Clinical trial NCT02424734
Conditions: Late-onset Sepsis
Keywords: Late-onset Sepsis
Sponsor: Pfizer
Start date: 2015-08-04; Completion date: 2017-12-26
Enrollment: 11 participants; Allocation: ; Intervention model: 

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of ceftaroline for the treatment of Late Onset Sepsis in neonates and young infants aged 7 to \<60 days

Detailed description:
This is a multicentre, multinational, open-label, single treatment arm study of intravenous (IV) ceftaroline fosamil and ampicillin, plus an optional aminoglycoside of choice, in hospitalized neonates and young infants aged 7 to \< 60 days with late-onset sepsis (LOS).

Baseline assessments for study eligibility will occur within 36 hours before administration of the first dose of study therapy. Study Day 1 is defined as the 24-hour period starting at the onset of the first administration of study therapy. Thereafter, subsequent Study Days are to follow the same pattern.

Safety assessments will occur throughout the study. Clinical outcome evaluations will occur at End-of-Therapy (EOT; within 24 hours after completion of last infusion) and Test-of-Cure (TOC; 8 to 15 days after the last dose of study therapy).

Arms: arm 1: Ceftaroline Fosamil
Interventions: intervention 1: Ceftaroline Fosamil intervention 2: Ampicillin intervention 3: Aminoglycoside
Intervention descriptions: intervention 1: Ceftaroline fosamil will be given at a dose of 6 mg/kg IV over 60 (± 10) minutes every 8 hours (q8h) (± 1 hour). intervention 2: Ampicillin IV is required for the first 48 hours if the presence of an organism that requires treatment with ampicillin cannot be excluded. Will be given as per local standard of care. intervention 3: Optional, will be given as per local standard of care.

Protocol documents:
Prot_000.pdf: 
1(88)
Clinical Study Protocol 
Drug Substance
Ceftaroline fosamil
United States (US) Investigational 
New Drug (IND) Number:
71,371
European Clinical Trials Database 
(EudraCT) Number:
2014-003243-34
Pfizer Study Code
C2661002
Astra ZenecaStudy Code
D3720C00009
Version
5.0
Phase
2
Date
25May 2017
Open-label, Multicentre Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Ceftaroline in Neonates and Young 
Infants with Late-Onset Sepsis
Sponsor:Pfizer Inc., 235East 42ndStreet, New York, NY 10017, USA (as of Version5.0) 
Prior Sponsor:AstraZeneca AB, 15185Södertälje, Sweden
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Clinical Study Protocol 
Drug Substance Ceftaroline fosamil
Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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VERSION HISTORY
Version5.0, 25May 2017
The previous version of the protocol (Edition 4, dated 25August 2015) hasbeen revised to reflect 
change in Sponsorship to Pfizer Inc and to include the latest protocol template language of the current 
Sponsor, Pfizer.  The visit window for the Safety Follow Up (SFU) assessment was changed to 28 to 
35 days to be consistent withPfizer’s requirement to follow safety for a minimum of 28 days after the 
last dose of study therapy.  In addition, minor text changes were made to improve protocol clarity.
Version4, 25August2016
The previous version of the protocol (Edition 3, dated 16December 2015) has been 
transferred to the latest AstraZeneca designated template (Protocol Template Version 17.0). 
In addition, the following changes were incorporated into Version 4of the protocol:
Date of pediatricapprovalin the US (May 2016) and EU (June2016) was added.
Inclusion criterion5wasrevised so that patients must meet at least 1of the listedlaboratory
criteria, rather than 2of the criteria.
Followingarequest fromthe Italian Ministry of Health,ajustification was provided forthe dose 
increase to 6mg/kgthat was described in Edition 3of the protocol.
Clarification was added to the effect that theindividual dose of Ceftaroline fosamil should be 
calculated based on the patient’s first weight of the day.
Note: previous versions of the protocol were numbered “Edition 1”, “Edition 2”, etc, but “Edition” has 
now been replaced with “Version”.
Edition 3, 16December 2015
An AstraZeneca Research and Development site representative was added as a signatory to the 
revised protocol.
Clarification was provided for when ampicillin administration is mandatory.
The dose of ceftaroline fosamil to be given was increased to 6mg/kg.
The estimated date for last patient completed and studyend were updated to align with the Pediatric
Investigation Plan for ceftaroline fosamil.
Minor wording changes were added to the text as clarifications.
Note: in addition to the changes listed above, minor formatting/style changes were made.
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Drug Substance Ceftaroline fosamil
Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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Edition 2, 23April 2015
1. The definition of preterm neonate wasrevised in order to align with the World Health 
Organization definition of preterm neonates used world-wide. The age requirement for 
Cohort 2(term neonates) wastherefore revisedfrom gestational age ≥38weeks to 
gestational age ≥37weeks.The age requirement for Cohort 3(preterm neonates) was 
revised from gestational age ≥34to <38weeks togestational age ≥34to <37weeks.
2. The discrepancy between units and values for white blood cell and platelet counts in the 
inclusion criteria wascorrected.
3. The definition of Study Day wasclarified –Study Days were to be calculated starting from 
the onset of the first dose of study therapy, in 24-hour increments.
In addition, some minor typographic errors werecorrected.
Edition 1, 18November 2013
Initial creation 
This amendment incorporates all revisions to date, including amendments made at the request 
of country health authorities and institutional boards (IRBs)/ethics committees (ECs).
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to the Sponsorand opportunity to object.
The clinical study protocol is publicly registered and the results are disclosed and/or published 
according to the Sponsor publication policyand in compliance with prevailing laws and 
regulations.
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Drug Substance Ceftaroline fosamil
Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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PROTOCOL SYNOPSIS
Open-label, Multicentre Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Ceftaroline in Neonates and Young 
Infants with Late-Onset Sepsis
International Co-ordinating Investigator
The name and contact details of the International Co-ordinating Investigator will be 
communicated by the Sponsor or Sponsor representative to all study centres and any 
applicable regulatory authorities via a certified letter.
Study site(s) and number of patients planned
The study will be conducted in approximately 30centres worldwide.  At least 24patients 
evaluable for safety will be enrolled and treated within the following age cohorts:
Cohort 1: young infants aged >28days to <60days (n=8)
Cohort 2: term neonates (defined as gestational age ≥37weeks) aged 7to ≤28days 
(n=8)
Cohort 3: preterm neonates (defined as gestational age ≥34to <37weeks) aged 
7to≤28days (n=8).
Study period
Estimated date of first patient enrolled
Q12015
Estimated date of last patient completed
December 2017
Study design
This is a multicentre, multinational, open-label, single treatment arm study of intravenous (IV) 
ceftaroline fosamil and ampicillin, plus an optional aminoglycoside of choice, in hospitalized 
neonates and young infants aged 7to <60days with late-onset sepsis (LOS).
Baseline assessments for study eligibility will occur within 36hours before administration of 
the first dose of study therapy.  Study Day 1is defined as the 24-hour period starting at the 
onset of the first administration of study therapy.  Thereafter, subsequent Study Days are to 
follow the same pattern.
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Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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Safety assessments will occur throughout the study.  Clinical outcome evaluations will occur 
at End-of-Therapy (EOT; within 24hours after completion of last infusion) and Test-of-Cure 
(TOC; 8to 15days after the last dose of study therapy).
Objectives
Primary Objective:
Outcome Measure:
To evaluate the safety and tolerability of 
ceftaroline for the treatment of LOS in 
neonates and young infants aged 7to <60days
Safety assessments will include adverse events (AEs), 
serious adverse events (SAEs), deaths, and 
discontinuations due to AEs.
Secondary Objective:
Outcome Measure :
To evaluate the pharmacokineticprofile of 
ceftaroline in neonates and young infants aged 
7to <60days with LOS
Concentrations of ceftaroline fosamil, ceftaroline, and 
ceftaroline M-1in plasma (and if available, 
concentrations of ceftaroline and ceftaroline M-1in 
cerebrospinal fluid [CSF])  
To evaluate the efficacy of ceftaroline for the 
treatment of LOS in neonates and young 
infants aged 7to <60days
Efficacy outcome measures will include clinical 
outcome at EOT and TOC in the Modified 
Intent-to-Treat (MITT) Analysis Set.  
Target patientpopulation
Male or female patients, gestational age ≥34weeks, and chronological age 7to <60days with 
a diagnosis of sepsis within 36hours before enrolment, defined as the presence of at least 
2clinical criteria and at least 1laboratory criterionin the presence of or as a result of 
suspected or proven bacterial infection that requires IV antibiotic therapy.
Duration of treatment
Patient participation will require up to 49days.  The total duration of study therapy is 48hours 
(minimum) to 14days (maximum).  Hospitalization is required while on IV study therapy.  
Baseline assessments for study eligibility will occur within 36hours before the first dose of 
study therapy.  The Safety Follow-up(SFU) assessments will occur 28to 35days after the last 
dose of study therapy.
Investigational product, dosage and mode of administration
Ceftaroline fosamil will be given at a dose of 6mg/kg IV over 60(± 10) minutes every 
8hours (q8h) (±1hour).  IV ampicillin and optional aminoglycoside will be given as per 
standard of care.  If the presence of an organism that requires treatment with ampicillin cannot 
be excluded, then the use of IV ampicillin for the first 48hours is mandatory.  If the resultsof 
additional microbiology, polymerase chain reaction (PCR) or other investigations indicate that 
ampicillin during the first 48hours of treatment is not required, then its use is at the discretion 
of the investigator.
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Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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Statistical methods
Descriptive statistics (number, mean, standard deviation, median, minimum, and maximum) 
will be provided for continuous variables, and frequency distributions (counts and 
percentages) will be shown for categorical variables.  All variables will be summarized overall 
and by age cohort.  Listings of individual patients’ data will also be produced.
The primary objective of this study is to evaluate the safety and tolerability of ceftaroline in 
neonates and young infants with LOS and the study is not powered for formal statistical 
inference.  The Safety Analysis Set will include all patients who received any amount of 
ceftaroline fosamil.  Safety parameters include AEs, SAEs, deaths, clinical laboratory 
parameters, and vital signs.  For each safety parameter, the last assessment made before the 
first dose of study therapy will be used as the baseline for all analyses.  The incidence of 
adverse events (AEs), serious adverse events (SAEs), deaths, and discontinuations due to AEs 
will be summarized overall and within each age cohort, by system organ class and preferred 
term according to the Medical Dictionary for Regulatory Activities (MedDRA), by 
relationship to the study therapy, and by severity.
Efficacy outcomes will be summarized descriptively using the modified Intent-to-treat 
(MITT) Analysis Set, which will include all patients who receive any amount of ceftaroline 
fosamil and who meet minimal disease criteria of LOS.  An assessment of clinical outcome 
will be made by the investigator at EOT.  Possible outcomes are clinical cure, clinical failure 
or indeterminate.  A favourable clinical outcome is clinical cure.  An outcome of clinical 
failure at EOT will be carried forward to TOC.  A further assessment of clinical outcome will 
be made at TOC.
Per-patientmicrobiological response at TOC will be determined programmatically based on 
individual outcomes for each baseline pathogen.  In order for a patient to have a favourable 
microbiological response, the outcome for each baseline pathogen must be favourable 
(eradicated or presumed eradicated).  If the outcome for any pathogen is unfavourable 
(persistence or presumed persistence), the patient will be considered to have an unfavourable 
microbiological response.
Summaries of demographics and other baseline characteristics will be provided.  The 
incidence of AEs, SAEs, deaths, and discontinuations due to AEs will be summarized by 
system organ class and preferred term according to the Medical Dictionary for Regulatory 
Activities, by relationship to study therapy, and by severity.  Descriptive statistics of observed 
results and the change from baseline to selected postbaseline time points will be presented for 
clinical laboratory results and vital signs.  The incidence of selected potentially clinically 
significant laboratory results will be summarized.
The pharmacokinetic (PK) Analysis Set will include all patients who receive a known amount 
of ceftaroline fosamil and who have had at least 1PK sample collected.  The PK data 
acquisition and analysis strategy in this study entails the use of a sparse PK sampling 
schedule, conducted only at selected investigational centres.  Plasma concentrations of 
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Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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ceftaroline fosamil, ceftaroline and ceftaroline M-1, and cerebrospinal fluid (CSF) 
concentrations of ceftaroline and ceftaroline M-1will be listed by age cohort.  Ceftaroline 
plasma concentration data, along with other information including demographic data, will be 
combined with appropriate data from other clinical studies and analysed using a population 
PK approach and reported separately.
