameter is outside the 
reference range. A listing of all data outside the reference range of the clinical laboratory will be 
provided. Clinical laboratory data will be presented descriptively, where applicable.
3.6.2.3.3
Vital Signs and Electrocardiograms
Vital signs and ECG parameters will be listed and presented descriptively, where applicable.
3.6.2.3.4
Physical Examination
Physical examinations will be listed.

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3.6.3
Determination of Sample Size
This is an exploratory study where no prospective calculations of statistical power have been made. 
The sample size is based on obtaining adequate PK, PD, safety, and tolerability, data to achieve the 
objectives of the study. For this study, no prospective calculations of statistical power have been 
made. Any p values to be calculated according to the SAP will be interpreted in the perspective of 
the explorative character of this study.
3.7
Data Quality Assurance
The study may be audited by the Quality Assurance Department at ICON to assess adherence to 
the clinical study protocol (CSP) and Quality System. During the conduct of the study, 
process-related audits may be performed. An audit certificate outlining any audits and other related 
activities performed may be provided in the appendices of the final CSR. 
The clinical research site will be monitored by the study monitor to ensure correct performance of 
the study procedures and assure that the study is conducted according to the relevant regulatory 
requirements. The eCRF entries will be verified with the source documentation.
Regulatory authorities, the Independent Ethics Committee (IEC), and/or the Sponsor’s clinical quality 
assurance group may request access to all source documents, eCRFs, and other study 
documentation for on-site audit or inspection. Direct access to these documents must be guaranteed 
by the Investigator, who must provide support at all times for these activities. If there are any missing 
or spurious data, they will be queried by the data manager and/or the study monitor.
Quality control principles will be applied throughout the performance of this study. Review 
procedures will be followed at ICON for all documents that are generated in relation with the study. 
An explanation will be given for all missing and spurious data in the relevant sections of the CSR.

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4.
ETHICS
4.1
Ethical Conduct of the Study
This study will be conducted in accordance with the ethical principles that have their origin in the 
World Medical Association (WMA) Declaration of Helsinki.9
This study is also designed to comply with International Council for Harmonisation (ICH) E6(R2) 
Guideline for Good Clinical Practice (GCP) (European Medicines Agency [EMA]/Committee for 
Medicinal Products for Human Use [CHMP]/ICH/135/1995)10, and the EU Clinical Trial Regulation 
(CTR) (Regulation Number 536/2014)11 and other applicable laws, regulations, and regulatory 
guidance.
Whenever the term “Investigator” is noted in the CSP text, it may refer to either the Investigator at 
the site or an appropriately appointed sub-investigator.
4.2
Independent Ethics Committee 
The CSP, ICF/subject information leaflet, investigational medicinal product dossier (IMPD), IB and 
any other documents required by the EU CTR (Regulation Number 536/2014)11 will be submitted via 
Clinical Trial Information System (CTIS) to obtain regulatory approval before the clinical study is 
started. The submission package will be evaluated by Independent Ethics Committees in the 
Member States concerned.
When applicable, the Sponsor will also submit and obtain approval for substantial modifications to 
the original approved documents via CTIS. A ‘substantial modification’ is defined in the CTR as any 
change to any aspect of the clinical study which is made after notification of approval and which is 
likely to have a substantial impact on the safety or rights of the subjects or on the reliability and 
robustness of the data generated in the clinical study. Substantial modifications must not be 
implemented before approval, unless necessary to eliminate hazards to the subjects.
During the study, the Sponsor will notify within 15 days through CTIS each Member State concerned 
of the following:

the start of the clinical study in relation to that Member State

the first visit of the first subject in relation to that Member State 

the end of the recruitment of subjects for a clinical study in that Member State

the end of a clinical study in relation to that Member State

the end of a clinical study in all Member States concerned and in all third countries in which the 
clinical study has been conducted.
In case of a temporary halt of a clinical study in all Member States concerned for reasons not 
affecting the benefit-risk analysis, the Sponsor will inform each Member State within 15 days through 
CTIS. If the clinical study is resumed, this will also be notified through CTIS. 
The Sponsor will notify early termination of the clinical study for reasons not affecting the benefit-risk 
balance through CTIS. The reasons for such action and, when appropriate, follow-up measures for 
the subjects will be provided as well.
The Sponsor will suspend the study if there is sufficient ground that continuation of the study will 
jeopardize subject health or safety. The temporary halt or early termination of a clinical study for 
reasons of a change of the benefit-risk balance will be notified to the Member States concerned 

