Clinical trial NCT05205486
Conditions: Infections
Keywords: Cephalosporin antibiotic infection control surgical prophylaxis
Sponsor: B. Braun Medical Inc.
Start date: 2022-04-05; Completion date: 2023-07-13
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to evaluate the pharmacokinetics (PK) of a single 3 gm dose of cefazolin from a DUPLEX container, in adult subjects (weighing \>/= 120 kg) scheduled for surgery. Cefazolin will be administered as a 30-minute intravenous (IV) infusion, per cefazolin Package Insert. Five PK samples per subject will be obtained up to 8 hours after dosing. These data will then be assessed by the validated Cefazolin PK Model to verify there are no significant PK changes within this study population.

Detailed description:
This is a Phase 1, open-label, single-dose, multiple-center, study to determine the pharmacokinetics of a single 3 g dose of cefazolin administered as a 30 minute IV infusion prior to surgery in adult subjects weighing \>/= 120 kg. Adult subjects will be enrolled in order to ensure at least 12 subjects complete the study. Enrollment will be competitive across the study sites. All subjects will have Screening and baseline evaluations performed to ensure their eligibility for the study The Screening Period is up to 30 days before administration of study drug on Day 1.

Study drug will be administrated as an infusion over 30 minutes starting approximately 0.5 hours before surgery begins and following institutional guidelines on Day 1 (day of surgery). Planned surgical procedures may be performed outpatient or inpatient and are expected to last no longer than 3 hours.

If the surgery is extended unexpectedly beyond the 3-hour limit, additional doses of study drug are permitted according to institutional guidelines. PK blood sample collection will continue after the administration of an additional dose of cefazolin. Safety in this population will also be assessed.

All subjects will have five (5) individual whole blood samples (4 mL each) collected for the estimation of cefazolin concentration in plasma at the following times after the start of the infusion: 0.5 (+/-10 min) end of infusion, 1 h (+/-15 min), 2 h (+/-15 min), 4 h (+/-15 min) and 8 h (+/-15 min).

Safety will be assessed by monitoring adverse events (AEs), physical examination, vital signs, and clinical laboratory tests. A follow-up visit will be performed on Day 8 (+/-1 day) for safety assessments.

A subject is considered a study completer if he/she has completed all study related procedures through the end of surgery and the required PK sample collections. It is highly preferred that the subjects also participate in the Day 8 (+/-1 day) Safety Follow-up. For subjects who withdraw or are withdrawn before study completion of the study, every effort will be made to perform all Safety Follow up procedures.

Any subject who withdraws or is withdrawn before collection of at least 4 of the 5 PK samples will not be consider as a PK completer. If necessary, additional subjects must be enrolled to ensure that there are at least 12 PK completers.

On Day 8 (+/-1 day), a Safety follow-up will be conducted. If this is an in-person visit, the following will be performed: vital signs, clinical laboratory tests, examination of the infusion site, review of AEs and concomitant medication. If an in-person visit is not possible, every effort will be made to contact the subject by phone and the subjects will be asked about any AEs and concomitant medication they may have taken.

Arms: arm 1: Study drug will be administrated as an infusion over 30 minutes starting approximately 0.5 hours before surgery begins and following institutional guidelines on Day 1 (day of surgery). All subjects will have five (5) individual whole blood samples (4 mL each) collected for the estimation of cefazolin concentration in plasma at the following times after the start of the infusion: 0.5 (+/-10 min) end of infusion, 1 h (+/-15 min), 2 h (+/-15 min), 4 h (+/-15 min), and 8 h (+/-15 min).
Interventions: intervention 1: Cefazolin 3gm for Injection USP and Dextrose Injection USP
Intervention descriptions: intervention 1: Cefazolin 3gm for Injection USP and Dextrose Injection USP in the DUPLEX® Drug Delivery System. Administration will occur once as a 30 minute IV infusion prior to surgery in adult subjects weighing \>/= 120 kg

Protocol documents:
Prot_000.pdf: 
ConﬁdenƟal 
 
B. Braun Medical Inc.  
CLINICAL STUDY PROTOCOL 
 
 
A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of a Single 
3 Gram Dose of Cefazolin in Adult Subjects Weighing ≥120 kg Scheduled for Surgery 
 
 
Protocol Number: US-G-H-2101 
ClinicalTrials.gov Identifier: NCT05205486 
Document Date: 31 August 2021 
 





















































































SAP_001.pdf: 
ConﬁdenƟal 
 
B. Braun Medical Inc.  
STATISTICAL ANALYSIS PLAN 
 
 
A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of a Single 
3 Gram Dose of Cefazolin in Adult Subjects Weighing ≥120 kg Scheduled for Surgery 
 
 
Protocol Number: US-G-H-2101 
ClinicalTrials.gov Identifier: NCT05205486 
Document Date: 15 March 2022 
 


 
Confidential 
 
 
 
B. Braun Medical Inc. 
 
US-G-H-2101 
 
A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics 
of a Single 3 Grams Dose of Cefazolin in Adult Subjects Weighing ≥ 120 kg 
Scheduled for Surgery 
 
15MAR2022 
 
 Final Statistical Analysis Plan 
 
Version 1.0 
 
Prepared by:  
Prasanna Anant Dillikar 
Associate Biostatistician 
 
PPD 
9th Floor, Valence Building 
Prestige Tech Park, Bengaluru, India-560103 
 
 
 
 


B. Braun Medical Inc. 
 
                         Statistical Analysis Plan, Version 1.0 
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                            Date Issued: 15MAR2022 
 
 
 
 II
Document History – Changes compared to previous version of SAP: 
Version Date Issued 
SAP Section Detail of Changes 
0.1 
15FEB2022 
 
Draft 
0.2 
07MAR2022 
8.3.2, 8.3.3, 
8.3.4 
Text related to missing of relationship and 
severity of adverse events, are removed. 
 