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Drug Substance Ceftaroline fosamil
Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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TABLE OF CONTENTS
PAGE
LIST OF TABLES..................................................................................................................14
LIST OF FIGURES.................................................................................................................14
1. INTRODUCTION...............................................................................................................18
1.1. Background and rationale for conducting this study..............................................18
1.2. Rationale for study design, doses and control groups.............................................19
1.3. Benefit/risk and ethical assessment........................................................................20
1.4. Study Design...........................................................................................................22
2. STUDY OBJECTIVES.......................................................................................................24
2.1. Primary objective....................................................................................................24
2.2. Secondary objectives..............................................................................................24
2.3. Safety objectives.....................................................................................................24
2.4. Exploratory objectives (not applicable)..................................................................24
3. PATIENT SELECTION, ENROLMENT, RANDOMISATION, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL.................................................................24
3.1. Inclusion criteria.....................................................................................................24
3.2. Exclusion criteria....................................................................................................25
3.3. Patient enrolment....................................................................................................26
3.4. Procedures for handling incorrectly enrolled patients............................................27
3.5. Methods for assigning treatment groups.................................................................27
3.5.1. Stratification by age and cohort..................................................................27
3.5.2. Assignment to PK schedule........................................................................27
3.6. Methods for ensuring blinding................................................................................28
3.7. Methods for unblinding...........................................................................................28
3.8. Restrictions.............................................................................................................28
3.9. Discontinuation of investigational product.............................................................28
3.9.1. Procedures for discontinuation of a patient from investigational 
product.............................................................................................................28
3.9.1.1. Discontinuations Due to Safety................................................28
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Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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3.9.1.2. Discontinuations Due to Insufficient Therapeutic Effect.........29
3.10. Criteria for withdrawal..........................................................................................30
3.10.1. Screen failures..........................................................................................30
3.10.2. Withdrawal of the informed consent........................................................31
3.11. Discontinuation of the study.................................................................................31
3.12. Sponsor’s Qualified Medical Personnel................................................................31
4. STUDY PLAN AND TIMING OF PROCEDURES..........................................................32
4.1. Baseline...................................................................................................................35
4.1.1. Baseline assessments..................................................................................35
4.1.1.1. Clinical assessments..................................................................35
4.1.1.2. Laboratory assessments............................................................36
4.1.1.3. Microbiological assessments....................................................36
4.2. Treatment period.....................................................................................................37
4.2.1. StudyDay 1(starts with onset of study drug administration)....................37
4.2.1.1. Study therapy administration....................................................37
4.2.1.2. Clinical assessments -after at least 1dose of study therapy....37
4.2.1.3. Laboratory assessments -after at least 1dose of study 
therapy...............................................................................................38
4.2.1.4. Microbiological assessments -after at least 1dose of study 
therapy...............................................................................................38
4.2.2. Study Day 2(starts 24hours after onset of study drug administration).....38
4.2.2.1. Study therapy administration....................................................38
4.2.2.2. Clinical assessments -any time during study day....................39
4.2.2.3. Laboratory assessments -any time during study day...............39
4.2.2.4. PK procedures...........................................................................39
4.2.2.5. Microbiological assessments -any time during study day.......40
4.2.3. Study Day 3(starts 48hours after onset of study drug administration).....40
4.2.3.1. Study therapy administration....................................................40
4.2.3.2. Clinical assessments -any time during study day....................41
4.2.3.3. Laboratory assessments -any timeduring study day...............41
4.2.3.4. Microbiological assessments -any time during study day.......41
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Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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4.2.3.5. PK procedures...........................................................................42
4.2.4. Study Days 4through 14(starts 72hours after onset of study drug 
administration and an extra 24hours for each day thereafter)........................42
4.2.4.1. Study therapy administration....................................................42
4.2.4.2. Clinical assessments -any time during study day....................42
4.2.4.3. Laboratory assessments -any time during study day...............43
4.2.4.4. Microbiological assessments -any time during study day.......43
4.2.4.5. PK procedures...........................................................................43
4.2.5. End-of-Therapy (EOT)...............................................................................43
4.2.5.1. Clinical assessments -after the last dose of study therapy.......44
4.2.5.2. Laboratory assessments -after the last dose of study 
therapy...............................................................................................44
4.2.5.3. Microbiological assessments -after the last dose of study 
therapy...............................................................................................45
4.3. Follow-up period.....................................................................................................45
4.3.1. Test-of-Cure (TOC)....................................................................................45
4.3.1.1. Clinical assessments..................................................................45
4.3.1.2. Laboratory assessments............................................................46
4.3.1.3. Microbiological assessments....................................................46
4.3.2. Safety Follow-Up (SFU)............................................................................46
4.3.2.1. If SFU conducted via telephone................................................46
4.3.2.2. If SFU conducted in person......................................................47
5. STUDY ASSESSMENTS...................................................................................................47
5.1. Efficacy assessments...............................................................................................47
5.2. Microbiological assessments..................................................................................48
5.2.1. Blood sample for culture............................................................................48
5.2.2. Urine sample for culture.............................................................................48
5.2.3. Cerebrospinal fluid for culture...................................................................48
5.2.4. Other specimens and tissue samples for culture.........................................49
5.3. Safety assessments..................................................................................................49
5.3.1. Laboratory safety assessments...................................................................49
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Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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5.3.2. Other clinical assessments..........................................................................50
5.3.3. Adverse events...........................................................................................51
5.4. Pharmacokinetics....................................................................................................51
5.4.1. Collection of blood samples.......................................................................51
5.4.2. Collection of cerebrospinal fluid samples..................................................52
5.4.3. Determination of drug concentration.........................................................52
5.4.4. Storage and destruction of pharmacokinetic samples................................52
5.5. Pharmacodynamics (not applicable).......................................................................53
5.6. Pharmacogenetics (not applicable).........................................................................53
5.7. Biomarker analysis (not applicable).......................................................................53
5.8. Volume of blood.....................................................................................................53
6. ADVERSE EVENT REPORTING AND MEDICAL MANAGEMENT..........................53
6.1. Requirements..........................................................................................................53
6.1.1. Additional Details On Recording Adverse Events on the CRF.................55
6.1.2. Eliciting Adverse Event Information.........................................................55
6.1.3. Withdrawal From the Study Due to Adverse Events.................................55
6.1.4. Time Period for Collecting AE/SAE Information......................................55
6.1.4.1. Reporting SAEs to Pfizer Safety...............................................55
6.1.4.2. Recording Non-serious AEs and SAEs on the CRF.................56
6.1.5. Causality Assessment.................................................................................56
6.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities..................56
6.2. Definitions...............................................................................................................56
6.2.1. Adverse Events...........................................................................................56
6.2.2. Abnormal Test Findings.............................................................................57
6.2.3. Serious Adverse Events..............................................................................58
6.2.4. Hospitalization............................................................................................58
6.3. Severity Assessment...............................................................................................60
6.4. Special Situations....................................................................................................60
6.4.1. Potential Cases of Drug-Induced Liver Injury...........................................60
6.4.2. Exposure to the Investigational Product During Pregnancy or
Breastfeeding, and Occupational Exposure.....................................................62
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6.4.2.1. Exposure During Pregnancy.....................................................62
6.4.2.2. Exposure During Breastfeeding................................................62
6.4.2.3. Occupational Exposure.............................................................62
6.4.3. Medication Errors and Lack of Efficacy....................................................62
6.4.3.1. Medication Errors.....................................................................63
6.4.3.2. Lack of Efficacy........................................................................63
6.5. Study governance and oversight.............................................................................63
6.5.1. Data and Safety Monitoring Board............................................................63
7. INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS..................................64
7.1. Identity of investigational product(s)......................................................................64
7.1.1. Ceftaroline Fosamil....................................................................................64
7.1.1.1. Directions for Use.....................................................................64
7.1.1.2. Drug Storage.............................................................................64
7.1.2. Ampicillin and Optional Aminoglycoside.................................................65
7.2. Dose and treatment regimens..................................................................................65
7.2.1. Ceftaroline fosamil.....................................................................................65
7.2.2. Ampicillin...................................................................................................65
7.2.3. Aminoglycoside..........................................................................................65
7.2.4. Dose adjustment.........................................................................................66
7.3. Labelling.................................................................................................................66
7.4. Storage....................................................................................................................66
7.5. Compliance.............................................................................................................67
7.6. Accountability.........................................................................................................67
7.6.1. Study drug handling and disposal..............................................................67
7.7. Concomitant and other treatments..........................................................................67
7.7.1. Other concomitant treatment......................................................................68
8. STATISTICAL ANALYSES..............................................................................................68
8.1. Statistical considerations.........................................................................................68
8.2. Sample size estimate...............................................................................................68
8.3. Definitions of analysis sets.....................................................................................68
8.3.1. Intent-to-treat analysis set..........................................................................68
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Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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8.3.2. Safety analysis set......................................................................................68
8.3.3. Modified intent-to-treat (MITT) analysis set.............................................68
8.3.4. Pharmacokinetic (PK) analysis set.............................................................68
8.4. Outcome measures for analyses..............................................................................69
8.4.1. Efficacy response definitions.....................................................................69
8.4.1.1. Clinical outcome at End-of-Therapy........................................69
8.4.1.2. Clinical outcome at Test-of-Cure..............................................70
8.4.2. Microbiological response definitions.........................................................71
8.4.2.1. Microbiological Outcome at Test-of-Cure................................71
8.5. Methods for statistical analyses..............................................................................72
8.5.1. Analysis of the study population and patient characteristics.....................72
8.5.2. Analysis of the primary variable................................................................72
8.5.3. Analysis of the secondary variables...........................................................73
8.5.3.1. Pharmacokinetic sample collection and analyses.....................73
8.6. Interim Analysis......................................................................................................73
9. STUDY AND DATA MANAGEMENT............................................................................74
9.1. Training of study site personnel..............................................................................74
9.2. Monitoring of the study..........................................................................................74
9.2.1. Source data.................................................................................................75
9.2.2. Study agreements.......................................................................................75
9.2.3. Archiving of study documents...................................................................75
9.2.3.1. Data handling and record keeping............................................76
9.3. Study timetable and end of study............................................................................77
9.3.1. Study completion........................................................................................77
9.3.2. Guidance to investigators on when to end study therapy...........................77
9.3.3. Study termination by Sponsor and termination criteria..............................78
9.4. Data management....................................................................................................78
10. ETHICAL AND REGULATORY REQUIREMENTS....................................................79
10.1. Ethical conduct of the study..................................................................................79
10.2. Patient data protection...........................................................................................80
10.3. Ethics and regulatory review................................................................................80
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Study Code D3720C00009/C2661002
Version 5.0
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10.4. Informed consent..................................................................................................81
10.5. Changes to the protocol and informed consent form............................................82
10.6. Audits and inspections..........................................................................................82
10.7. Reporting of safety issues and serious breaches of the protocol or ICH GCP.....83
10.8. Publication of study results...................................................................................83
10.9. Communication of results by the Sponsor............................................................83
10.9.1. Publications by investigators....................................................................84
11. LIST OF REFERENCES...................................................................................................86
APPENDIX A
INTERNATIONAL AIRLINE TRANSPORTATION 
ASSOCIATION (IATA) 6.2GUIDANCE DOCUMENT.................................................88
LIST OF TABLES
Table 1
Study Plan detailing the procedures.....................................................................33
Table 2
Laboratory Safety Variables.................................................................................50
Table 3
Volume of blood per patient.................................................................................53
Table 4
Clinical outcome categories at End-of-Therapy...................................................70
Table 5
Clinical outcome categories at Test-of-Cure........................................................71
Table 6
Per-pathogen microbiological outcomes categories at End of Treatment and 
Test-of-Cure.........................................................................................................72
LIST OF FIGURES
Figure 1
Study Diagram......................................................................................................23
Figure 2
Study Analysis Sets..............................................................................................69
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Drug Substance Ceftaroline fosamil
Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ABSSSI
Acute bacterial skin and skin structure infections
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24h
Area under the curvefrom 0to 24hours
BE
Base excess
CA
Competent Authority
CABP
Community acquired bacterial pneumonia
CAP
Community-acquired pneumonia
CBC
Complete blood count
CRF
Case report form
Cmax
Maximum concentration
CNS
Central nervous system
CRF
Case Report Form (electronic/paper)
CRP
C-reactive protein
CRS
Catheter-related sepsis
CSA
Clinical Study Agreement
CSF
Cerebrospinal fluid
CSR
Clinical Study Report
CT
Computed tomography 
CXR
Chest radiograph  
DILI
Drug-induced liver injury
DSMB
Data and Safety Monitoring Board  
EDC
Electronic data capture 
EOT
End-of-Therapy 
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration 
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Abbreviation or 
special term
Explanation
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
International 
Co-ordinating 
investigator
If a studyis conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally  
IP
Investigational product 
IRB
Institutional Review Board
ITT
Intent-to-treat  
IV
Intravenous
IXRS
Interactive voice/web response system
LOS
Late-onset sepsis
MedDRA
Medical Dictionary for Regulatory Activities 
MIC
Minimum inhibitory concentration
MITT
Modified intent-to-treat (MITT) 
MRI
Magnetic resonance imaging
MRSA
Methicillin-resistant Staphylococcus aureus
NEC
Necrotizing enterocolitis
PCR
Polymerase chain reaction
PCS
Potentially clinically significant
PI
Principal Investigator 
PK
Pharmacokinetic
PTA
Probability of target attainment
q8h
Every 8hours
q12h
Every 12hours
SAE
Serious adverse event 
SAP
Statistical analysis plan 
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Drug Substance Ceftaroline fosamil
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Version 5.0
Date 25 May 2017
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Abbreviation or 
special term
Explanation
SFU
Safety follow-up
SPC
Summary of product characteristics
Tbili
Total bilirubin
TOC
Test-of-Cure 
ULN
Upper limit of normal
US
United States
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Clinical Study Protocol 
Drug Substance Ceftaroline fosamil
Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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1.INTRODUCTION
1.1.Background and rationalefor conducting this study
Ceftaroline is a β-lactam antibiotic of the cephalosporin class with broad-spectrum activity 
against gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA) 
and penicillin-resistant S. pneumonia (PRSP), as well as against common gram-negative 
bacteria.  Ceftaroline inhibits bacterial cell wall biosynthesis by binding to 1or more 
penicillin-binding proteins, which inhibits their function and causes the bacteria to die.  
Ceftaroline exhibits unique properties that distinguish it from other β-lactams due to its high 
affinity for PBP2a in MRSA, and PBP2x in PRSP that contribute to its potent antibacterial 
activity against these organisms.
Teflaro®(ceftaroline fosamil, the prodrug of ceftaroline) is indicated in adult and pediatric
patients 2months of age and older for the treatment of acute bacterial skin and skin structure 
infections (ABSSSI) and for the treatment of community-acquired bacterial pneumonia 
(CABP).  Teflaro was approved in the US for ABSSSI and CABP in adults in October 2010.  
Pediatricapproval in the US was May 2016.  In August 2012, it was approved as Zinforo™ 
for use in adults for the treatment of complicated skin and soft tissue infection and 
community-acquired pneumonia (CAP) in the European Union and Chile.  Pediatricapproval 
in the European Union was June 2016.  Since 2012, Zinforo™ has been approved in over 
50countries, including Russia, Australia, Malaysia, and Singapore, and approval is being 
sought in additional countries.  Refer to the current ceftaroline fosamil Investigator’s Brochure 
(IB) and ceftaroline fosamil product information18,19for summaries of the nonclinical, 
microbiology, pharmacology, and clinical studies.
A pediatricdevelopment program to evaluate the use of ceftaroline fosamil in children under 
18years old is currently underway.  Two Phase I studies designed to assess the safety, 
tolerability, and pharmacokinetics (PK) of ceftaroline fosamil in children have been 
completed (Study P903-15in adolescent patients aged 12to 17years and Study P903-21in 
children aged from birth to <12years).  The program includes three completed studies in 
patients from 2months to <18years of age: 2Phase 2/3studies (Study P903-23in ABSSSI 
and Study P903-31in CABP requiring hospitalization) and a Phase 4study (Study P903-24in 
complicated CABP). 