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through the EU portal CTIS without undue delay, but not later than in 15 days of the date of the 
temporary halt or early termination. The notification will include the reasons for such action and 
specify follow-up measures. The restart of the clinical study following a temporary halt in this case 
will be deemed to be a substantial modification subject to the above-described authorization 
procedure.
4.3
Subject Information and Consent
All subjects will be informed verbally and in writing regarding the objectives, procedures, and risks 
of study participation. The subjects will have to sign the ICF before any study-related procedures 
are started. The ICF contains information about the objectives of the study, the procedures followed 
during the study, and the risks and restrictions of the study, with special reference to possible side 
effects of the study drug and potential interactions. In addition, insurance coverage provided during 
the study is explained. The elements addressed in the ICF are according to the ICH E6(R2) 
Guideline for GCP (EMA/CHMP/ICH/135/1995).10
4.4
Privacy
All personal details will be treated as confidential by the Investigator and staff at ICON, the Sponsor, 
and any subcontractors involved, and handling of personal data will be in compliance with the EU 
General Data Protection Regulation12.

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5.
STUDY ADMINISTRATIVE STRUCTURE
5.1
Distribution of Activities
5.1.1
Study Drug
The active medication and the probe substrate will be commercially obtained by the Sponsor. 
5.1.2
Electronic Case Report Form Design
The eCRF design will be performed by the Sponsor or designee.
5.1.3
Data Management
Data management will be performed by the Sponsor or designee.
5.1.4
Statistics
A SAP will be provided by the Sponsor or designee. The safety analysis and the statistical evaluation 
of PK and PD parameters will be conducted by the Sponsor or designee. Statistical analysis will be 
performed with the computer program SAS® (SAS Institute Inc, Cary, NC, US). PK and PD 
parameters will be calculated using Phoenix WinNonlin (Certara, Princeton, NJ, US). Additional PK
or PD computations can also be performed in SAS®.
5.1.5
Clinical Study Report Writing
The CSR, structured in accordance with the guideline “Structure and Content of Clinical Study 
Reports ICH E3”13, will be written by ICON.
5.2
Documentation
5.2.1
Archiving
All documents concerning the study will be kept on file in the Central Archives of ICON for at least 
25 years after conduct of the study. The Sponsor will receive the completed eCRFs (upon request, 
as PDF file).
5.2.2
Recording of Data in Source Documents and Electronic Case Report Forms
Source documents provide evidence for the existence of the participant and substantiate the integrity 
of the data collected. Source documents are filed at the investigator site.
Data entered in the eCRF that are from source documents must be consistent with the source 
documents, or the discrepancies must be explained. If necessary, the Investigator may request 
previous medical records or transfer records. Current medical records must be available. A 
study-specific source document identification list will be finalized with the Sponsor prior to the start 
of the clinical phase of the study.
The Investigator must maintain accurate documentation (source data) that supports the information 
entered in the eCRF.
The Sponsor or designee will perform monitoring to confirm that data entered into the eCRF by 
authorized site personnel are accurate, complete, and verifiable from source documents when 
applicable; that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, ICH 
GCP guidelines, and all applicable regulatory requirements.
For screening failures and participants who are eligible for inclusion in the study but do not receive 
the study drug, only applicable data will be entered in the eCRFs, such as informed consent, 
demographics, reason for screen failure, and SAEs, if any.

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6.
CONFIDENTIALITY AND PUBLICATION POLICY
All information generated in this study is considered confidential and must not be disclosed to any 
person or entity not directly involved with the study unless prior written consent is gained from the 
Sponsor, unless the disclosure is to authorized regulatory officials, the Sponsor, or the Sponsor’s
authorized representatives under applicable laws and regulations.
All study subjects must be informed that their personal study-related data will be handled by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be explained 
to the subject, who will be required to give consent for their data to be used as described in the ICF. 
The subjects must be informed that their medical records may be examined by auditors or other 
authorized personnel appointed by the Sponsor, by appropriate IEC members, and by inspectors 
from regulatory authorities.
Identification of subjects and eCRFs must be by unique subject numbers only. 
All relevant aspects regarding publication will be part of the contract between the Sponsor and ICON.