 
12.2 
The figure related to mean plasma concentration 
vs time profile is removed and figure with 
individual plasma concentration and mean plasma 
concentration vs time profile will be presented 
together.. 
1.0 
15MAR2022 
 
Finalized version  
 
 


B. Braun Medical Inc. 
 
                         Statistical Analysis Plan, Version 1.0 
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                            Date Issued: 15MAR2022 
 
 
  III
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... V 
1. 
INTRODUCTION ............................................................................................................ 6 
1.1 
BACKGROUND INFORMATION ............................................................................................. 6 
2. 
OBJECTIVES ................................................................................................................... 7 
2.1 PRIMARY OBJECTIVE .............................................................................................................. 7 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 7 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 7 
3.2. TREATMENTS ...................................................................................................................... 8 
3.3. DOSE ADJUSTMENT/MODIFICATIONS ................................................................................. 8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 9 
4.1. SAMPLE SIZE .................................................................................................................... 10 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 10 
4.3. ANALYSIS SET .................................................................................................................. 10 
4.3.1. 
Enrolled Set ............................................................................................................... 10 
4.3.2. 
Safety Analysis Set .................................................................................................... 11 
4.3.3. 
PK Analysis Set ......................................................................................................... 11 
5. 
SUBJECT DISPOSITION ............................................................................................. 11 
5.3. DISPOSITION ..................................................................................................................... 11 
5.4. PROTOCOL DEVIATIONS ................................................................................................... 11 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 12 
6.1. DEMOGRAPHICS ................................................................................................................ 12 
6.2. MEDICAL HISTORY ........................................................................................................... 12 
6.2.1. 
General Medical History .......................................................................................... 12 
6.3. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 12 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 13 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................... 13 
7.2. STUDY TREATMENTS ........................................................................................................ 13 
7.2.1 DURATION OF INFUSION ..................................................................................................... 13 
7. 
EFFICACY ANALYSIS................................................................................................. 13 
8. 
SAFETY ANALYSIS ..................................................................................................... 13 
8.1. ADVERSE EVENTS ............................................................................................................. 14 
8.3.1. 
Incidence of Adverse Events ..................................................................................... 14 
8.3.2. 
Relationship of Adverse Events to Study Drug ......................................................... 14 
8.3.3. 
Severity of Adverse Event.......................................................................................... 15 
8.3.4. 
Serious Adverse Events ............................................................................................. 15 
8.3.5. 
Adverse Events Leading to Treatment Discontinuation............................................ 15 
8.3.6. 
Adverse Events Leading to Study Discontinuation ................................................... 15 
8.3.7. 
Death ......................................................................................................................... 16 


B. Braun Medical Inc. 
 
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  IV
8.4. CLINICAL LABORATORY EVALUATIONS ........................................................................... 16 
8.5. VITAL SIGN MEASUREMENTS ........................................................................................... 17 
8.6. PHYSICAL EXAMINATION ................................................................................................. 17 
8.7. ELECTROCARDIOGRAM ..................................................................................................... 17 
8.8. OTHER SAFETY DATA ....................................................................................................... 18 
8.8.1. 
INFUSION SITE REACTION............................................................................................... 18 
9. 
PHARMACOKINETICS ............................................................................................... 18 
9.1 PHARMACOKINETIC MEASUREMENT ..................................................................................... 18 
9.2 PHARMACOKINETIC ANALYSIS ............................................................................................. 18 
10. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 19 
11. 
REFERENCES ................................................................................................................ 19 
12. 
APPENDICES ................................................................................................................. 20 
12.1.  SCHEDULE OF EVENTS ...................................................................................................... 20 
12.2. TABLE OF CONTENTS OF TABLES, LISTINGS AND FIGURES ................................................ 22 


B. Braun Medical Inc. 
 
                         Statistical Analysis Plan, Version 1.0 
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 V 
List of Abbreviations 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration  
IV 
Intravenous 
ICF 
Informed Consent Form  
ICH 
International Conference On Harmonisation 
MedDRA 
Medical Dictionary For Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAEs 
Treatment-Emergent Adverse Events 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 
 