Late-onset sepsis (LOS), or sepsis neonatorum, is a severe infectious disease, one of the main 
causes of mortality andmorbidity among neonates and young infants around the world, and 
has different epidemiology, microbiology, and pathophysiology than other age populations.
1,8
The purpose of this study is to assess the safety, tolerability, PK, and efficacy of ceftaroline 
fosamil and ampicillin, plus an optional aminoglycoside of choice, in neonates and young 
infants with LOS.
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Version 5.0
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1.2.Rationale for study design, doses and control groups
This open-label, multicentre, multinational, single treatment arm study will evaluate the 
safety, tolerability, PK, and efficacy of ceftaroline in the target population, neonates and 
young infants with LOS.  Pediatricpatients (7to <60days) with suspected or confirmed LOS 
will be enrolled in this study.
The aetiology of LOS is nosocomial or community acquired.  Ceftaroline has activity against 
common gram-positive pathogens, including MRSA, and gram-negative pathogens including 
Enterobacteriaceae (with the exception of those producing extended-spectrum β-lactamase), 
which makes it appropriate for use in community-acquired and nosocomial infections.
5,14,18
Immediate administration of antibiotic therapy with broad-spectrum activity is critical in 
patients with LOS.  The purpose of therapy is to prevent morbidity and decrease mortality 
which is likely to happen without therapy or with inadequate therapy.  Starting the appropriate 
antibacterial drug without delay, while awaiting culture results, decreases mortality rate 
dramatically.4,10  As therapy must be prescribed as soon as possible, the choice of drugs 
should be made empirically based on epidemiology and possible aetiology agent.  The priority 
should be given to bactericidal drugs with broad-spectrum coverage of gram-positive and 
gram negative microorganisms. 
Ceftaroline, with its broad-spectrum activity has the potential to provide a valuable therapeutic 
option in the treatment of LOS.  Ceftaroline was well tolerated in adult and pediatricclinical 
trials and has a safety profile consistent with available marketed cephalosporins, a class of 
antibiotics with a long history of clinical use.
The combination of ampicillin and an optional aminoglycoside of choice was chosen as the 
recommended empirical therapy because of its ability to achieve maximum coverage of 
gram-positive andgram-negative pathogens of LOS and as an effective standard of care 
antibiotic therapy for this indication, which is accepted in clinical practice 
worldwide.2,9,11,15,16,17
The dosing regimen for ceftaroline (6mg/kg q8h as a 1-hour infusion)was chosen based on a 
population PK model updated with PK data from three multiple dose safety and efficacy 
studies in children from 2months to <18years (Studies P903-23, P903-31and P903-24).13  
These data have been used in conjunction with adult patient and healthy volunteer data and 
data from single dose ceftaroline PK studies conducted in children from neonates to 
<18years. The ceftaroline population PK model incorporates allometric scaling for body 
weight and maturation of renal function.  This model was used in Monte Carlo simulations to 
choose and justify the dose regimens for children from 2months to 18years, now included on 
the European Summary of Product Characteristics (SmPC)and US Food and Drug
Administration(FDA)label.  The same model hasbeen used to predict doses for children 
<2months, including pre-term neonates (with a post-menstrual age of 28to 41weeks). 
Post-menstrual age is defined as gestational age plus chronological age.  Various dosing 
regimens simulated using body weights for each simulated patient were predicted based on 
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Study Code D3720C00009/C2661002
Version 5.0
Date 25 May 2017
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age in accordance with either CDC growth charts
7for neonates that were born to term orin 
accordance with intrauterine growth curves
12for preterm and to-term neonates (gestational 
age 32-40weeks).  One hundredsimulations were performed for each dose with 
600(300male and 300female) patients from each age group.  The age groups were 
categorised as follows: 28to <30, 30to <32, 32to <34, 34to <36, 36to<38, 38to 
<40post-menstrual weeks, 0to <1, 1to <2, 2to <6, 6to <12, 12to <18, 18to<24months.
Using this model, several dose regimens have been assessed and a dose of 6mg/kg ceftaroline 
fosamil q8h as a 1-hour infusion is predicted to achieve >90% probability of target attainment
(PTA)for minimum inhibitory concentrations (MICs)≤2mg/L.  Predicted ceftaroline 
exposures (based on steady-state maximum concentration [Cmax]and area under the curve 
from 0to24hours[AUC0-24h]) in pediatricpatients younger than 2months old and of 
gestational age 32-48weeks dosed with 6mg/kg q8h as a 1-hour infusion do not appreciably 
exceed ceftaroline exposures in adults dosed with the currently approved ceftaroline fosamil 
regimen of 600mg every 12hours (q12h). The median steady-state ceftaroline C
maxvalues in 
pediatricpatients in this age range dosed with the proposed regimen are predicted to be less 
than the median C
maxvalue in adults dosed with 600mg q12h.  Median steady-state 
ceftaroline AUC
0-24hvalues in pediatricpatients younger than 2months old and of gestational 
age 32-48weeks dosed with the proposed regimen are predicted to be no more than 
17%higher than the median adult value. 
Based on these findings, the updated model has been used to optimise the dose(6mg/kg q8h 
as a 1-hour infusion). 
1.3.Benefit/risk and ethical assessment
Patients enrolled into this clinical study will have LOS of sufficient severity to require 
hospitalization and treatment with IV antibiotics.  The potential benefit to patients 
participating in this study is that they will receive effective antibiotic therapy for their 
infection.  The potential benefit of this study, in general, is theidentification of a new addition 
to the available antibiotic therapy that is a safe and effective treatment for LOS, in the face of 
the changing pattern of antibiotic resistance. 
It is possible that ceftaroline fosamil and ampicillin will not prove to bea sufficiently effective 
treatment for LOS.  This risk is mitigated by the possible option of adding an aminoglycoside, 
by close monitoring of study patients, and by management with appropriate therapies as 
determined by the investigator providing treatment.
The risk considerations for this study encompass the known and potential risks for ceftaroline 
fosamil, as well as those risks associated with other treatments that may be administered as 
described in this protocol (ampicillin and optional aminoglycoside).  As the risks for these 
marketed products are widely available in their respective prescribing information, these risks 
will not be discussed within this section.
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Study Code D3720C00009/C2661002
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The risks for use of ceftaroline fosamil in children <2months of age have not been fully 
elucidated; however it is assumed that known or potential risks for ceftaroline fosamil should 
include those identified from adult use and in clinical studies in adults and in children and 
adolescents.  Additional risk information for ceftaroline fosamilis located in the Investigator’s 
Brochure.
The full risk profile for ceftaroline fosamil is described in the prescribing information for the 
product.  Important risks as laid out in the warnings and precautions in product labelling for 
ceftaroline fosamilinclude:
Hypersensitivity reactions:  though patients with hypersensitivity reactions to β lactam 
antibiotics are excluded from the trial, first-time episodes of such reactions could 
occur.
Antibiotic-associated diarrhoea: Clostridium difficile-associated diarrhoeahas been 
reported for nearly all systemic antibacterial agents, including ceftaroline fosamil, and 
may range in severity from mild diarrhoea to fatal colitis.
Direct Coombs
' Test Seroconversion: seroconversion from a negative to a positive test 
result occurred in more patients receiving ceftaroline fosamil than comparator drugs in 
pooled data from 4Phase III clinical trials.  If anaemia develops during or after 
treatment with ceftaroline fosamil, drug-induced haemolytic anaemia should be 
considered.
Development of Drug-Resistant Bacteria: prescribing ceftaroline fosamil in the 
absence of a proven or strongly suspected bacterial infection is unlikely to provide 
benefit to the patient and increases the risk of the development of drug-resistant 
bacteria.
Adverse Reactions: in the four pooled Phase III clinical trials, SAEs occurred in 
98/1300(7.5%) of patients receiving ceftaroline fosamil and 100/1297(7.7%) of 
patients receiving comparator drugs.  Treatment discontinuation due to adverse events 
occurred in 35/1300(2.7%) of patients receiving ceftaroline fosamil and 
48/1297(3.7%) of patients receiving comparator drugs with the most common adverse 
events leading to discontinuation being hypersensitivity for both treatment groups at a 
rate of 0.3% in the ceftaroline fosamil group and 0.5% in the comparator group.
No adverse reactions occurred in greater than 5% of patients receiving ceftaroline 
fosamil.  The most common adverse reactions occurring in >2% of patients receiving 
ceftaroline fosamil in the pooled Phase 3clinical trials were diarrhea, nausea, and rash.
No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil.  There 
is minimal potential for drug-drug interactions between ceftaroline fosamil and 
CYP450substrates, inhibitors, or inducers; drugs known to undergo active renal secretion; 
and drugs that may alter renal blood flow.
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Study Code D3720C00009/C2661002
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Date 25 May 2017
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Safety and effectiveness in pediatricpatients <2months of age have not been established.
Dosage adjustment is required in patients with moderateor severe renal impairment and in 
patients with end-stage renal disease (CrCl <15mL/min).
The PK of ceftaroline in patients with hepatic impairment has not been established.
1.4.Study Design 
This will be an open-label, single arm study with no randomization.  The study will be 
conducted in approximately 30centres worldwide.  At least 24patients with LOS will be 
enrolled and treated within three age cohorts of 8patients: young infants aged >28days to 
<60days; term neonates aged 7to ≤28days; and preterm neonates aged 7to ≤28days. 
Study therapy consists of standard of care ampicillin plus an optional aminoglycoside of 
choice, with the addition of intravenous (IV) ceftaroline fosamil, and will be given to all 
patients.  If the presence of an organism that requires treatment with ampicillin cannot be 
excluded, then the use of IV ampicillin for the first 48hours is mandatory.  If the resultsof 
additional microbiology, polymerase chain reaction (PCR) or other investigations indicate that 
ampicillin during the first 48hours of treatment is not required, then its use is at the discretion 
of the investigator. 
Ceftaroline fosamil will be given at a dose of 6mg/kg IV over 60(± 10) minutes q8h 
(±1hour). 
Patient participation will require up to 49days.  The total duration of study therapy is 48hours 
(minimum) to 14days (maximum).  Hospitalization is required during IV study therapy.  
Baseline assessments for study eligibility will occur within 36hours before the first dose of 
study therapy.  The Safety Follow-up(SFU) assessments will occur 28to 35days after the last 
dose of study therapy.
Safety assessments will be done throughout the study.  Between Day 2and Day 14, 2blood 
samples will be collected for PK analysis.  The efficacy of ceftaroline will be evaluated based 
on the clinical outcome (clinical cure, clinical failure or intermediate) at end of therapy (EOT) 
and test-of-cure (TOC) assessment. 
An external Data and Safety Monitoring Board (DSMB) will review data on a regular basis to 
assess the safety of all patients enrolled in this and other ongoing pediatricstudies 
(Section6.5.1).
The study design is described in the Study Diagram (Figure 1).
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Study Code D3720C00009/C2661002
Version 5.0
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Figure 1 Study Diagram
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Study Code D3720C00009/C2661002
Version 5.0
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2.STUDY OBJECTIVES
2.1.Primary objective
Primary Objective:
Outcome Measure:
To evaluate the safety and tolerability of 
ceftaroline for the treatment of LOS in 
neonatesand young infants aged 7to <60days
Safety evaluations will be conducted in the Safety 
Analysis Set and assessments will include AEs, 
SAEs, deaths, and discontinuations due to AEs.
2.2.Secondary objectives
Secondary Objective:
Outcome Measure :
To evaluatethe PK profile of ceftaroline in 
neonates and young infants aged 7to <60days 
with LOS
Concentrations of ceftarolinefosamil, ceftaroline,and 
ceftaroline M-1in plasma (and if available, 
concentrations of ceftaroline and ceftaroline M-1in 
cerebrospinalfluid [CSF])  
Evaluate the efficacy of ceftaroline for the 
treatment of LOS in neonates and young 
infants aged 7to <60days
Efficacy outcome measures will include clinical 
outcome at EOT and TOC in the Modified 
Intent-to-Treat (MITT) Analysis Set.  
2.3.Safety objectives
Safety is the primary objective.
2.4.Exploratory objectives(not applicable)  
3.PATIENT SELECTION, ENROLMENT, RANDOMISATION, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particularsubject is suitable for this protocol.
Subject eligibility should be reviewed and documented by the investigator or appropriate 
member his/hersite study team before subjects are included in the study.  Each patientshould 
meet all of the inclusion criteria and none of the exclusion criteria for this study.  Under no 
circumstances can there be exceptions to this rule.
3.1.Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1. Informed consent in writing from parent(s) or other legally-acceptable representative(s)
2. Male or female, gestational age ≥34weeks, and chronological age 7to <60days at the 
time of screening
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3. Diagnosis of sepsis within 36hours before enrolment, defined as the presence of at least 
2clinical criteriaand at least 1laboratory criterionin the presence of or as a result of 
suspected or proven bacterial infection that requires IV antibiotic therapy.
4. Patients must meet at least 2of the following clinical criteria:
a. Hypothermia (<36°C) OR fever (>38.5°C)
b. Bradycardia OR tachycardia OR rhythm instability
c. Urine output 0.5to 1mL/kg/h OR hypotension OR mottled skin OR impaired 
peripheral perfusion
d. Petechial rash OR sclerema neonatorum
e. New onset or worsening of apnoea episodes OR tachypnoea episodes OR increased 
oxygen requirements OR requirement for ventilation support
f. Feeding intolerance OR poor sucking OR abdominal distension
g. Irritability
h. Lethargy
i. Hypotonia.
5. Patients must meet at least 1of the following laboratory criteria:
a. White blood cell count ≤4.0× 109/L OR ≥20.0× 109/L
b.Immature to total neutrophil ratio >0.2
c. Platelet count ≤100× 109/L
d. C-reactive protein (CRP) >15mg/L OR procalcitonin ≥2ng/mL
e. Hyperglycaemia OR Hypoglycaemia
f. Metabolic acidosis.