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7.
REFERENCES
1. Investigator’s Brochure Ceftobiprole medocaril (BAL5788), Edition 23, 24 April 2024.
2. Prueksaritanont et al. Pitavastatin is a more sensitive and selective organic anion-transporting 
polypeptide 1B clinical probe than rosuvastatin. Br J Clin Pharmacol 2014;78:587–98.
3. Mori D, Kimoto E, Rago B, Kondo Y, King-Ahmad A, Ramanathan R, Wood LS, Johnson JG, Le 
VH, Vourvahis M, David Rodrigues A, Muto C, Furihata K, Sugiyama Y, Kusuhara H.
Dose-Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive 
Evaluation of Candidate Biomarkers and OATP1B Probe Drugs. Clin Pharmacol Ther 
2020;107:1004–1013.
4. Suzuki et al. Relationship of hemoglobin level and plasma coproporphyrin- I concentrations as 
an endogenous probe for phenotyping OATP1B. Clin Transl Sci. 2021;14:1403–11.
5. Kunze A, Ediage EN, Dillen L, Monshouwer M, Snoeys J. Clinical Investigation of 
Coproporphyrins as Sensitive Biomarkers to Predict Mild to Strong OATP1B-Mediated Drug-
Drug Interactions. Clin Pharmacokinet. 2018;57:1559–70.
6. Hui CK, Cheung BM, Lau GK. Pharmacokinetics of pitavastatin in subjects with Child-Pugh A 
and B cirrhosis. Br J Clin Pharmacol. 2005;59:291–7.
7. Luo Z, Zhang Y, Gu J, Feng P, Wang Y. Pharmacokinetic Properties of Single- and Multiple-
Dose Pitavastatin Calcium Tablets in Healthy Chinese Volunteers. Curr Ther Res Clin Exp. 
2015;77:52–7.
8. Center for Drug Evaluation and Research. Application Number: 22-363. Clinical Pharmacology 
and Biopharmaceutics Review(S). 2009
(https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022363s000_ClinPharmR_P1.pdf)
9. World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Medical 
Research Involving Human Subjects (18th WMA General Assembly 1964), revised at 64th WMA 
General Assembly, Fortaleza, Brazil, Oct 2013.
10. International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline, E6(R2): Integrated 
Addendum to ICH E6(R1): Guideline for Good Clinical Practice. Adopted by the European 
Medicines Agency (EMA), Committee for Human Medicinal Products, Document Reference 
EMA/CHMP/ICH/135/1995), 14 Jun 2017.
11. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 
on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, 
Official Journal of the European Union, 57: 1-76.
12. The General Data Protection Regulation (GDPR). Regulation (EU) 2016/679 of the European 
Parliament and the Council of the European Union, 27 Apr 2016, applicable as of 25 May 2018.
13. International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline, E3: Structure and 
Content of Clinical Study Reports. Note for Guidance on Structure and Content of Clinical Study 
Reports. Adopted by the Committee for Human Medicinal Products, European Medicines 
Agency (EMA), Document Reference CPMP/ICH/137/95, Jul 1996.
14. International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline, E2A: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. Note for Guidance on Clinical 
Safety Data Management. Adopted by the Committee for Human Medicinal Products, European 
Medicines Agency (EMA), Document Reference CPMP/ICH/377/95, Jun 1995.

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8.
APPENDICES
8.1
Drug Accountability
Upon receipt of the study drug, it will be inspected and counted by the responsible pharmacist. If 
necessary, all study drug will be repacked per dosing occasion and labeled according to the clinical 
site SOPs.
All study drug must be kept in the ICON Pharmacy or in a locked and secured storage facility 
accessible only to the pharmacist and other pharmacy staff.
The responsible pharmacist must keep an inventory which includes a description of the formulation 
and quantity of study drug received for the study, and a record of what is dispensed, to whom, and 
when.
On termination of the study, the responsible pharmacist must conduct a final inventory of the study 
drug supply and record the results of this inventory in the Drug Accountability Form. Unused study 
drug will be returned to the Sponsor at the end of the study or will be locally destroyed according to 
the clinical site standard procedures.
8.2
Adverse Events and Serious Adverse Events Evaluation and Reporting
8.2.1
Adverse Events
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medical treatment or procedure that may or may 
not be considered related to the medical treatment or procedure. AE definitions will be followed as 
stated in the “Note for Guidance on Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting” (ICH topic E2A).14
All AEs reported by the subjects or apparent from their physical appearance during the clinical study 
will be reported on the AE eCRF page.
The Investigator will assess severity for each AE and SAE reported during the study and assign it to 
one of the following categories, according to CTCAE 5-point scale (version 5.0). Grade refers to the 
severity of the AE with unique clinical descriptions of severity for each AE based on this general 
guideline:

Mild (Grade 1): Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.

Moderate (Grade 2): Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).

Severe (Grade 3): Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.

Life-threatening (Grade 4): Life-threatening consequences; urgent intervention indicated. 

Death (Grade 5): Death related to AE.
If an AE has multiple aspects, the aspect with the highest severity will be graded.
It is emphasized that the term severe is a measure of severity; thus, a severe AE is not necessarily 
serious. An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. For example, itching for several 
days may be rated as severe, but may not be clinically serious.

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In addition, clinically significant changes in physical examination findings and abnormal objective 
test findings (e.g., laboratory, x-ray, ECG) should also be recorded as AEs. 
Any abnormal laboratory test results that meet any of the conditions below must be considered as 
“clinically significant”: 

Are associated with accompanying symptoms, and/or

Require additional diagnostic testing or medical/surgical intervention, and/or

Lead to a change in study dosing or discontinuation from the study; result in the addition of 
significant additional concomitant drug treatment or other therapy, and/or

Lead to any of the outcomes included in the definition of an SAE, and/or

Are considered to be an AE by the Investigator or Sponsor.
Reporting as an AE should not be triggered by:

Merely repeating an abnormal test, or 

Any abnormal test result that is determined to be an error.
The relationship of any AE to the study drug will be assessed and graded as related or not related.