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1. Introduction 
This Statistical Analysis Plan (SAP) defines the statistical methods and data presentations to 
be used by PPD Biostatistics in the analysis and presentation of data for the B. Braun Medical 
Inc. study US-G-H-2101, entitled “A Phase 1, Open-Label, Single-Dose Study to Evaluate 
the Pharmacokinetics of a Single 3 Grams Dose of Cefazolin in Adult Subjects Weighing 
≥120 kg Scheduled for Surgery”. 
1.1 Background Information 
Cefazolin is an antibacterial agent that in in vitro testing has been shown to act by inhibition 
of bacterial cell wall synthesis. Cefazolin for Injection United States Pharmacopeia (USP) 
and Dextrose Injection USP is a sterile, nonpyrogenic, single-use, packaged combination of 
Cefazolin Sodium USP (lyophilized) and sterile iso-osmotic diluent (i.e., Dextrose Injection 
USP) in the DUPLEX® sterile container.  
Cefazolin Sodium USP and Dextrose Hydrous USP are supplied as a lyophilized form 
equivalent to either 1 gram or 2 grams of cefazolin (i.e., contains approximately 2 grams 
dextrose [4.0% weight to volume ratio (w/v)] and 1.5 g dextrose [3.0% w/v] for the 1 gram 
and 2 grams dosages, respectively).   
For the Investigational 3grams Cefazolin dosage utilized in this study, the concentration of 
dextrose in the diluent is 2.0% w/v, as dextrose monohydrate.  
The pharmacokinetic/pharmacodynamic (PK/PD) relationship for cefazolin has not been 
evaluated in patients. However, it is commonly accepted that β-lactam antibiotics exhibit 
time-dependent killing of bacteria. Thus, the percentage of time that drug concentrations 
remain above the minimum inhibitory concentration (MIC) of the bacterial pathogen is the 
relevant PK-PD index for cefazolin. 
Patients weighing ≥ 120 kg may not achieve a similar or therapeutic level of exposure to 2 
grams of Cefazolin as patients weighing ≤ 120 kg. In order to ensure a therapeutic exposure 
to cefazolin from a single dose in this heaver population of patients, B. Braun Medical Inc. 
is developing a 3 grams Cefazolin DUPLEX® bag for use in individuals who weigh at least 
120 kg. To support this dosing recommendation, a thorough literature search was performed 
to obtain information regarding Cefazolin use in patients weighing at least 120 kg. Monte 
Carlo simulations were then performed using the previously developed population PK model 
constructed from one study in healthy adults and 2 studies in pediatric patients (ICPD 2019). 
This population PK model was used to perform model-based simulations of a 2-grams or 3-
grams dose of Cefazolin in 2 simulated populations of obese (≥ 120 kg) adult patients.   
This Phase 1 study was based on the above population PK model and is designed to evaluate 
the pharmacokinetics (PK) of a single 3 grams dose of Cefazolin from a DUPLEX container, 
in adult subjects (weighing ≥ 120 kg) scheduled for surgery. Cefazolin will be administered 
as a 30-minute intravenous (IV), per cefazolin Package Insert for surgical prophylaxis. These 
data are planned to be assessed by a validated Cefazolin PK Model (Schmitz ML 2020) to 


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verify there are no significant PK changes within this study population. The results of this 
modelling analyses will be reported separately from the Clinical Study Report.   
2. Objectives 
2.1 Primary Objective 
The primary objective of this study is to determine the PK of a single IV 3 grams dose of 
Cefazolin administered to adult subjects (weighing ≥ 120 kg) scheduled for surgery. Safety 
in this population will also be assessed. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a Phase 1, open-label, single-dose, multiple-center, study to determine the 
pharmacokinetics of a single 3 grams dose of Cefazolin administered as a 30-minute IV 
infusion in adult subjects (weighing ≥ 120 kg) scheduled for surgery. Adult subjects will be 
enrolled in order to ensure at least 12 subjects complete the study. Enrolment will be 
competitive across the study sites.  
The Screening Period is up to 30 days before administration of study drug on Day 1. All 
subjects will have screening and baseline evaluations to ensure their eligibility for the study.  
Study drug will be administrated as an infusion over 30 minutes starting approximately 0.5 
hours before surgery begins and following institutional guidelines on Day 1 (day of surgery). 
Planned surgical procedures may be performed outpatient or inpatient and are expected to 
last no longer than 3 hours.  
If the surgery is extended unexpectedly beyond the 3-hours limit, additional doses of study 
drug are permitted according to institutional guidelines. PK blood sampling will not be 
halted due to this 2nd dose of study drug. The amount of study drug administered and the 
start and stop time of this 2nd dose of study medication must be recorded. PK blood sample 
collection will continue after the administration of an additional dose of Cefazolin. Safety in 
this population will also be assessed.  
All subjects will have five (5) individual whole blood samples (4 mL each) collected for the 
estimation of cefazolin concentration in plasma at the following times after the start of the 
infusion: 0.5 (±10 min) end of infusion, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min) and 8 
h (±15 min).  
Safety will be assessed by monitoring adverse events (AEs), physical examination, vital 
signs, and clinical laboratory tests. A follow-up visit or phone call will be performed on Day 
8 (±1 day) for safety assessments.  
A subject is considered a study completer if he/she has completed all study related 
procedures through the end of surgery and the required PK sample collections. It is highly 
preferred that the subjects also participate in the Day 8 (±1 day) Safety Follow-up. For 


B. Braun Medical Inc.                                                                                                                               Statistical Analysis Plan, Version 1.0 
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subjects who withdraw or are withdrawn before study completion of the study, every effort 
will be made to perform all Safety Follow up procedures.  
Any subject who withdraws or is withdrawn before collection of at least 4 of the 5 PK 
samples will not be consider as a PK completer. If necessary, additional subjects must be 
enrolled to ensure that there are at least 12 PK completers.  
On Day 8 (±1 day), a safety follow-up will be conducted. If this is an in-person visit, the 
following will be performed: vital signs, clinical laboratory tests, examination of the infusion 
site, review of AEs and concomitant medication. If an in-person visit is not possible, every 
effort will be made to contact the subject by phone and the subjects will be asked about any 
AEs and concomitant medication they may have taken. 
3.2. Treatments   
Cefazolin for Injection USP and Dextrose Injection USP is a sterile, non-pyrogenic, single-
use, packaged combination of Cefazolin Sodium USP (lyophilized) and iso-osmotic diluent 
(i.e., Dextrose Injection USP) in the DUPLEX container. The DUPLEX container is a 
flexible dual-chamber container. Cefazolin Sodium USP (active ingredient) is currently 
supplied in the drug chamber as a lyophilized form equivalent to 1 gram or 2 grams of 
Cefazolin. The diluent chamber contains approximately 50 mL of Dextrose Injection USP.  
For the Investigational 3grams Cefazolin dosage utilized in this study, the concentration of 
dextrose in the diluent is 2.0% w/v, as dextrose monohydrate. The diluent chamber contains 
approximately 50 mL of Dextrose Injection USP.  
In pre-reconstituted form, the Cefazolin appears as a white or almost white powder and the 
dextrose is a clear fluid. When reconstituted, the prepared solution is clear. 
A peripheral venous catheter will be placed for all subjects before the start of the study drug 
administration for the IV infusion of the Cefazolin and dextrose solution. After 
reconstitution, the solution will be administered over 30 minutes through an infusion line by 
using an infusion pump on Day1 (day of surgery) for surgery prophylaxis and following 
institution guidelines. The study drug administration will begin approximately 0.5 hours 
prior to the start of surgery and following institution guidelines. If the surgery is 
unexpectedly extended beyond the 3 hours limit, additional doses of study drug are permitted 
according to institutional guidelines. However, dose administered and the start and stop time 
of the infusion must be recorded. 
3.3. Dose Adjustment/Modifications 
If the surgery is unexpectedly extended beyond the 3 hours limit, additional doses of study 
drug are permitted according to institutional guidelines. However, dose administered and the 
start and stop time of the infusion must be recorded.  
It is necessary that a separate venous catheter for PK sample collection be placed in the 
contralateral arm to the catheter used for study drug infusion.  