3.2.Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Documented history of any hypersensitivity or allergic reaction to any β-lactam antibiotic 
or aminoglycoside
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2. At study entry, has confirmed infection with a pathogen known to be resistant to the 
combination of ceftaroline fosamil, ampicillin, and the optional aminoglycoside of choice 
OR confirmed viral, fungal, or parasitic pathogen as the sole cause of infection
3. Refractory septic shock within 24hours before enrolment that does not resolve after 
60minutes of vasopressor therapy
4. Moderate or severe renal impairment defined as serum creatinine ≥2times the upper limit 
of normal (× ULN) for age OR urine output <0.5mL/kg/h (measured over at least 8hours) 
OR requirement for dialysis
5. Evidence of progressively fatal underlying disease, or life expectancy of ≤60days
6. Documented history of seizure
7. Requiring or currently taking antiretroviral therapy for human immunodeficiency virus 
(HIV) or a child from an HIV positive mother
8. Proven or suspected central nervous system (CNS) infection (eg, meningitis, brain 
abscess, subdural abscess), osteomyelitis, endocarditis, or necrotizing enterocolitis (NEC)
9. Any condition (eg, cystic fibrosis, urea cycle disorders), antepartum/peripartum factors, or 
procedures that would, in the opinion of the investigator, make the patient unsuitable for 
the study, place a patient at risk, or compromise the quality of data
10.Patient
's parent(s) or legally-acceptable representative(s) involvement in the planning 
and/or conduct of the study (applies to both Sponsorstaff and/or staff at the study site).  
Concurrent participation in another clinical study with an investigational product (IP), 
previous enrolment/participation in this study, or participation in another study of 
ceftaroline fosamil within 14days before the intended start of the first dose of study 
therapy.
For procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3.Patientenrolment 
This is a non-randomized open-label study.  Patients will be enrolled ifthey meet all the 
inclusion criteria, including informed consent in writing from parent(s) or other 
legally-acceptable representative(s), and none of the exclusion criteria.  Patients will be 
stratified by age cohort as described in Section 3.5.1.  Patients will be randomly assigned in 
the PK portion of the study to PK Schedule 1or 2(Section 3.5.2). 
The investigator(s) will be responsible for patient management.  Assessments and procedures 
should be conducted as noted in Section 4.  The Pharmacist or designee will prepare study 
therapy infusions and manage dose adjustments, as applicable.
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Patients who are withdrawn from study before receiving any amount of study therapy will be 
replaced in order to enrol a total of 24treated patients for safety evaluations.
3.4.Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, receive 
study medication.  There can be no exceptions to this rule.  Patients who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be initiated on treatment.
Where a patient does not meet all the eligibility criteria but is incorrectly started on treatment, 
the investigator should inform the Sponsorstudy physician/designee immediately, and a 
discussion should occur between theSponsorstudy physician/designee and the investigator 
regarding whether to continue or discontinue the patient from treatment.  The Sponsorstudy 
physician/designee must ensure all decisions are appropriately documented.
3.5. Methods for assigning treatment groups
3.5.1.Stratification by age and cohort
This study is not randomized, but patients will be stratified by age cohort and randomly 
assigned for assessment of PK to PK Schedule 1or 2(Section 3.5.2).
At least 24patients evaluable for safety will be enrolled and treated within the following age 
cohorts:
Cohort 1: young infants aged >28days to <60days (n=8)
Cohort 2: term neonates (defined as gestational age ≥37weeks) aged 7to ≤28days 
(n=8)
Cohort 3: preterm neonates (defined as gestational age ≥34to <37weeks) aged 
7to≤28days (n=8).
3.5.2.Assignment to PK schedule
Two PK samples (approximately 0.3to 0.6mL perdraw) will be obtained at steady state from 
at least 20patients.  Patients will be randomly assigned (1:1) at the time of enrolment to one 
of the PK sample collection schedules: 
PK Schedule 1: at the end of the ceftaroline fosamil infusion (± 5minutes)and 3to 
4hours after the end of the infusion
PK Schedule 2: 15minutes to 2hours after the end of the ceftaroline fosamil infusion 
and 5to 7hours after the end of the infusion (before the start of the next infusion)
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3.6.Methods for ensuring blinding
Thisstudy is not blinded.  The investigators, pharmacists or designees, study centre personnel, 
and parent(s)/legally-acceptable representative(s) will be aware of study therapy being 
administered.
3.7. Methods for unblinding 
The study is not blinded.
3.8.Restrictions
Concomitant use of potentially effective systemic antibacterial therapy (other than study 
therapy), or any drug known to exhibit a contraindicated drug-drug interaction with any study 
therapy or labelled contraindication to use of any study therapy is not allowed.
3.9.Discontinuation of investigational product
At any time, parent(s) or legally-acceptable representative(s) are free to discontinue the patient 
from treatment with IPor withdraw the patient from the study (ie, IPand assessments –see 
Section 3.10.2), without prejudice to further treatment.  Parent(s) or legally-acceptable 
representative(s) who decide to discontinue a patient from treatment with IPwill always be 
asked about the reason(s) and the presence of any adverse events.  If possible, the patient will 
be seen and assessed by an investigator(s).  Adverse events will be followed up until SFU, 
28to 35days after the last dose of study therapy (See Section 6).  Any AEs that are 
unresolved at the patient’s last AE assessment in the study are followed up by the investigator 
for as long as medically indicated, but without further recording in the CRF.
3.9.1.Procedures for discontinuation of a patientfrom investigational product 
3.9.1.1.Discontinuations Due to Safety
Assessments and Procedures: A patient who is prematurely discontinued from study therapy 
administration for safety reasons should have EOT assessments conducted per Section 
4.2.5and undergo subsequent assessments at TOC and SFU.
Clinical Outcome Assessment: If a patient is prematurely discontinued from study therapy due 
to an AE and the clinical signs and symptoms of sepsis have resolved completely or improved 
such that no further antibacterial therapy is necessary, the patient should be assessed as a 
clinical cure at EOT and reassessed at TOC.
If a patient is prematurely discontinued from study therapy due to astudy therapy-related AE 
and requires alternative non-study antibacterial for treatment for LOS, the patient should be 
assessed as a clinical failure.
Reasons for premature discontinuation from study therapy administration due to safety may 
include, but are not limited to, occurrence of an AE that, in the opinion of the investigator, 
warrants the patient’s permanent discontinuation from study therapy administration.
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3.9.1.2.Discontinuations Due to Insufficient Therapeutic Effect
Assessments and Procedures: A patient who is prematurely discontinued from study therapy 
administration due to insufficient therapeutic effect should have EOT assessments conducted 
per Section 4.2.5and undergo subsequent safety assessments at TOC and SFU.
If a patient is discontinued from study therapy administration due to insufficient therapeutic 
effect and is switched to an alternative IV antibiotic, that therapy should be documented.
Clinical Outcome Assessment: A patient who is prematurely discontinued from study therapy 
administration (at any time after the required minimum treatment duration of 48hours) due to 
insufficient therapeutic effect should be assessed as a clinical failure on the day of 
discontinuation (ie, EOT).  Such a patient will be automatically assigned an outcome of 
clinical failure at all subsequent evaluation time points.
Reasons: Reasons for discontinuation from study therapy administration due to insufficient 
therapeutic effect may include, but are notlimited to, the following:
Clinical Worsening: A patient who shows signs of clinical worsening may be 
discontinued from study therapy administration at any time.  If the investigator deems 
the benefit-to-risk ratio of continuing study therapy acceptable, study therapy 
administration for at least 48hours is encouraged before discontinuation
Lack of Clinical Progress: For a patient who is stable, yet does not show signs of 
improvement, the investigator is encouraged to continue study therapy administration 
at least 48hours before such a patient is assessed as a clinical failure and the patient is 
discontinued from study therapy
Resistant Pathogen(s): If an organism resistant to one or more of the components of 
study therapy is isolated, the investigator will determine whether the patient remains 
on study therapy.  If clinical improvement is observed in the setting of a resistant 
isolate, the patient may be kept on study therapy at the discretion of the investigator.  
Treatment with the study therapy should be discontinued if the patient develops a 
concomitant bacterial infection with an organism that is not susceptible to the study 
therapy and requires further parenteral therapy
CNS Infection, Osteomyelitis, Endocarditis, or NEC: At Baseline, the investigator
should use clinical judgment to determine whether an imaging study is indicated to 
rule out the presence of CNS infection (eg, meningitis, brain abscess, or subdural 
abscess), osteomyelitis, endocarditis, or NEC.  If the patient is diagnosed with any of 
these conditions after enrolment into the study, the Medical Monitor should be 
notified, and the patient should be discontinued from study therapy, appropriately 
treated per standard of care, and be assessed as indeterminate.
If a patientis withdrawn from study, see Section 3.10.
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3.10.Criteria for withdrawal 
Assessments and Procedures: A patient may be withdrawn from the study at the request of his 
or her parent(s), legally-acceptable representative(s), the investigator, or Sponsor.  A patient 
who is withdrawn completely from this study should be encouraged to undergo, if possible, 
EOT assessments per Section 4on the day of withdrawal.  Patients withdrawn from the study 
need not undergo subsequent TOC efficacy assessments.
Clinical Outcome Assessment: Patients who are withdrawn from the study and have not been 
assessed as clinical failure should be assessed as indeterminate for all remaining scheduled 
clinical assessments.
Reason(s) for withdrawal from the study may include, but are not limited to, the following:
Lost to follow-up
Withdrawal of consent
Significant patient noncompliance, as judged by the investigator, defined as 
parent(s)/legally-acceptable representative(s) refusal or inability to adhere to study 
procedures
Investigator determination that it is in the best interest of the patient to withdraw from 
the study, due to reasons other than an AE.
The investigator is encouraged to discuss with the Medical Monitor any extenuating 
circumstance that led to or may lead to withdrawal.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s source documentation.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved adverse events (AEs).
3.10.1.Screen failures 
Screenfailures are patients who do not fulfil the eligibility criteria for the study, and therefore 
must not be included in the study.  These patients should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (ie, patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures. 
Where a patient is incorrectly started on treatment the patient may continue or discontinue 
treatment, depending on the outcome of the discussion between the Sponsorstudy 
physician/designee and the investigator.
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3.10.2.Withdrawal of the informed consent
A parent/legally-acceptable representative is free to withdraw their child from the study at any 
time (IP and assessments), without prejudice to further treatment.
A parent/legally-acceptable representative who withdraws consent will always be asked about 
the reason(s) and the presence of any adverse events (AE).  The investigator will follow up 
AEs outside of the clinical study. 
Ifthe parent/legally-acceptable representative also withdraws consent for disclosure of future 
information, no furtherevaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
If a parent/legally-acceptable representative withdraws their child from participation in the 
study, then the child
's enrolment code cannot be reused.  Withdrawn patients will be replaced.
3.11.Discontinuation of the study
The study may be stopped if, in the judgment of the Sponsor, trial patients are placed at undue 
risk because of clinically significant findings that:
Meet individual stopping criteriaor are otherwise considered significant 
Are assessed as causally related to study drug, 
Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patientat the time of 
discontinuation of follow-up must be recorded in the Case Report Form (CRF). All reasons 
for discontinuation of treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
3.12.Sponsor’s Qualified Medical Personnel
The contact information for the sponsor
's appropriately qualified medical personnel for the 
study is documented in thestudy contact list located in the Investigator File. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subject’s parent(s)/legal guardian/legally acceptable representative are 
provided with a contact card.Thecontact card contains, at a minimum, protocol and 
investigational product identifiers, subject study numbers, contact information for the 
investigator site, and contact details for a contact center in the event that the investigator site 
staff cannot be reached to provide advice on a medical question or problem originating from 
another healthcare professional not involved in the subject’s participation in the study.  The 
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contact number can also be used by investigator staff if they are seeking advice on medical 
questions or problems; however, it should be used only in the event that the established 
communication pathways between the investigator site and the global study team are not 
available.  It is therefore intended to augment, but not replace, the established communication 
pathways between the investigator site and the global study team for advice on medical 
questions or problems that may arise during the study.The contact center contact number is 
not intended for use by the subject’s parent(s)/legal guardian/legally acceptable representative
directly; if a subject’s parent(s)/legal guardian/legally acceptable representative calls that 
number, he or she will be directed back to the investigator site.
4.STUDY PLAN AND TIMING OF PROCEDURES
Study Day 1will start at the onset of study therapy and will end 24hours later.  Subsequent 
Study Days are to follow the same pattern.  Any time reference to a Study Day within the 
protocol is to be calculated in reference to the given Study Day at the time of onset ofthe first 
dose of study therapy (eg, within 24hours of Day 3means the period starting 24hours before 
Day 3at the onset time of study therapy up to 24hours after Day 3at the onset time of study 
therapy).
Procedures will be performed according to the Study Plan located in Table 1.  The 
assessments and procedures should be conducted in person by the investigator or designee, 
unless otherwise indicated.
Results from any protocol-specified evaluations already performed locally aspart of the 
patient’s regular medical care can be recorded on the CRFs and do not have to be repeated for 
purposes of this study, as follows:
Baseline clinical, laboratory, and microbiological tests: if performed within 36hours 
of the first dose of studytherapy
Baseline chest radiograph (CXR), computed tomography (CT) scans, or other imaging 
tests: if performed as part of the patient’s regular medical care within 72hours of the 
first dose of study therapy 
After Baseline, any protocol-specified evaluations:  if performed within 24hours of 
any study day.
Table 1provides an overview of the protocol visits and procedures.  Refer to the Study 
Assessments section of the protocol for detailed information on each procedure and 
assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities table, in order to conduct evaluations or assessments required to protect 
the well-being of the subject.
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Table 1
Study Plan detailing the procedures
Assessment or Procedure
Baselinea
Treatment period
Follow-up
Study Days*
1 2 3 4-14 EOTb TOCc SFUd
Written informed consent
X
Inclusion/exclusion criteria
e
X
Clinical
Medical history (including 
antepartum/peripartum period)
X
Adverseeventreview(AEsandSA
Es)
X 
X X X X 
X 
X 
X
Prior and concomitant medicationsf
X 
X X X X 
X 
X 
X
Length
X
Weight
X 
X X X X 
X 
X 
X
Physical examination
X 
X X X X 
X 
X
Vital signsand oxygen saturationg
X 
X X X X 
X 
X 
X
Clinical outcome
X 
X
Record adjunctive therapeutic 
procedures (if performed)
X X X X 
X 
X
CXR, CT scan, or other imaging 
tests
h
Xj
Laboratory
CBC with differentiali
X
Xj
X 
Xj
Xj
Chemistry panel
i
X
Xj
X 
Xj
Xj
Base excess
Xj
CRP and Procalcitonini
Xj
Urinalysis
X
Xj
X 
Xj
Urine output
Xk
X X X 
Xj
CSF
Xj
PK
Assignment to PK schedulel
X
PK blood samplem
X
CSF sample (if collected per 
standard of care) & matching blood 
sample
n
X
Micro
Blood culture
Xj
Urine culture
Xj
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CSF culture
Xj
Other specimen or tissue cultures
Xj
Administration of study therapy
X X X X 
X
* Study Day 1 will start at the onset of study therapy and will end 24 hours later.  Subsequent Study Days are to 
follow the same pattern.