The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE or SAE. The Investigator will use clinical judgment to determine the 
relationship.

A ‘reasonable possibility’ of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration, will be 
considered and investigated.

The Investigator will also consult the IB and/or product information, for marketed products, in 
their assessment.

For each AE or SAE, the Investigator must document in the medical notes that they have 
reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that the 
Investigator always assesses causality for every event before the initial transmission of the SAE 
data to the Sponsor.

The Investigator may change their opinion of causality in light of follow-up information and send 
an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
If the Investigator does not know whether the study intervention caused the event, then the event 
will be handled as ‘related to study intervention’ for reporting purposes, as defined by the Sponsor. 
In addition, if the Investigator determines that an SAE is associated with study procedures, the 
Investigator must record this causal relationship in the source documents and CRF, and report such 
an assessment in the dedicated section of the SAE Report Form and in accordance with the SAE 
reporting requirements.

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8.2.2
Serious Adverse Events
An SAE is any untoward medical occurrence that, on the basis of medical and scientific judgment:

Results in death, or

Is life-threatening (this refers to an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe), or 

Requires inpatient hospitalization for a medical reason or prolongation of existing hospitalization 
(this refers to hospital admission required for treatment of the AE). (Note: this does not include 
confinement in, for example, a respite unit; a skilled nursing unit; rehabilitation facility; the clinical 
research center; or confinement due to planned or unplanned reason unrelated to study), or

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect.

Medically significant: Medical or scientific judgment should be exercised by the Investigator in 
deciding whether SAE reporting is appropriate in other situations, such as significant medical 
events that may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should usually be 
considered serious.
SAEs will be collected from the time of informed consent until Follow-up. SAEs that are related to 
the investigational drug and continue beyond the normal collection period (i.e., are ongoing at the 
time a subject exits the study) will be followed until resolution or until stabilized with or without 
sequelae. SAEs that begin after the subject’s participation in the study is complete, but that the 
Investigator considers to be related to study drug, may be reported at any time. 
The Investigator or clinical site personnel must notify the Sponsor’s pharmacovigilance service 
provider, the Sponsor’s Pharmacovigilance Unit and Medical Monitor of all SAEs, regardless of 
relationship to the investigational drug, immediately within 24 hours of clinical site personnel 
becoming aware of the event. The Investigator will provide the initial notification by sending a 
completed “Safety Report Form”, which must include the Investigator’s assessment of the 
relationship of the event to investigational drug and must be signed by the Investigator.
In addition, notification is sent by ICON to the IEC and the subject’s General Practitioner, 
if applicable.
SAEs should be reported on the SAE Report Form, which is to be sent to the Sponsor’s 
pharmacovigilance service provider PrimeVigilance, as shown below. 
Pharmacovigilance service provider
PrimeVigilance Limited
The Surrey Research Park
1 Occam Court Guildford
Surrey GU2 7HJ, UK
Email: Basilea@primevigilance.com
Copy: drug.safety@basilea.com
Follow-up information, or new information regarding an ongoing SAE, must be provided promptly as 
specified above.

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CLINICAL STUDY PROTOCOL
BPR-CP-101/0680-0062
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All SAE reports should be sent to the contacts provided on Page 4: SAE Contact Information.
8.2.3
Suspected Unexpected Serious Adverse Reactions
An SAE that is also an unexpected adverse event related to study drug or when causality is unknown
is called a suspected unexpected serious adverse reaction (SUSAR). Unexpected adverse reactions 
are adverse reactions of which the nature or severity is not consistent with the applicable product 
information (IB Section 6 for ceftobiprole, the Summary of Product Characteristics or USPI for 
pitavastatin).
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal obligations 
and ethical responsibilities toward the safety of participants and the safety of a study intervention 
under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The Sponsor 
will comply with country specific regulatory requirements relating to safety reporting to the regulatory 
authority, IECs, and Investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory requirements 
and Sponsor policy and forwarded to Investigators as necessary. An Investigator who receives 
SUSARs or other specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the study documentation and will notify the IEC, if appropriate 
according to local requirements.
Expedited reporting will occur no later than 15 calendar days after the Sponsor or its representative 
has first knowledge of the adverse reactions. For fatal or life-threatening cases, the term will be 
maximally 7 calendar days for a preliminary report with another 8 calendar days for completion of 
the report. 
8.2.4
Follow-up of Adverse Events
All AEs and SAEs are followed up until the end of the study (FU/Early termination) or until 
resolution/stabilization or death. All SAEs considered related to study medication will be reported 
regardless of time on study, even if the study has been closed (see Section 8.2.2).