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NOTE: The catheter that is used for study drug infusion and the arm it is inserted in cannot 
be used for collection of the PK samples. 
4. General Statistical Considerations 
Continuous data will be described using descriptive statistics (i.e., n, mean, standard 
deviation, median, minimum, and maximum). Categorical data will be described using the 
subject count and percentage in each category. For the summary statistics of all numerical 
variables unless otherwise specified, minimum and maximum will be displayed to the same 
level of precision as reported. Mean and median will be displayed to one level of precision 
greater than the data collected. Standard deviation / standard error will be displayed to two 
levels of precision greater than the data collected. All data will be displayed in listings sorted 
by subject number and visit/time, if applicable. Listings will be included all visits including 
unscheduled visits. 
For summaries by visit (/time), if multiple records fall on the same visit (/time), then the 
record which is closest to the target visit (/time) will be considered. In case of a tie, the 
record with the latest date (/time) will be chosen. If multiple records on same day (/time), 
will consider the latest record. Unless otherwise specified, unscheduled will not be 
summarized but will be listed. 
When count data are presented, the percentage will be suppressed when the count is zero in 
order to draw attention to the non-zero counts. A row denoted “Missing” will be included in 
count tabulations where specified on the shells to account for dropouts and missing values. 
The denominator for all percentages will be the number of subjects in treatment within the 
analysis set of interest, unless otherwise specified. Percentage will be presented to one 
decimal place.  
“No data available for this report” will be presented when there are no data available to 
report. 
Baseline is defined as the last non missing values obtained before surgery on Day 1. 
Study day is defined as:  
• Visit/examination date – date of first study drug administration when date is prior to 
the date of first study drug administration (day 1). 
• Visit/examination date – date of first study drug administration + 1 when date is after 
day 1 
For the purpose of inclusion in tables, incomplete start and stop dates (e.g. AEs and 
prior/concomitant medication) will be imputed as follows: 
Missing start dates (where UK and UKN indicate unknown or missing day and month 
respectively) will be handled as follows: 
• 
UK-MMM-YYYY: If the month and year are different from the month and year of 
the first dose of study drug, assume 01-MMM-YYYY. If the month and year are the 
same as the first dose of study drug month and year and the stop date (after any 


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imputation) is on or after the first dose of study drug, then assume the date of the first 
dose of study drug. If the month and year are the same as the first dose of study drug 
month and year and the stop date (after any imputation) is prior to the first dose of 
study drug, then assume the stop date for the start date; 
• 
DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first 
dose of study drug, assume 01-JAN-YYYY of the collected year. If the year is the 
same as the first dose of study drug year and the stop date (after any imputation) is 
on or after the first dose of study drug, then assume the date of the first dose of study 
drug. If the year is the same as the first dose of study drug and the stop date (after 
any imputation) is prior to the first dose of study drug, then assume the stop date for 
the start date.  
Missing stop dates (where UK and UKN indicate unknown or missing day and month 
respectively) will be handled as follows:  
• UK-MMM-YYYY: Assume the last day of the month; 
• DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
If a subject die during the study, the stop date will be imputed as the date of death if the 
imputed stop date is after date of death. 
All analyses will be conducted using SAS Version 9.4 or higher. 
4.1. Sample Size 
A range of sample sizes and PK sampling schemes were evaluated utilizing a previously 
approved PK model. The results of the model-based simulation analyses indicated that a 
sample size of 12 subjects, each of which provides 5 blood samples for cefazolin assay at 
times of 0.5 (±10 min) end of infusion, 1 h (±15 min), 2 h (±15 min), and 4 h (±15 min), 
and, 8 h (±15 min) after the start of the cefazolin infusion, would be expected to provide 
adequate power to determine the PK in adult subjects weighing ≥ 120 kg.  
Thus, subjects will be enrolled to ensure at least 12 subjects will complete the study. 
4.2. Randomization, Stratification, and Blinding 
This is an open-label study. No randomization or blinding will be performed. 
4.3. Analysis Set 
The following analysis sets will be used: Enrolled Set, Safety analysis Set and PK analysis 
Set. 
4.3.1. Enrolled Set 
The enrolled set will include all subjects who were signed informed consent.  