Abbreviations: AEs=adverse events; CBC=complete blood count; CRP=C-reactive protein; CSF=cerebrospinal 
fluid; CT=computed tomography; CXR=chest radiograph; EOT=End-of-Therapy; MRI=magnetic resonance 
imaging; PK=pharmacokinetic; SAEs=serious adverse events; SFU=Safety Follow-up; TOC=Test-of-Cure.
a. Conduct Baseline assessments within 36hours before first dose of study therapy.
b. Conduct EOT assessments within 24hours after the end of last infusion.  Study therapy may or may not be 
given on the same calendar day as EOT assessments; administration should be as for days 4-14.
c. Conduct TOC assessments 8to 15days after the last dose of study therapy.
d. Conduct SFU assessments, preferably in person, 28to 35days after the last dose of study therapy.  The SFU 
may be conducted via telephone for any patientwho has not experienced clinical relapse, did not have ongoing 
AEs or SAEs at TOC, or did not develop AEs or SAEs since TOC.  If symptoms of relapse or new AEs or 
SAEs are noted, or at the discretion of the investigator, the patientshould be immediately scheduled for an 
in-personvisit.  If the visit is in-person, weight, vital signs and oxygen saturation should be recorded.  If a 
patientwas previously assessed as a clinical failure, only safety assessments will be performed.
e. Refer tothe inclusion criteria (Section 3.1) for the recommended definitions of clinical and laboratory 
inclusion criteria.
f. For patients who are being breast fed, record all medications taken by the lactating mother for 3days before 
first dose of study therapy through SFU.
g. Postbaseline, record highest and lowest postdose temperature measurements.
h. At baseline, obtain results of CXR, CT scan, or other imaging tests (eg, echocardiogram, CT, MRI, 
sonography) if performed as part of the patient’s regular medical care within 72hours before first dose of 
study therapy.
i. Refer tothe inclusion criteria (Section 3.1) for list of tests.  Recommended to repeat at least every 7days.  If 
immature neutrophils are available, calculate I/T neutrophil ratio using the formula: I/T ratio=Immature 
cells/Total (mature+immature).
j. If clinically indicated.
k. For patients who have been hospitalized for ≥8hours, calculate urine output over the last 8-hour period.
l. Patients will be randomly assigned (1:1) to one of the following PK sample collection schedules collected after 
any dose between the end of the 4th infusion of ceftaroline fosamil and before EOT or Study Day 
14(whichever is earlier):
PK Schedule 1: at the end of the ceftaroline fosamil infusion (± 5minutes) and 3to 4hours after the end of the 
infusion
PK Schedule 2: 15minutes to 2hours after the end of theceftaroline fosamil infusion and 5to 7hours after the 
end of the infusion (before the start of the next infusion).
m. PK blood samples are NOT to be drawn if the patientreceived a blood or blood component transfusion within 
the past 24hours.  For patients who are at risk from additional blood loss, collection of PK samples will 
require assessment by the investigator.
n. Matching blood sample to be collected only if 2PK blood samples have not been collected already.  The 
matching blood sample replaces one ofthe PK samples, so that the total number of PK samples does not 
exceed 2.
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4.1.Baseline
Informed consent in writing will be obtained from parent(s) or legally-acceptable
representative(s) before initiating any study assessment or procedure.
Baseline procedures must be completed within 36hours before the start of the first dose of 
study therapy.  If any such procedures have been carried out as standard-of-care within the 
timeframe they can be considered as baseline procedures.  Potential patients who do not meet 
entrance criteria may, as appropriate, repeat Baseline evaluations at a later time for possible 
enrolment into the study. 
4.1.1.Baseline assessments
4.1.1.1.Clinical assessments
Obtain a complete medical and surgical history, including, but not limited to, history 
of delivery, antepartum and peripartum antibacterials, vaccinations, congenital 
abnormalities, and all active conditions and all conditions diagnosed after birth
Identify, assess, and record any AEs and SAEs starting from the time that informed 
consent is obtained
Record prior medications (Section 7.7) taken or received within 7days before the first 
dose of study therapy.  For children who are being breast fed, record all medications 
taken by the lactating mother during the 3days before the first dose of study therapy.
Record the findings of a complete physical examination, including, but not limited to:
Physical findings of LOS
Presence of central venous catheter (eg, umbilical catheter); evaluate the 
possibility of catheter-related sepsis (CRS) and if CRS is suspected, remove the 
catheter when it is safe and clinically feasible 
Presence of other medical devices such as ventilator, cardiac devices, CSF 
shunts, orthopedic transplants, or urinary catheter
Record weight and length
Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation
Record at least 2heart rate/pulse measurements taken during a 30minute 
period
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Record at least 2blood pressuremeasurements, or record highest and lowest 
measurements if continuously monitored, over a 30minute period
Record CXR or chest CT scan results if performed as part of the patient’s regular 
medical care within 72hours before the start of the first dose ofstudy therapy
Record other imaging study results (eg, echocardiogram, CT, MRI, sonography) if 
performed as part of the patient’s regular medical care within 72hours before the start 
of the first dose of study therapy.
4.1.1.2.Laboratory assessments
Obtain blood samples for complete blood count (CBC) with differential and chemistry 
panel (see Laboratory Manual)
If blood gases are available, calculate base excess (BE) using the formula: 
BE=0.9287(HCO324.4+ 14.83(pH -7.4))
Record CRP and serum procalcitonin levels if tests are performed as part of the 
patient’s regular medical care
Perform urinalysis (see Laboratory Manual)
For patients who have been hospitalized for ≥8hours, calculate urine output over the 
last 8-hour period
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF sample.
4.1.1.3.Microbiological assessments  
Microbiological assessments should be performed preferably before any antibiotics are 
administered.
If clinically indicated and performed as part of patient’s regular medical care, obtain 
blood and urine samples for testing per Section 5.2.1and 5.2.2, respectively; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF or other specimens/tissue samples per Section 5.2.3and 5.2.4, respectively; 
cultures may be repeated per standard of care upon knowledge of a positive result.
Obtain any prior microbiological and clinical data (eg, notes in medical records 
confirming worsening of signs and symptoms of sepsis) that may help determine 
eligibility (Section 5.2)
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Enrol the patient and assign to PK schedule after verifying that the patient meets all inclusion 
and no exclusioncriteria.  There should be no medically inappropriate delay in administration 
of study therapy.
4.2.Treatment period
Procedures for this period will be performed according to the schedule outlined in the Study 
Plan (Table 1) and thefollowing are descriptions of specific requirements for the treatment 
period:
4.2.1.Study Day 1(starts with onset of study drug administration)
Study Day 1is the 24-hour period starting at the onset of the first administration of study 
therapy.  Baseline assessments may be conducted within 36hours before the onset of study 
therapy; therefore, Study Day 1procedures described below are to be conducted within 
24hours of the onset of study therapy.
4.2.1.1.Study therapy administration
Ceftaroline fosamil, IV: 6mg/kg IV over 60(± 10) minutes q8h (±1hour).  The dose 
should be calculated based on the patient’s first weight of the day.
Ampicillin, IV: if mandated as per Section 7.2.2; dosage per institutional guidelines
Optional aminoglycoside, IV: choice of aminoglycoside and dosage per institutional 
guidelines and investigator’s judgment.  Gentamicin is preferred. 
4.2.1.2.Clinical assessments -after at least 1dose of study therapy
Identify, assess, and record any new or ongoing AEs or SAEs
Record concomitant medications (Section 7.7).  For patients who are being breast fed, 
record all medications taken by the lactating mother.
Record the findings of a complete physical examination, including, but not limited to, 
physical findings of LOS, presence of central venous catheter or other medical devices 
(if applicable)
Record the patient’s first weightof the day
Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record highest and lowest postdose temperature measurements
Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed
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If clinically indicated, obtain resultsof CXR, CT scan, or other imaging tests 
performed as part of the patient’s regular medical care.
4.2.1.3.Laboratory assessments -after at least 1dose of study therapy
If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual)
If blood gases are available, calculate BE
If clinically indicated, obtain CRP and serum procalcitonin levels
If clinically indicated, perform urinalysis (see Laboratory Manual)
For patients who have been hospitalized for ≥8hours, calculate urine output over the 
last 8-hour period
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF sample.
4.2.1.4.Microbiological assessments -after at least 1dose of study therapy
If clinically indicated and performed as part of patient’s regular medical care, obtain 
blood and urine samples for testing per Section 5.2.1and 5.2.2, respectively; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed.
If a lumbar puncture (or any CSF sample collection) is performed after the first 
infusion of ceftaroline fosamil, a matching PK blood sample should be drawn at the 
time ofCSF collection (± 5minutes).  This PK blood sample will replace the closest 
corresponding PK blood sample based on the PK times described above.
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF or other specimens/tissue samples per Section 5.2.3and 5.2.4, respectively; 
cultures may be repeated per standard of care upon knowledge of a positive result.
4.2.2.Study Day 2(starts 24hours after onset of study drug administration)
4.2.2.1.Study therapy administration
Ceftaroline fosamil, IV: 6mg/kg IV over 60(± 10) minutes q8h (±1hour). The dose 
should be calculated based on the patient’s first weight of the day.
Ampicillin, IV: if mandated as perSection 7.2.2; dosage per institutional guidelines
Optional aminoglycoside, IV: choice of aminoglycoside and dosage per institutional 
guidelines and investigator’s judgment.  Gentamicin is preferred. 
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4.2.2.2.Clinical assessments -any time during study day
Identify, assess, and record any new or ongoing AEs and SAEs
Record concomitant medications (Section 7.7).  For patients who are being breast fed, 
record all medications taken by the lactating mother
Record the findings of a complete physical examination, including, but not limited to, 
physical findings of LOS, presence of central venous catheter or other medical devices 
(ifapplicable)
Record the patient’s first weightof the day
Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record highest and lowest daily temperature measurements
Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed
If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the patient’s regular medical care.
4.2.2.3.Laboratory assessments -any time during study day
If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual)
If blood gases are available, calculate BE
If clinically indicated, obtain CRP and serum procalcitonin levels 
If clinically indicated, perform urinalysis (see Laboratory Manual)
Calculate urine output over the last 8-hour period
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF sample.
4.2.2.4.PK procedures
Do not draw PK blood samples if the patient received a blood or blood component 
transfusion within the past 24hours.  For patients who are at risk from additional 
blood loss, collection of PK samples will require assessment by the investigator.
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Obtain 2PK blood samples after any infusion of ceftaroline fosamil, between the end 
of the fourth infusion and before EOT or Study Day 14(whichever is earlier), 
according to the patient’s assigned PK schedule shown below:
PK Schedule 1
At the end of the ceftaroline fosamil infusion (± 5minutes)
3to 4hours after the end of the infusion
PK Schedule 2
15minutes to 2hours after the end of the ceftaroline fosamil infusion
5to 7hours after the end of the infusion (before the start of the next 
infusion)
If a lumbar puncture (or other CSF sample collection) is expected and the 2PK blood 
samples have not been collected, the time of one of the PK blood samples should be 
adjusted to correspond to the time of the lumbar puncture; the total number of PK 
blood samples collected will not exceed 2.
After the 2PK blood samples have been collected, any portion of a CSF sample 
(collected as part of standard of care) not required for the patient’s medical care should 
be retained for PK analysis.
4.2.2.5.Microbiological assessments -any time during study day
If clinically indicated and performed as part of patient’s regular medical care, obtain 
blood and urine samples for testing per Section 5.2.1and 5.2.2, respectively; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed.
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF or other specimens/tissue samples per Section 5.2.3and 5.2.4, respectively; 
cultures may be repeated per standard of care upon knowledge of a positive result.
4.2.3.Study Day 3(starts 48hours after onset of study drug administration)
4.2.3.1.Studytherapy administration
Ceftaroline fosamil, IV: 6mg/kg IV over 60(± 10) minutes q8h (±1hour).  The dose 
should be calculated based on the patient’s first weight of the day.
Ampicillin, IV: dosage per institutional guidelines (after 48hours, the duration of 
treatment with ampicillin is at the discretion of the investigator)
Optional aminoglycoside, IV: choice of aminoglycoside and dosage per institutional 
guidelines and investigator’s judgment.  Gentamicin is preferred. 
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4.2.3.2.Clinical assessments -any timeduring study day
Identify, assess, and record any new or ongoing AEs and SAEs
Record concomitant medications (Section 7.7).  For patients who are being breast fed, 
record all medications taken by the lactating mother
Record the findings of a complete physical examination, including, but not limited to, 
physical findings of LOS, presence of central venous catheter or other medical devices 
(if applicable)
Record the patient’s first weightof theday
Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record highest and lowest daily temperature measurements
Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed
If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the patient’s regular medical care.
4.2.3.3.Laboratory assessments -any time during study day
If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual)
If blood gases are available, calculate BE
If clinically indicated, obtain CRP and serum procalcitonin levels
If clinically indicated, perform urinalysis (see Laboratory Manual)
Calculate urine output over the last 8-hour period
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF sample.
4.2.3.4.Microbiological assessments -any time during study day
If clinically indicated and performed as part of patient’s regular medicalcare, obtain 
blood and urine samples for testing per Section 5.2.1and 5.2.2, respectively; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed
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Study Code D3720C00009/C2661002
Version 5.0
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If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF or other specimens/tissue samples per Section 5.2.3and 5.2.4, respectively; 
cultures may be repeated per standard of care upon knowledge of a positive result.