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4.3.2. Safety Analysis Set 
The safety analysis set will consist of all subjects who received any study drug. Safety will 
be assessed by monitoring AEs, physical examinations, vital signs, ECGs, and clinical 
laboratory results. 
4.3.3. PK Analysis Set 
The PK analysis set will consist of all subjects from whom at least 4 of the 5 PK samples are 
obtained. 
5. 
Subject Disposition 
5.3. Disposition 
A summary of the analysis sets includes the number and percentage of subjects for the 
following categories: enrolled set, safety analysis set, and PK analysis set. All percentages 
will be based on the number of enrolled subjects. A listing will be presented by subjects for 
showing each subject in which analysis population set they are included. 
Subject disposition will be summarized using enrolled set. A disposition of subjects includes 
the number and percentage of subjects who completed the study and subjects who 
discontinued from the study. 
The reasons for study discontinuation will also be summarized in this table. The reason for 
study discontinuation includes the following:  
• Does not meet the protocol inclusion or exclusion criteria 
• Noncompliance with the protocol 
• A Serious or Intolerable Adverse Event 
• Lost to Follow-up 
• Pregnancy 
• Investigator Decision 
• Withdrawal of Informed Consent 
• Other 
 
Subject disposition data will be presented in a listing. 
5.4. Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by 
the subject or investigator that results in a significant, additional risk to the subject. 
Significant deviations can include nonadherence to inclusion or exclusion criteria or 
nonadherence to FDA regulations or ICH GCP guidelines, and will lead to the subject being 
withdrawn from the study. 


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The number and percentage of subjects with protocol deviation will be summarized by 
category (major, minor). Protocol deviations will be listed with date of occurrence, 
deviation category, deviation description from which subject is excluded. All summaries 
and listings will be performed using the safety analysis set. 
6. 
Demographics and Baseline Characteristics 
6.1.Demographics 
A summary of demographics and baseline information will be presented. The demographic 
characteristics consist of age (year), sex, race, ethnicity, child bearing potential and 
menopause status. The baseline characteristics consist of baseline height (cm), baseline 
weight (kg), and baseline body mass index (BMI) (kg/m^2. Body mass index is calculated 
as (body weight in kilograms) / (height in meters)2. 
Age (year), baseline height (cm), baseline weight (kg), and baseline BMI (kg/m^2) will be 
summarized using descriptive statistics. The number and percentage of subjects by sex 
(Male, Female), race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, and Other), ethnicity (Hispanic or Latino, 
Not Hispanic or Latino), child bearing potential (Yes, No) and menopause status (Prior 
bilateral oophorectomy, Age >= 60 years, Age <60 years and amenorrhoeic for at least 12 
months) will also be reported. Percentages will be based on the total number of subjects in 
the safety analysis set. Percentages for the child bearing potential and menopause status 
summary will be based on the number of female subjects from the safety analysis set. 
Subject demographic and baseline characteristics will be presented in a listing. All listings 
will be performed using the safety analysis set. 
6.2.Medical History 
6.2.1. General Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.0 or higher. Body systems will be included as recorded on the eCRF. 
Subject medical history data including specific details will be presented in a listing using the 
safety analysis set. 
6.3.Inclusion and Exclusion Criteria 
The details of the inclusion and exclusion criteria can be found in sections 4.2 and 4.3 of 
the protocol. The status of eligibility criteria met, inclusion criteria not met, or exclusion 
criteria met details will be listed using the enrolled set.  


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7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
A prior medication is defined as any medication where the start date and stop date are before 
the date of first dose of study drug. A concomitant medication is defined as one where the 
start or stop date is either on or after the date of first dose of study drug. All medications will 
be coded according to the World Health Organization drug dictionary (WHODRUG 2020 
March or later). Incomplete dates will be imputed following rules in Section 4. All 
medications will be listed. 
The total number of prior and/or concomitant medications and the number and percentages 
of subjects with at least one prior and/or concomitant medication will be summarized. The 
number and percentages of all prior and/or concomitant medication will be summarized and 
listed by ATC (Anatomical Therapeutic Chemical) level 4 and preferred term. At each level 
of summarization, a subject is counted once if the subject reported one or more medication 
at that level.  Any medications and treatments taken prior to and not stopped prior to the 
infusion of study drug will be counted in concomitant medication. 
All prior/concomitant medication summaries and listing will be presented using safety 
analysis set. 
7.2.Study Treatments 
Study treatment and modification is detailed in section 3.2 and 3.3. 
7.2.1 Duration of Infusion  
Duration of infusion will be calculated in hours as end time of study drug infusion – start 
time of study drug infusion. Interruption of study drug infusion may also occur during the 
study, in such case, the duration of the infusion will be computed after adjusting the 
interrupted duration. 
Duration of infusion (hours) and infusion rate (mL/h or mL/min) will be summarized using 
descriptive statistics along with number and percentage of subjects who had infusion 
interruptions and additional study drug infusion will also be presented in table for safety 
analysis set.  
A summary of each subject’s study drug infusion will be presented in a listing. 
7. Efficacy Analysis 
Not applicable. 
8. Safety Analysis 
All analyses of safety will be conducted using safety analysis set.   


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8.1.Adverse Events 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug. 
A treatment-emergent AE (TEAE) is defined as an AE that meets any of the following 
conditions, based on the actual AE dates or imputed dates: 
• begins on or after the start of study drug infusion;  
• begins before the start of study drug infusion and worsens in either intensity or 
frequency on or after the first dose of study drug.; 
• is completely missing a start date and the stop date; 
• is completely missing a start date and the stop date is on or after the study drug 
infusion. 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be 
imputed as explained in section 4.  
All AEs will be classified by System Organ Class (SOC) and Preferred Term (PT) according 
to MedDRA (Version 24.0 or higher).  
Number and percentage of subjects with any AE, SAE, TEAE, serious TEAEs, study drug-
related TEAEs, study drug-related serious TEAEs, TEAE leading to treatment 
discontinuation,  TEAE leading to study discontinuation, and AE leading to death will be 
summarized. Percentages will be calculated using number of subjects in the safety analysis 
set.  
All AEs will be presented in a listing using the safety analysis set. 
8.3.1. Incidence of Adverse Events 
Number and percentage of subjects with at least one TEAE and the total number of TEAEs 
will be summarized. TEAEs will be presented by SOC and PT. At each level of subject 
summarization, a subject is counted once if the subject reported one or more events. 
Percentages will be calculated using number of subjects in the safety analysis set.  
TEAEs will be sorted in descending order of frequency of SOC. Within each SOC, PTs will 
be sorted in alphabetical order of preferred terms. 
8.3.2. Relationship of Adverse Events to Study Drug 
The investigator will provide an assessment of the relationship of the event to the study 
drug. The possible relationships are “Unrelated”, “Possibly Related”, “Probably Related” 
and “Definitely Related”.  
A summary of TEAEs related to Cefazolin will be presented in a table same as mentioned 
in section 8.3.1. TEAEs that with a relationship other than “Unrelated” will be considered 
as “Related”. Percentages will be calculated out of the number of subjects in the safety 
analysis set. 


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8.3.3. Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table. The severity that will be 
presented represents the most extreme severity captured on the eCRF page. The possible 
severities are “Mild”, “Moderate”, and “Severe”.  In the TEAE severity table, if a subject 
reported multiple occurrences of the same TEAE, only the most severe will be presented. 
Percentages will be calculated out of the number of subjects in the Safety analysis set. 
The TEAE data will be categorized and presented by SOC, PT, and severity in a manner 
similar to that described in section 8.3.1. 
8.3.4. Serious Adverse Events 
A serious AE (SAE) is defined as any event that results in death, is immediately life 
threatening, requires inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/incapacity, or is a congenital anomaly/birth 
defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Serious treatment-emergent adverse events (Serious TEAEs) will be presented in a table. 
Serious TEAEs which are related to study drug will also be presented in a table.  
At each level of subject summarization, a subject is counted once if the subject reported one 
or more events. Percentages will be calculated out of the number of subjects in the safety 
analysis set.  
The serious TEAEs data will be categorized and presented by SOC and PT in a manner 
similar to that described in section 8.3.1. 
8.3.5. Adverse Events Leading to Treatment Discontinuation 
A summary of TEAEs where the answer to “Action Taken” are “Drug Withdrawn” will be 
presented in a table by SOC and PT in a manner similar to that described in section 8.3.1. 
At each level of subject summarization, a subject is counted once if the subject reported one 
or more events. Percentages will be calculated using number of subjects in the safety 
analysis set.   
8.3.6. Adverse Events Leading to Study Discontinuation 
A summary of TEAEs where the answer to “Caused Study Discontinuation” is “Yes” will 
be presented in a table by SOC and PT in a manner similar to that describe in section 8.3.1. 
At each level of subject summarization, a subject is counted once if the subject reported one 
or more events. Percentages will be calculated using number of subjects in the safety analysis 
set. 


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8.3.7. Death 
A summary of AEs where the answer to “Outcome” is “Death Related to Adverse Event” 
will be presented in a table by SOC and PT in a manner similar to that describe in section 
8.3.1. At each level of subject summarization, a subject is counted once if the subject 
reported one or more events. Percentages will be calculated out of the number of subjects in 
the safety analysis set.  
All subjects who have an AE with an outcome of “Death Related to Adverse Event” will be 
presented in a listing.  
8.4. Clinical Laboratory Evaluations 
Laboratory assessments will be performed by the local or central laboratory. All summaries 
and listings will be presented in SI units.  
Summary tables presenting observed values and changes from baseline will be presented for 
clinical laboratory tests (Hematology and Clinical Chemistry) with numeric values for 
subjects in the safety analysis set. All hematology, clinical chemistry and pregnancy test will 
be listed in separate listings using safety analysis set. 
Table 8.1: Clinical Laboratory Tests 
Hematology 
• Hemoglobin  
• Hematocrit  
• Mean corpuscular volume  
• Mean corpuscular hemoglobin  
• Mean corpuscular hemoglobin concentration  
• Platelets  
• Red blood cell  
• White blood cell with differential count  
Clinical 
Chemistry 
• Alanine aminotransferase  
• Albumin  
• Alkaline phosphatase  
• Aspartate aminotransferase  
• Blood urea nitrogen  
• Serum creatinine1  
• Total bilirubin  
• Sodium  
• Potassium  
• Chloride  
• Bicarbonate  
• Glucose  
• Uric acid  
• Calcium  


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• Phosphate  
• Total protein  
• Creatine phosphokinase (CPK)  
• Lactic acid dehydrogenase (LDH)  
1At Screening, serum creatinine performed within 3 months of the planned surgical procedure will 
be accepted if the subject was in stable medical condition at the time of the test and has remained in 
stable medical condition since the test was performed. 
8.5. Vital Sign Measurements 
Summary tables presenting observed values and changes from baseline to each scheduled 
post-baseline will be presented for vital sign data, including systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), heart rate (bpm), respiration (breaths/minute), and 
temperature (C) for subjects in the safety analysis set.  
Number and percentage of subject’s vital signs interpretation will be presented by each time 
point using safety analysis set. 
All vital sign results and interpretation will be presented in a listing by visit/timepoint using 
the safety analysis set. 
8.6. Physical Examination 
A physical examination will be performed by the investigator or his/her qualified designee 
according to the schedule of events (Appendix 12.1). A complete physical examination will 
be performed and will include the following body systems general appearance and a review 
of systems (dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, 
and respiratory, cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, 
and psychiatric systems). 
Physical examination results for all subjects will be presented in a listing by visits using the 
safety analysis set. 
8.7. Electrocardiogram 
All subjects will have a standard electrocardiogram (ECG) performed at the time points as 
scheduled (Appendix 12.1), that will be recorded in single reading.  
The summary tables of observed values and changes from baseline will be presented for 
electrocardiogram data, including Ventricular rate (beats per minute), PR-interval (msec), 
QRS-duration (msec), QT-interval (msec) and QTc interval (msec) for subjects in the safety 
analysis set. Normal sinus rhythm (yes/no) will be presented with number and percentage of 
subjects by visit using the safety analysis set. 
A table will summarize ECG interpretations by visit for the safety analysis set. Interpretation 
results include Normal, Abnormal Not Clinically Significant, Abnormal Clinically 
Significant, and Not Done. 