4.2.3.5.PK procedures
Do not draw PK blood samples if the patient received a blood or blood component 
transfusion within the past 24hours.  For patients who are at risk from additional 
blood loss, collection of PK samples will require assessment by the investigator.
If not previously collected, obtain 2PK blood samples after any infusion of ceftaroline 
fosamil, between the end of the fourth infusion and before EOT or Study Day 
14(whichever is earlier), according to the patient’s assigned PK schedule (see 
Section4.2.2.4for schedule and adjustment for CSF sample collection). 
4.2.4.Study Days 4through 14(starts 72hours after onset of study drug administration 
and an extra 24hours for each day thereafter)
4.2.4.1.Study therapy administration
Ceftaroline fosamil, IV: 6mg/kg IV over 60(± 10) minutes q8h (±1hour). The dose 
should be calculated based on the patient’s first weight of the day.
Ampicillin, IV: dosage per institutional guidelines (after 48hours, the duration of 
treatment with ampicillin is at the discretion of the investigator)
Optional aminoglycoside, IV: choice of aminoglycoside and dosage per institutional 
guidelines and investigator’s judgment.  Gentamicin is preferred. 
4.2.4.2.Clinical assessments -any time during study day
Identify, assess, and record any new or ongoing AEs and SAEs
Record concomitant medications (Section 7.7).  For patients who are being breast fed, 
record all medications taken by the lactating mother
Record the findings of a complete physical examination, including, but not limited to, 
physical findings of LOS, presence of central venous catheter or other medical devices 
(if applicable)
Record the patient’s first weight of the day, daily
Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record highest and lowest daily temperature measurements
Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed 
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If clinically indicated, obtain results of CXR, CT scan, or other imaging test performed 
as part of the patient’s regular medical care.
4.2.4.3.Laboratory assessments -any time during study day
If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual); recommended to repeat CBC with differential and 
chemistry panel at least every 7days
If blood gases are available, calculate BE
If clinically indicated, obtain CRP and serum procalcitonin levels
If clinically indicated, perform urinalysis (see Laboratory Manual) and calculate urine 
output over the last 8-hour period
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF sample.
4.2.4.4.Microbiological assessments -any time during study day
If clinically indicated and performed as part of patient’s regular medical care, obtain
blood and urine samples for testing per Section 5.2.1and 5.2.2, respectively; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF or other specimens/tissue samples per Section 5.2.3and 5.2.4, respectively; 
cultures may be repeated per standard of care upon knowledge of a positive result.
4.2.4.5.PK procedures
Do not draw PK blood samples if the patient received a blood or blood component 
transfusion within the past 24hours. For patients who are at risk from additional 
blood loss, collection of PK samples will require assessment by the investigator.
If not previously collected, obtain 2PK blood samples after any infusion of ceftaroline 
fosamil, between the end of the fourth infusion and before EOT or Study Day 
14(whichever is earlier), according to the patient’s assigned PK schedule (see 
Section4.2.2.4for schedule and adjustment for CSF sample collection)
4.2.5.End-of-Therapy (EOT)
Conduct EOT assessments within 24hours after administration of the last dose of study 
therapy.  Conduct the EOT assessments in place of the regular study visit (eg, Study Days 4to 
≤14) assessments that would have been performed the day of that visit.  If applicable, refer to 
guidance on whento end study therapy in Section 3.9.
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If applicable, as study therapy may or may not be given on the same calendar day as EOT 
assessments, administer studytherapy as described in Section 4.2.4.
4.2.5.1.Clinical assessments -after the last dose of study therapy
Identify, assess, and record any new or ongoing AEs and SAEs
Record concomitant medications (Section 7.7).  For patients who are being breast fed, 
record all medications taken by the lactating mother
Record the findings of a complete physical examination, including,but not limited to, 
physical findings of LOS; presence of central venous catheter or other medical devices 
(if applicable)
Record weight 
Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record highest and lowest daily temperature measurements
Assess clinical outcome (per Table 5, Section 8.4.1)
Record adjunctive therapeutic procedures (eg, drainage of foci ofinfection), if 
performed 
If clinically indicated, obtain results of CXR, CT scan, or other imaging test performed 
as part of the patient’s regular medical care.
4.2.5.2.Laboratory assessments -after the last dose of study therapy
Obtain blood samples for CBC with differential and chemistry panel (see Laboratory 
Manual)
If blood gases are available, calculate BE
If clinically indicated, obtain CRP and serum procalcitonin levels
Perform urinalysis (see Laboratory Manual)
If clinically indicated, calculate urinary output over the last 8-hour period
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF sample.
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4.2.5.3.Microbiological assessments -after the last dose of study therapy
If clinically indicated and performed as part of patient’s regular medical care, obtain 
blood and urine samples for testing per Section 5.2.1and 5.2.2, respectively; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF or other specimens/tissue samples per Section 5.2.3and 5.2.4, respectively; 
cultures may be repeated per standard of care upon knowledge of a positive result.
4.3.Follow-up period
Procedures for this period will be performed according to the schedule outlined inthe Study 
Plan (Table 1) and the following are descriptions of specific requirements for the Follow-up 
period: 
4.3.1.Test-of-Cure (TOC)
Conduct TOC assessments 8to 15days after administration of the last dose of study therapy.
4.3.1.1.Clinical assessments
Identify, assess, and record any new or ongoing AEs and SAEs
Record concomitant medications (Section 7.7).  For patients who are being breast fed, 
record all medications taken by the lactating mother
Record the findings of a complete physical examination, including, but not limited to, 
physical findings of LOS, presence of central venous catheter or other medical devices 
(if applicable)
Record weight
Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record highest and lowest daily temperature measurements
Assess clinical outcome (per Table 5, Section 8.4.1)
Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed
If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the patient’s regular medical care; if test was performed after 
EOT but before TOC, record the latest result.
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4.3.1.2.Laboratory assessments
If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual)
If clinically indicated, perform urinalysis (see Laboratory Manual)
If clinically indicated, calculate urinary output over the last 8-hour period
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF sample.
4.3.1.3.Microbiological assessments
If clinically indicated and performed as part of patient’s regular medical care, obtain 
blood and urine samples for testing per Section 5.2.1and 5.2.2, respectively; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed
If clinically indicated and performed as part of patient’s regular medical care, obtain 
CSF or other specimens/tissue samples per Section 5.2.3and 5.2.4, respectively; 
cultures may be repeated per standard of care upon knowledge of a positive result.
If a patient was previously assessed as a clinical failure, perform only safety assessments (ie, 
AEs and SAEs, concomitant medications, weight, vital signs, CBC with differential, 
chemistry panel).
4.3.2.Safety Follow-Up (SFU)
Conduct SFU assessments, preferably in person, 28to 35days after the last dose of study 
therapy.  The SFU may be conducted via telephone for any patient who has not experienced 
clinical relapse, did not have ongoing AEs or SAEs at TOC, or did not develop AEs or SAEs 
since TOC.  If symptoms of relapse or new AEs or SAEs are noted, or at the discretion of the 
investigator, the patient should be immediately scheduled for an in-person visit.  If a patient 
was previously assessed as a clinical failure, only safety assessments should be performed.
4.3.2.1.If SFU conducted via telephone
Record concomitant medications (Section 7.7).  For patients who are being breast fed, 
record all medications taken by the lactating mother
Identify, assess, and record any new or ongoing AEs or SAEs.
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Study Code D3720C00009/C2661002
Version 5.0
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4.3.2.2.If SFU conducted in person
Clinical assessments
Identify, assess, and record any new or ongoing AEs or SAEs
Record concomitant medications (Section 7.7).  For patients who are being breast fed, 
record all medications taken by the lactating mother
Record weight
Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record highest and lowest daily temperature measurements.
Laboratory assessments
If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual).
5.STUDY ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that fromtime to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to perform 
the test.  In these cases the investigator will take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol-required test cannot be performed, the investigator 
will document the reason for this and any corrective and preventive actions that he or she has 
taken to ensure that normal processes are adhered to as soon as possible.  The global study 
team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior to 
initiation of the study.
The investigator will ensure that data are recorded on the CRF as specified in the study 
protocol and in accordance with the CRF completion instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA).  
The investigator will sign the completed CRF.  A copy of the completed CRF will be archived 
at the study site.
5.1.Efficacy assessments
Efficacy outcome measures will include clinical outcome at EOT and TOC in the Modified 
Intent-to-Treat (MITT) Analysis Set.  Clinical outcome will be assessed by the investigator 
Categories of clinical outcome are described in Section 8.4.1.1and 8.4.1.2.  A favourable 
clinical outcome is clinical cure.
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Study Code D3720C00009/C2661002
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5.2.Microbiological assessments
5.2.1.Blood sample for culture
If clinically indicated and performed as part of patient’s regular medical care, obtain blood for 
culture at Baseline (preferably before any antibiotics are administered) and at any time 
through TOC.  Cultures should be repeated per standard of care upon knowledge of a positive 
result until sterilization is confirmed.  Perform culture and organism identification at the local 
or regional laboratory, as applicable.  Send all isolates to the central laboratory for organism 
identification and susceptibility testing.
Refer to the study-specific clinical and microbiology laboratory manual for specific 
procedures pertaining to the collection, processing, storage, and shipment of blood culture or 
isolates.
This protocol complies with European Union’s recommendations for blood loss associated 
with pediatricresearch
3and the World Health Organization guidelines “Blood Sample 
Volumes in Child Health Research: Review of Safe Limits”.
6  To minimize risk from blood 
loss associated with this study, standard of care laboratory results will be used whenever 
possible.  All safety laboratory tests will be limited to local processing.  In addition, pediatric
blood collection tubes will be used and capillary method of blood draw will be implemented 
whenever feasible.  PK samples will be collected from patients unless deemed unsafe due to 
the risk from additional blood loss (per the investigator’s judgment).
5.2.2.Urine sample for culture
If clinically indicated and performed as part of patient’s regular medical care, obtain urine for 
culture as clinically indicated at Baseline (preferably before any antibiotics are administered) 
and at any time through TOC.  Cultures should be repeated per standard of care upon 
knowledge of a positive result until sterilization is confirmed.  Perform Gram stain, culture, 
and organism identification at the local or regional laboratory, as applicable.  Send all isolates 
to the central laboratory for organism identification and susceptibility testing.
Refer to the study-specific clinical and microbiology laboratory manual for specific 
procedures pertaining to the collection, processing, storage, and shipment of urine culture or 
isolates.
5.2.3.Cerebrospinal fluid for culture
If clinically indicated and performed as part of patient’s regular medical care, obtain CSF for 
culture and/or PCR as clinically indicated at Baseline (preferably before any antibiotics are 
administered) and at any time through TOC.  Cultures may be repeated per standard of care 
upon knowledge of a positive result.  Perform Gram stain, culture/PCR, and organism 
identification at the local or regional laboratory, as applicable.  Send all isolates to the central 
laboratory for organism identification and susceptibility testing.
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Refer to the study-specific clinical and microbiology laboratory manual for specific 
procedures pertaining to the collection, processing, storage, and shipment of CSF culture or 
isolates.
5.2.4.Other specimens and tissue samples for culture
If clinically indicated and performed as part of patient’s regular medical care, obtainother 
specimen and tissue samples from potential foci of infection for culture as clinically indicated 
at Baseline (preferably before any antibiotics are administered) and at any time through TOC.  
Cultures may be repeated upon knowledge of a positive result, if obtained per standard of 
care.  Perform Gram stain (if applicable), culture, and organism identification at the local or 
regional laboratory.  Send all isolates to the central laboratory for organism identification and 
susceptibility testing.
Referto the study-specific microbiology and clinic laboratory manual for specific procedures 
pertaining to the collection, processing, storage, and shipment of other specimens/tissues for 
culture or isolates.
5.3.Safety assessments
Patients must be evaluated by a physician or an appropriately trained health care professional 
at every visit, and the evaluation must be documented.  The procedures discussed below will 
be completed at the designated visits.
5.3.1.Laboratory safety assessments
Blood samples and urine samples will be collected according to the study plan (Table 1) at 
baseline and EOT.  Samples may also be collected at any time during the treatment period, at 
TOC and SFU if clinically indicated.
The following laboratory variables will be measured: 
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Table 2 
Laboratory Safety Variables
Chemistry panel
CBC and differential
Urinalysis
Albumin
Haematocrit
Urinalysis will be done
Alkaline phosphatase
Haemoglobin
Alanine aminotransferase
Red Blood Cellcount
Aspartate aminotransferase
White Blood Cell count
Bilirubin, total and direct
Eosinophils
c
Blood urea nitrogen/urea
Lymphocytesc
Calcium
Monocytesc
Chloride
Neutrophilsc
Creatininea
Neutrophils, immature
c
Glucose, nonfastinga
Platelets
Potassium
Sodium
Bicarbonate (HCO3)
b
Lactateb
pH
b
C-reactive protein
b
Procalcitoninb
a
Required for eligibility
b
Test not mandatory for eligibility if other eligibility criteria are met.
c
absolute count and/or %
If a patient’s urine output decreases to <0.5mL/kg/h (measured over at least 8hours) or serum 
creatinine level increases ≥2× ULN during the treatment period, the Medical Monitor should 
be contacted to discuss the patient’s safe continuation in the study.  If a patient’s haemoglobin 
or haematocrit decreases significantly (investigator’s judgment) during study therapy, an 
evaluation for haemolytic anaemia should be conducted per standard of care.
Scheduled and clinically indicated laboratory tests (emergency or unscheduled tests) should be 
conducted at the local or regional laboratory.
5.3.2.Other clinical assessments
Safety parameters will be monitored according to standard medical practice and guidelines for 
IV administration of study therapy. 
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Vital sign assessments will be conducted at the specified time points outlined in the Study 
Plan(Table 1).
Medical and surgical history including antepartum/peripartum period, prior and concomitant 
medications, length, weight, and physical examination findings (including LOS physical 
findings and presence of central venous catheter or other medical devices) will be recorded at 
Baseline and, if applicable, during the study according to the Study Plan (Table 1). 
If performed, adjunctive therapeutic procedures will be recorded throughout the treatment
period until TOC.
If performed as part of the patient’s regular medical care, results of CXR, CT scan or other 
imaging tests will be obtained at Baseline, throughout the treatment period, at EOT and at 
TOC.