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All ECG results and interpretation will be presented in a listing for subjects by visit using 
the safety analysis set. 
8.8. Other Safety Data 
8.8.1. Infusion site reaction 
The number and percentages of subjects having infusion site reaction will be summarize by 
severity and the diameter of redness (Erythema) and diameter of swelling hardness will be 
summarized using descriptive statistics by timepoints and visits. All summarizations will be 
done using the safety analysis set. 
All infusion site reaction status and related data will be presented in a listing using the safety 
analysis set. 
9. 
Pharmacokinetics 
9.1 Pharmacokinetic Measurement 
PK blood samples (4 mL each) will be obtained at 0.5 (±10 min) end of infusion 1 h (±15 
min), 2 h (±15 min), 4 h (±15 min) and 8 h (±15 min) after the start of the study drug 
infusion. The total amount of blood obtained from each subject for the PK samples will be 
approximately 20 mL. 
If the surgery is extended unexpectedly beyond the 3-hour limit, additional doses of study 
drug are permitted according to institutional guidelines. PK blood sampling will not be 
halted due to this 2nd dose of study drug. The amount of study drug administered and the 
start and stop time of this 2nd dose of study medication must be recorded. PK blood sample 
collection will continue after the administration of an additional dose of Cefazolin and 
remaining collection times will be based on the start time of the 1st dose of study drug.   
9.2 Pharmacokinetic Analysis 
Individual plasma concentrations of Cefazolin will be presented in data listings using the 
safety analysis set. Plasma concentrations will be summarized at scheduled timepoints using 
the PK analysis set and descriptive statistics (number of non-missing observations, mean, 
standard deviation (SD), mean coefficient of variation (CV), geometric mean, geometric 
coefficient of variation, median, minimum, and maximum). For the descriptive statistics, all 
plasma concentrations that are below the limit of quantification (BLQ) will be set to zero. 
Plasma concentration data will be analyzed with the same precision as the source data 
regardless of how many significant figures or decimals the data carry. After analysis, 3 
significant digits will be used as the standard rounding for all statistics except for coefficient 
of variation. Coefficient of variation will always be reported to 1 decimal place. 
Plasma concentrations over scheduled time will be provided which include a single line 
profile for each of the 12 subjects and a mean (± Standard deviation) profile of all the 
subjects. This will be plotted on both linear and semi-logarithmic scale for the PK analysis 
set.  


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10. Changes in the Planned Analysis 
Enrolled set is added to section 4.3 to trace the screen failed subjects in Table or 
Listings.  
As per section 12.1 of protocol, “baseline demographic and background variables will 
be summarized by arm and overall, for all subjects” but we have modified this 
statement in section 6.1. Since we have only one study treatment, we have designed 
the demographic summary table with a single column summary.    
11. References 
B. Braun Medical Inc. Cefazolin for Injection USP and Dextrose Injection USP in 
DUPLEX® Container, Investigator’s Brochure, Bethlehem (PA); 2021. 
FDA Guidance for Industry Pharmacokinetics in Patients with Impaired Renal 
Function – Study Design, Data Analysis, and Impact on Dosing. Draft September 03 
2020, Revision 2. 
ICH Harmonized Tripartite Guideline – Statistical Principles for Clinical Trials, E9 
(http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/statistical-
principles-for-clinical-trials.html). 
Institute for Clinical Pharmacodynamics, Inc. Population pharmacokinetic analysis of 
cefazolin in healthy adults and pediatric surgery patients aged 10-17 years. Final 
Report. ICPD Report no. 00477. November 22, 2019. 
Schmitz ML, Rubino CM,Onufrak NJ, et al. Pharmacokinetics and Optimal Dose 
Selection 
of 
Cefazolin 
for 
Surgical 
Prophylaxis 
of 
Pediatric 
Patients. 
2020;https://doi.org/10.1002/jcph.1785. 
 
 


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12. Appendices 
12.1.  Schedule of Events 
Study Phase 
Screening 
Treatment 
Follow-up2 
Visit  
Screening1 
Day 1 
Pre- Dose 
 
Day 1 
Day 2 (Or at 
Discharge) 
 
Day 8 
Procedure 
Up to 30 Days before Study 
Drug Administration 
Pre dose 
0 h 
(±10min) 
0.5 h 
(±15min) 
1 h 
(±15min) 
2 h 
(±15min) 
4 h 
(±15min) 
8 h 
(±15min) 
 
 
Admission to the Study Site 
 
 
 
 
 
 
 
 
 
 
Sign Study Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Height and Weight3 
X 
X4 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Review Medical History 
 
X 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
Review Medication History 
 
X 
 
 
 
 
 
 
 
 
Full Physical 
X 
X 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
X5 
 
X 
 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
X 
 
Clinical Laboratory Tests6 
X 
X5 
 
 
 
 
 
 
X2 
X 
Pregnancy Test7 
X 
X5 
 
 
 
 
 
 
 
 
Study Drug Administration8 
 
 
X 
 
 
 
 
 
 
 
Assess Study Drug Infusion Site 
 
 
 
X 
X 
X 
X 
X 
X2 
X 
Pharmacokinetic Samples9 
 
 
 
X 
X 
X 
X 
X 
 
 
Concomitant Medication 
continuous 
Collection of Adverse Events 
continuous 
1 Screening Visit may occur on Day 1 (Day of Surgery). All Screening procedures must be completed before study drug administration on Day 1.   
2 Assessments will be performed for subjects who received study medication and were an early termination, if possible.  For Day 8, this will either be an in-person visit or a
phone call.  
3 To be measured with indoor clothing and without shoes.  
4 Weight only 
5 To be completed approximately 30 minutes before study drug administration.  
6 Screening Clinical labs must be completed by the local laboratory. Study clinical labs need to be performed by the Central lab if a Central lab is used, otherwise a local lab is
acceptable.  