5.3.3.Adverse events
Adverse events will be reviewed at Baseline, throughout the Treatment Period, and at EOT, 
TOC and SFU.  AEs and SAEs are defined in Section 1.1and1.3, respectively.  AEs will be 
collected and reported as described in Section 1.1.
5.4.Pharmacokinetics
5.4.1.Collection of blood samples
Two PK blood samples (approximately 0.3to 0.6mL per draw) will be obtained at steady 
state from at least 20patients.  Patients will be randomly assigned (1:1) at the time of 
enrolment to one of the PK sample collection schedules shown below.  The PK samples may 
be collected anytime between the end of the fourth infusion of ceftaroline fosamil and before 
EOT or Study Day 14(whichever is earlier).  For patients who are at risk from additional 
blood loss, collection of PK samples will require assessment by the investigator. 
If CSF sample collection is expected per standard of care, delay any PK sample collection and 
collect it at the time of CSF collection (± 5minutes) as a matching PK blood sample.  Record 
the time of the matching PK blood sample collection.
If the 2PK blood samples have not been collected and a lumbar puncture (or any CSF sample 
collection) is performed after the first infusion of ceftaroline fosamil and within 8hours after 
the last infusion, a matching PK blood sample will be drawn at the time of CSF collection 
(±5minutes).  This PK blood sample will replace the closest corresponding PK blood sample 
based on the PK times described below.  The total number of PK blood samples collected will 
not exceed 2.
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PK Schedule 1
At the end of the ceftaroline fosamil infusion (± 5minutes)
3to 4hours after the end of the infusion
PK Schedule 2
15minutes to 2hours after the end of the ceftaroline fosamil infusion
5to 7hours after the end of the infusion (before the start of the next 
infusion)
The PK sampling time may be adjusted by the Sponsor based on emerging data, but the total number of samples 
will not be increased.
5.4.2.Collection of cerebrospinal fluid samples
For patients who have CSF collected as part of standard of care, the remainder of any CSF 
sample obtained after the first dose of ceftaroline fosamil will be retained to compare 
ceftaroline concentrations in the CSF to those in plasma.  After the 2PK blood samples have 
been collected, any portion of a CSF sample (collected as part of standard of care) not 
required for the patient’s medical care should be retained for PK analysis.
Blood and CSF samples will be collected, labelled, stored and shipped as detailed in the 
Laboratory Manual.
5.4.3.Determination of drug concentration
Samples for determination of ceftaroline fosamil, ceftaroline, and ceftaroline M-1(inactive 
metabolite) concentrationsin plasma and any available samples for determination of 
ceftaroline and ceftaroline M-1concentrations in CSF will be analysed by Covance 
Laboratories on behalf of the Sponsor, using appropriate bioanalytical methods.  Full details 
of the analytical methods used will be described in a separate bioanalytical report.
5.4.4.Storage and destruction of pharmacokinetic samples
PK samples will be disposed of after the Bioanalytical Report finalization or 6months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling.  
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reportedin the Clinical Study 
Report (CSR) but separately in a Bioanalytical Report.
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Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be stored at a secure laboratory designated by the 
Sponsor; see details in the Laboratory Manual).
5.5.Pharmacodynamics (not applicable)
5.6.Pharmacogenetics(not applicable)
5.7.Biomarker analysis (not applicable)
5.8.Volume of blood
Table 3shows the maximum volume of blood that will be drawn from each patient for the 
purposes of the study, apart from blood that is taken as part of patient’s normal standard of 
care.  The volume drawn for study purposes may be lower, as samples taken as standard of 
care will be used where possible.  The combined volume of all blood samples taken from a 
patientby the end of the study for investigational laboratory tests (ie, CBC with differential, 
chemistry panel, and PK analyses)is to be no more than 2.4cc/kg or 10cc total whichever is 
less.  Any deviation from this should be clinically justified.
Table 3
Volume of blood per patient
Assessment or Procedure
Baseline
Treatment period
Study Days
1 2 3 4-14
EOT TOC SFU
Laboratory
CBC with differentiala
0.5ml
0.5ml
Chemistry panela
1.2ml
1.2ml
PK
PK blood sampleb
1.2ml 
Maximum blood volume required per protocol
1.7ml
1.2ml
1.7ml
a
These samples are likely to be required per standard of care
b 2PK samples (0.6ml each) to be taken during the period from Day 2to Day 14, at the discretion of the 
investigator
6.ADVERSE EVENT REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1.Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3types of events: (1) SAEs; (2) 
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non-serious adverse events (AEs); and (3) exposure to the investigational product under study 
during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardlessof whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of suspected causal relationship to the 
investigational product(s) will be reported as described in the following paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24hours of awareness of the event by the investigatorare to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event within 
24hours after learning of it and document the time of his/her first awareness of the event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of the 
case and independent determination of possible causality.  Any information relevant to the 
event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLYupon request.
As part of ongoing safety reviews conducted by the sponsor, anynon-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
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in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
6.1.1.Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reportingof SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
6.1.2.Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the parent(s)/legal guardian/legally acceptable representative.  In addition, each 
parent(s)/legal guardian/legally acceptable representativewill be questioned about the 
occurrence of AEs in a non-leading manner.
6.1.3. Withdrawal From the Study Due to Adverse Events 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirementssection above.
6.1.4.Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins fromthe time the subject provides informed consent, which is 
obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
The time period for actively eliciting and collecting AEs and SAEs (“activecollection 
period”) for each subject begins from the time the parent(s)/legal guardian/legally acceptable 
representative provides informed consent, which is obtained before the subject’s participation 
in the study (ie, before undergoing any study-related procedure and/or receiving 
investigational product), through and including SFU Visit. 
6.1.4.1.Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
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SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to investigational product must 
be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
6.1.4.2.Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
6.1.5.Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator
's causality assessment is “unknown but not related” 
to investigational product, this should be clearly documented on study records. 
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 CT SAE Report Form and in accordance 
with the SAE reporting requirements.
6.1.6.Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out in 
accordance with applicable local regulations.
6.2.Definitions
6.2.1.Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment or 
usage.  Examples of AEs include, but are not limitedto: 
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Abnormal test findings;
Clinically significant signs and symptoms;
Changes in physical examination findings;
Hypersensitivity;
Progression/worsening of underlying disease;
Drug abuse;
Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:
Drug overdose;
Drug withdrawal;
Drug misuse; 
Drug interactions;
Extravasation;
Exposure during pregnancy (EDP);
Exposure via breastfeeding;
Medication error;
Occupational exposure.
6.2.2.Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 
Test result is associated with accompanying symptoms; and/or
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or
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Test result leads to a change instudy dosing (outside of any protocol-specified 
dose adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy; and/or
Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
6.2.3.Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:
Results in death;
Is life-threatening (immediate risk of death);
Requires inpatient hospitalization or prolongation of existing hospitalization;
Results in persistent or significant disability/incapacity (substantial disruption of 
the ability to conduct normal life functions);
Results incongenital anomaly/birth defect.
Or that is considered to be:
An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the important 
medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.
6.2.4.Hospitalization
Hospitalization is defined as any initial admission (even less than 24hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includestransfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:
Rehabilitation facilities;
Hospice facilities;
Respite care (eg, caregiver relief);
Skilled nursing facilities;
Nursing homes;
Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical AE 
is not in itself an SAE.  Examples include:
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);
Social admission (eg, subject has no place to sleep);
Administrative admission (eg, for yearly physical examination);
Protocol-specified admission during a study (eg, for a procedure required by the 
study protocol);
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);
Hospitalization for observation without a medical AE;
Preplanned treatments or surgical procedures.  These should be noted in the 
baseline documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an SAE.  For example, an acute appendicitis 
that begins during the reporting period should be reported if the SAE requirements are met, 
and the resulting appendectomy should be recorded as treatment of the AE.
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6.3.Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject
's usual function.
MODERATE
Interferes to some extent with subject
's usual function.
SEVERE
Interferes significantly with subject
's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with the 
subject
's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.
6.4.Special Situations
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer Safety 
by the investigator as described in previous sections, and will be handled as SAEs in the safety 
database. 
6.4.1.Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed“tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury (DILI).  
Subjects who experience a transaminase elevation above 3times the upper limit of normal (×
ULN) should be monitored more frequently to determine if they are an “adaptor” or are 
“susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2×ULN) by several days 
or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated above 
3×ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  In rare 
instances, by the time TBili elevations are detected, AST/ALT values might have decreased.  
This occurrence is still regarded as a potential DILI.  Therefore, abnormal elevations in either 
AST OR ALT in addition to TBili that meet the criteria outlined below are considered 
potential DILI (assessed per Hy’s law criteria) casesand should always be considered 
important medical events, even before all other possible causes of liver injury have been 
excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
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following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:
Subjects with AST/ALT and TBilibaseline values within the normal range who 
subsequently present with AST OR ALT values >3×ULN AND a TBili value 
>2×ULN with no evidence of hemolysis and an alkaline phosphatase value <2×ULN 
or not available;
For subjects with baseline AST OR ALT ORTBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
Preexisting AST or ALT baseline values above the normal range:AST or ALT 
values >2times the baseline values AND >3×ULN; or >8×ULN (whichever is 
smaller).
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1× ULN orif the value reaches >3× ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug,supplement (herbal) use and consumption, family history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) may be warranted. 
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All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of reasonable 
investigations have been received and have excluded an alternative etiology.
6.4.2.Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Occupational exposure to the investigational product under study isreportable to Pfizer Safety 
within 24hours of investigator awareness.
6.4.2.1.Exposure During Pregnancy
Not applicable.  
6.4.2.2.Exposure During Breastfeeding
Not applicable.  
6.4.2.3.Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated SAE.  
Since the information does not pertain to a subject enrolled in the study, the information is not 
recorded on a CRF; however, a copy of the completed CT SAE Report Form is maintained in 
the investigator site file.
6.4.3. Medication Errors and Lack of Efficacy
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors and lack of efficacy.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24Hours of 
Awareness
Medication errorsand lack of 
efficacy
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
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6.4.3.1.Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or atthe wrong dosage strength, or at the 
wrong infusion rate. 
Medication errors include:
Medication errors involving subject exposure to the investigational product;
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be capturedon the CRFper 
CRF completion guidelines.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the CRF per CRF completion guidelines and, 
if applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of 
the CRF.
Medication errors should be reported to Pfizer Safety within 24hours on a CT SAE Report 
Form only when associated with an SAE.
6.4.3.2.Lack of Efficacy 
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
6.5.Study governance and oversight
The safety of all Pfizerclinical studies is closely monitored on an on-going basis by Pfizer and 
itsrepresentatives.  Issues identified will be addressed; for instance this could involve 
amendments to the study protocol and letters to Investigators.
6.5.1.Data and Safety Monitoring Board
An external DSMB meeting is to be held at regular intervals to evaluate the safety of this 
study and other ongoing pediatricstudies of ceftaroline fosamil.  The role of the DSMB 
members is to evaluate the safety ofthe pediatricstudies on an ongoing basis in order to 
determine whether any undue safety concerns are observed, and thus whether the studies 
should be allowed to continue enrolment.  The recommendations made by the DSMBto alter 
the conduct of the study will be forwarded to the Sponsor for final decision.  The Sponsorwill 
forward such decisions, which may include summaries of aggregate analyses of endpoint 
events and of safety data that are not endpoints, to regulatory authorities, as appropriate.
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A detailed DSMB charter will be prepared by the Sponsor and agreed to by all DSMB 
members before initiation of enrolment in this study.  This charter will document the timing, 
membership, analysis content, and review procedures for each DSMB meeting.  Safety 
information will be prepared in advance of each DSMB meeting by an independent reporting 
statistician.  Safety analyses will include, at a minimum, summaries of study disposition and 
all AEs, SAEs, deaths, and discontinuations due to AEs, potentially clinically significant 
(PCS) laboratory results, and individual patient listings of selected safety data.
7.INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference/comparator in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in a 
waydifferent from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E61.33). 
For this study, the investigational product is ceftaroline fosamil.
7.1.Identity of investigational product(s)
Investigational product
Dosage form and strength
Ceftaroline fosamil
600mg powder for concentrate for solution for infusion
7.1.1.Ceftaroline Fosamil
Ceftaroline fosamil for injection, 600mg per vial, is supplied as a sterile pale yellowish-white 
tolight yellow crystalline powder in a single-dose, clear glass 20mL vial.  The excipient 
L-arginine is added as an alkalizing agent to maintain the constituted solution between pH 
4.8and 6.5.
7.1.1.1.Directions for Use
Vials of ceftaroline fosamil are constituted with 20.0mL of sterile water for injection; the 
amount of solution containing the appropriate dose is further diluted in sterile normal saline 
before infusion.  Refer to the Investigational Product Handling Manual for detailed 
information on ceftarolinefosamil preparation.
7.1.1.2.Drug Storage
Vials containing unreconstituted ceftaroline fosamil are stored according to labelled 
requirements.  Constituted and diluted infusion bags or bottles should be stored and used per 
the directions presented in the Investigational Product Handling Manual.
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7.1.2.Ampicillin and Optional Aminoglycoside
Ampicillin (if mandated as per Section 7.2.2) is to be initiated at Baseline and to be 
administered for at least 48hours(minimum duration of study therapy); after 48hours, the 
duration of treatment with ampicillin is at the discretion of the investigator.
The use of an aminoglycoside is considered optional from Baseline through the entire study, 
ie, may be started and stopped at any time during the study at the discretion of the 
investigator.
Consult the product package insert, label, and local dosing guidelines for further information 
regarding dosage, administration, storage, maximum doses, contraindications, warnings, 
precautions, and AEs reported. 
7.2.Dose and treatment regimens
Patients will receive a combination of IV ceftaroline fosamil and ampicillin, plus an optional 
aminoglycoside of choice as an empiric therapy for LOS.  The total duration of study therapy 
is 48hours (minimum) to 14days (maximum).  Note that study therapy administration using a 
home health care service is not permitted.
7.2.1.Ceftaroline fosamil
Ceftaroline fosamil is approved for use in adults; thus, treatment with ceftaroline fosamil is 
limited in pediatricpatients to investigational use only.  In this study, each patient will receive 
ceftaroline fosamil 6mg/kg IV over 60(± 10) minutes q8h (±1hour).