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7 Urine pregnancy tests will be performed for all females of childbearing potential. If positive, a serum pregnancy test will be performed to confrim the results.  Pregnancy 
tests will be performed by the local laboratory.  
8 Study drug administration will be a 30-minute infusion and following institutional guidelines.  
9 Pharmacokinetic blood samples (4 mL) will be collected at selected timepoints after the start of study drug administration. NOTE: Pharmacokinetic samples cannot be collected
from the same line/port as the infusion nor from the same arm as the infusion.  
 
 
 


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12.2. Table of Contents of Tables, Listings and Figures 
 
List of Tables  
Table 14.1.1.1 Analysis Sets Enrolled Set 
Table 14.1.1.2 Subject Disposition Enrolled Set 
Table 14.1.3.1 Protocol Deviations Safety Analysis Set 
Table 14.1.4.1 Demographics Safety Analysis Set 
Table 14.1.6.1 Prior Medications Safety Analysis Set 
Table 14.1.6.2 Concomitant Medications Safety Analysis Set 
Table 14.1.7.1 Study Treatment Administration Safety Analysis Set 
Table 14.2.2.1 Summary of Plasma Concentration PK Analysis Set 
Table 14.3.1.1 Overall Adverse Events Safety Analysis Set 
Table 14.3.1.2 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Safety Analysis Set 
Table 14.3.1.3 Treatment-Emergent Adverse Events Related to Study Drug by System Organ Class and Preferred Term Safety 
Analysis Set 
Table 14.3.1.4 Treatment-Emergent Adverse Events by Severity Safety Analysis Set 
Table 14.3.1.5 Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Safety Analysis Set 
Table 14.3.1.6 Serious Treatment-Emergent Adverse Events Related to Study Drug by System Organ Class and Preferred Term Safety 
Analysis Set 
Table 14.3.1.7 Treatment-Emergent Adverse Events Leading to Treatment Discontinuation Safety Analysis Set 
Table 14.3.1.8 Treatment-Emergent Adverse Events Leading to Study Discontinuation Safety Analysis Set 
Table 14.3.1.9 Treatment-Emergent Adverse Events Leading to Death Safety Analysis Set 
Table 14.3.5.1 Descriptive Statistics of Observed Values and Change from Baseline in Hematology Safety Analysis Set 
Table 14.3.5.2 Descriptive Statistics of Observed Values and Change from Baseline in Chemistry Safety Analysis Set 
Table 14.3.6.1 Descriptive Statistics of Observed Values and Change from Baseline in Vital Signs Safety Analysis Set 
Table 14.3.6.2 Summary of Vital Signs Interpretation Safety Analysis Set  
Table 14.3.7.1 Descriptive Statistics of Observed Values and Change from Baseline in Electrocardiogram Safety Analysis Set 
Table 14.3.7.2 Summary of Electrocardiogram Interpretation by Visit Safety Analysis Set 
Table 14.3.8.1 Summary of Infusion Site Reaction - Overall Safety Analysis Set 


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Table 14.3.8.2 Summary of Infusion Site Reaction by Timepoints Safety Analysis Set 
 
List of Listings 
Listing 16.2.1.1 Analysis Set 
Listing 16.2.1.2 Subject Disposition Enrolled Set 
Listing 16.2.2.1 Protocol Deviations Safety Analysis Set 
Listing 16.2.4.1 Demographics Safety Analysis Set 
Listing 16.2.4.2 Medical History Safety Analysis Set 
Listing 16.2.4.3 Inclusion/Exclusion Criteria Enrolled Set 
Listing 16.2.4.4 Prior and Concomitant Medications Safety Analysis Set 
Listing 16.2.5.1 Study Drug Infusion Safety Analysis Set 
Listing 16.2.6.1 Individual Plasma Concentrations of Cefazolin Safety Analysis Set 
Listing 16.2.7.1 Adverse Events Safety Analysis Set 
Listing 16.2.7.2 Serious Adverse Events Safety Analysis Set 
Listing 16.2.7.3 Adverse Events Leading to Treatment Discontinuation Safety Analysis Set 
Listing 16.2.7.4 Adverse Events Leading to Study Discontinuation Safety Analysis Set 
Listing 16.2.7.5 Adverse Events Leading to Death Safety Analysis Set 
Listing 16.2.8.1 Laboratory Results – Hematology Safety Analysis Set 
Listing 16.2.8.2 Laboratory Results – Chemistry Safety Analysis Set 
Listing 16.2.8.3 Laboratory Results – Pregnancy Safety Analysis Set 
Listing 16.2.8.4 Vital Sign Results Safety Analysis Set 
Listing 16.2.9.1 Physical Examinations Safety Analysis Set 
Listing 16.2.10.1 Electrocardiogram Results Safety Analysis Set 
Listing 16.2.11.1 Infusion Site Reaction - Overall Safety Analysis Set 
Listing 16.2.11.2 Infusion Site Reaction by Timepoints Safety Analysis Set 
 
List of Figures 
Figure 14.2.2.1 Plasma Concentrations Versus Time Profiles PK Analysis Set