7.2.2.Ampicillin
Ampicillin (if mandated, see below) is to be initiated at Baseline and to be administeredfor at 
least 48hours (minimum duration of study therapy); after 48hours, the duration of treatment 
with ampicillin is at the discretion of the investigator. 
If the presence of an organism that requires treatment with ampicillin cannot be excluded, then
the use of IV ampicillin for the first 48hours is mandatory.  If the resultsof additional 
microbiology, PCR or other investigations indicate that ampicillin during the first 48hours of 
treatment is not required, then its use is at the discretion of theinvestigator (note: the findings 
of any such investigations must be fully documented in the patient’s source data).
7.2.3.Aminoglycoside
The use of an aminoglycoside is considered optional from Baseline through the entire study, 
ie, aminoglycoside may be started and stopped at any time during the study at the discretion of 
the investigator.  Gentamicin is preferred.
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7.2.4.Dose adjustment
Patients with moderately or severely impaired renal function at screening, defined as serum 
creatinine ≥2× ULN for age, urine output <0.5mL/kg/h (calculated from an 8-hour urine 
collection; for hospitalized patients), or requirement for dialysis, will not be enrolled in this 
study; thus, no ceftaroline fosamil, ampicillin, or aminoglycoside dose adjustments are 
expected to be required for renal impairment.
Ampicillin and/or aminoglycoside dose adjustments needed per the investigator’s judgment 
should be made per institutional guidelines.
However, if the patient’s serum creatinine level increases ≥2× ULN or the urine output 
decreases to <0.5mL/kg/h (calculated from an 8-hour urine collection), the Medical Monitor 
should be contacted with the option to miss or postpone dosing, or discontinue the study.
7.3.Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13requirements for labelling.  Label 
text will be translated into local language.
7.4.Storage
All study drugs should be kept in a secure place with controlled access under appropriate 
storage conditionsand in accordance with applicable regulatory requirements.  The IP label 
specifies the appropriate storage.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations.  This 
should be captured from the time of investigational product receipt throughout the study.  
Even for continuous-monitoring systems, a log or site procedure that ensures active evaluation 
for excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning theproduct to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizerprovides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of theinvestigational product prior to Pfizer approval will be 
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considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
7.5.Compliance
All treatments will be administered by hospital staff during hospitalization.  Treatment 
compliance will be documented by study staff in the CRF by recording the infusion date, time, 
and volume.
7.6.Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss,or 
other disposition of the investigational product supplies.  It is the responsibility of the 
Pharmacist or designee to ensure that current records of study drug inventory and 
accountability are maintained.  Records must be readily available for inspection by the 
Sponsor or Sponsor’s Representative and applicable regulatory authorities.
Upon receipt of study therapy drugs, the Pharmacist or designee will acknowledge receipt, 
visually inspect the shipment, verify the number of vials shipped are received, and document 
the condition of the drugs received.  Refer to the Investigational ProductHandling Manual for 
additional information.
7.6.1.Study drug handling and disposal
For general drug destruction (eg, left over drug at site), the investigator must ensure thatthe 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any specialinstructions provided by the Sponsor, and all destruction must be 
adequately documented.  Where at all possible the IP should be destroyed locally at site and a 
third party supplier for return and destruction should only be used where specific country 
regulations or local procedures state this is not possible.  Documentation should be provided 
by PRA or the Sponsoridentifying that this is the case.  For investigational product associated 
with a recall, the Sponsorwill determine what is to be destroyed.  The Sponsor or its 
representativewill manage the execution of destruction using standards acceptable to the 
Sponsoror its representative.
7.7.Concomitant and other treatments 
All prior medications (taken or received within 7days before the first dose of study therapy) 
and all concomitant medications (taken during the study), including,but not limited to, all 
antimicrobials, parenteral nutrition, and blood and blood-component transfusions will be 
documented.  For patients who are being breast fed, all medications taken by the lactating 
mother for 3days before first dose of study therapy through SFU will also be recorded.
Concomitant antibacterial therapy is not permitted except in the case of clinical failure.
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7.7.1.Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the CRF.
8.STATISTICAL ANALYSES
8.1.Statistical considerations
A comprehensive Statistical Analysis Plan (SAP) will be prepared and finalized before 
database lock and analysis of the data.
8.2.Sample size estimate
The primary objective of this study is to evaluate safety and tolerability of ceftaroline in 
neonates and young infants aged 7to <60days with LOS and the study is not powered for 
inferential statistical analysis.  The sample size (24patients; 3cohorts of 8patients) is 
considered adequate to evaluate the safety of ceftaroline in neonates and young infants with 
LOS.
8.3.Definitions of analysis sets
Analysis sets are described below and in Figure 2.
8.3.1.Intent-to-treat analysis set
The Intent-to-Treat (ITT) Analysis Set will consist of all enrolled patients.
8.3.2.Safety analysis set
The Safety Analysis Set will be a subset of the ITT Analysis Set and will include all patients 
who receive any amount of ceftaroline fosamil.
8.3.3.Modified intent-to-treat (MITT) analysis set
The MITT Analysis Set will include all patients who receive any amount of ceftaroline 
fosamil and who meet minimal disease criteria of LOS as described in the inclusion criteria in 
Section 3.1(diagnosis of sepsis within 36hours before enrolment, defined as the presence of 
at least 2clinical criteria and at least 1laboratory criterion in the presence of or as a result of 
suspected or proven bacterial infection that requires IV antibiotic therapy).  Patients with 
confirmed infection with a pathogen known to be resistant to the study therapy received and 
patients with a confirmed fungal, parasitic, or viral pathogen as the sole cause of infection will 
be excluded.  A list of resistant pathogens will be provided in the SAP.
8.3.4.Pharmacokinetic (PK) analysis set
The PK Analysis Set will include all patients who receive a known amount of ceftaroline 
fosamil and who have had at least 1PK sample collected (excluding those receiving blood or 
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blood component transfusions within 24hours before sample collection or who are at risk 
from additional blood loss per the discretion of the investigator).
Figure 2 Study Analysis Sets
8.4.Outcome measures for analyses
8.4.1.Efficacy response definitions
8.4.1.1.Clinical outcome at End-of-Therapy
An assessment of clinical outcome will be made by the investigator at EOT.  The clinical 
outcome categories are defined in Table 4.  A favourable clinical outcome is clinical cure.  An 
outcome of clinical failure at EOT will be carried forward to TOC.
Intent-to-Treat (ITT)
All subjects
Safety
Received any amount of ceftaroline fosamil
Modified Intent-to-Treat (MITT)
Meet minimal disease criteria of LOS(excluding 
subjects with confirmed infection with a resistant 
pathogen known to be resistant to study therapy 
received; or confirmed fungal, parasitic, or viral 
pathogen as the sole cause of the infection)
Pharmacokinetic (PK)
Received a known amount of 
ceftaroline fosamil and has ≥1 PK 
sample
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Table 4
Clinical outcome categories at End-of-Therapy
Outcome
Definition
Clinical Cure
Resolution of allacute signs and symptoms of LOS or improvement to such 
an extent that no further antibacterial therapy is required
Clinical Failure
Patients who received ≥48hours of study treatment and meet any of the 
following:
Discontinuation of study therapy due to insufficient therapeutic 
effect, including persistence, incomplete clinical resolution, 
worsening in signs and symptoms of LOS, or isolation of a resistant 
pathogen that requires alternative nonstudy antibacterial therapy
Discontinuation of study therapy due to a study therapy-related AE 
and requirement for alternative nonstudy antibacterial therapy for 
LOS
Death in which LOS is contributory
Indeterminate
Study data are not available for evaluation of efficacy for any reason, 
including:
Death in which LOS is clearly noncontributory
Lost to follow-up
Extenuating circumstances precluding classification as a cure or 
failure
Diagnosis of CNS infection, osteomyelitis, endocarditis, or NEC at 
any time after enrolment
Received <48hours of study therapy
Abbreviations: AE=adverse event; CNS=central nervous system; LOS=late-onset sepsis; NEC=necrotizing 
enterocolitis.
8.4.1.2.Clinical outcome at Test-of-Cure
An assessment of clinical outcome will be made by the investigator at TOC.  The clinical 
outcome categories are defined in Table 5.  A favourable clinical outcome is clinical cure.
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Table 5
Clinical outcome categories at Test-of-Cure
Outcome
Definition
Clinical Cure
Resolution of all acute signs and symptoms of LOS or improvement to such 
an extent that no further antibacterial therapy is required
Clinical Failure
Patients who received ≥48hours of study treatment and meet either of the 
following criteria:
Incomplete resolution or worsening of LOS signs or symptoms or 
development of new signs or symptoms, or isolation of a resistant 
pathogen requiring alternative nonstudy antibacterial therapy
Death in which LOS is contributory
Indeterminate
Study data are not available for evaluation of efficacy for any reason, 
including:
Death in which LOS is clearly noncontributory
Lost to follow-up
Extenuating circumstances precluding classification as a cure or 
failure
Diagnosis of CNS infection, osteomyelitis, endocarditis, or NEC at 
any time after enrolment
Received <48hours of study therapy
Abbreviations: CNS=central nervous system; LOS=late-onset sepsis; NEC=necrotizing enterocolitis.
8.4.2.Microbiological response definitions
8.4.2.1.Microbiological Outcome at Test-of-Cure
The per-pathogen microbiological outcome categories at EOT and TOC are defined in Table 
6.  Favourable microbiological outcomes are eradication orpresumed eradication.  Per-patient 
microbiological response at EOT and TOC will be determined programmatically based on 
individual outcomes for each baseline pathogen.  In order for a patient to have a favourable 
microbiological response, the outcome for each baseline pathogen must be favourable 
(eradicated or presumed eradicated).  If the outcome for any pathogen is unfavourable 
(persistence or presumed persistence), the patient will be considered to have an unfavourable 
microbiological response.
Baselinepathogens will be determined based on central laboratory data.  Rules for 
determination of pathogens will be described in the SAP.
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Table 6
Per-pathogen microbiological outcomes categories at End of Treatmentand
Test-of-Cure
Microbiological Responsea
Definition
Eradication
Source specimen demonstrated absence of the original 
baseline pathogen
Presumed eradication
Source specimen was not available to culture and the patient
was assessed as a clinical cure
Persistence
Source specimen demonstrates continued presence of the 
original baseline pathogen
Presumed persistence
Source specimen was not available to culture and the patient
was assessed as a clinical failure
Indeterminate
Source specimen was not available to culture and the 
patient’s clinical outcome was assessed as indeterminate
a
For patients who are clinical failures before TOC, the microbiological outcome will be carried forward to 
TOC and will be determined based on the cultures and/or clinical outcome at the time of the early clinical failure 
determination.
8.5. Methods for statistical analyses
Descriptive statistics (number, mean, SD, median, minimum, and maximum) will be provided 
for continuous variables, and frequency distributions (counts and percentages) will be shown 
for categorical variables.  All variables will be summarized overall and by age cohort.  
Listings of individual patients’ data will also be produced.
8.5.1.Analysis of the study population and patientcharacteristics
Patient disposition (enrolment, discontinuations from the study) overall and within each age 
cohort will be provided based on the ITT Analysis Set.  Reasons for exclusion from study 
analysis sets will be summarized for the ITT Analysis Set.
Demographics (age, race, gender), medical and surgical history including 
antepartum/peripartum period, baseline assessment of the clinical signs and symptoms of 
LOS, microbiological assessment of blood, CSF, urine, and other specimens or tissue samples 
will also be summarized for the ITT Analysis Set.
8.5.2.Analysis of the primary variable
The safety analysis will be performed using the Safety Analysis Set and will include all 
patients who receive any amount of study therapy.  Safety parameters include AEs, SAEs, 
deaths, clinical laboratory parameters (eg, CBC with differential, chemistry panel), and vital 
signs.
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For each safety parameter, the last assessment made before the first dose of study therapy will 
be used as the baseline for all analyses.  In the case of ECG where data are collected in 
triplicate, the mean of thethree recordings will be considered as the baseline.
The incidence of AEs, SAEs, deaths, and discontinuations due to AEs will be summarized 
overall and within each age cohort, by system organ class and preferred term according to the 
Medical Dictionary for Regulatory Activities (MedDRA), by relationship to the study therapy, 
and by severity.
Descriptive statistics of observed results and the change from baseline will be presented for 
clinical laboratory results and vital signs.  The incidence of selected PCS laboratory results 
will be summarized.  A list of PCS results will be provided in the SAP.
8.5.3.Analysis of the secondary variables
Efficacy response will be analysed using the MITT Analysis Set.  Proportions of patients with 
a favourable efficacy response will be displayed overall and within each age cohort.  The 
number and percentage of patients classified as clinical cure at EOT and TOC will be 
tabulated in the MITT Analysis Set.
Microbiological success at EOT and TOCS will be evaluated.  A summary of microbiological 
outcome by patient and by pathogen will be presented.
Every effort will be made to collect all data at specified times.  A detailed description of the 
handling of dropouts and missing data for all efficacy and safety evaluations will be provided 
in the SAP.
8.5.3.1.Pharmacokinetic sample collection and analyses
The PK data acquisition and analysis strategy in this study entails the use of a sparse PK 
sampling schedule, conducted only at selected investigational centres.  Centres will be 
selected based on location, ability to conduct PK sampling procedures with accuracy, and 
ability to store and ship PK samples appropriately.
Pharmacokinetic sample handling and shipping procedures are described in the PK Sample 
Handling and Shipping Manual.
Concentrationsof ceftaroline and ceftaroline M-1in CSF will be presented.
Plasma concentrations of ceftaroline fosamil, ceftaroline and ceftaroline M-1will be listed by 
age cohort.  Ceftaroline plasma concentration data, along with other information including 
demographic data, will be combined with appropriate data from other clinical studies and 
analysed using a population PK approach and reported separately. 
8.6.Interim Analysis
No formal interim analysis will be conducted for this study.
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9.STUDY AND DATA MANAGEMENT 
9.1.Training of study site personnel
A Co-ordinating Investigator will be selected from the investigators who will conduct the 
study (per European Union directive 75/318/EEC [as amended] Annex Part 4C).
Each investigator must adhere to the protocol as detailed inthis document and agree that the 
Sponsor must approve any change to the protocol before seeking approval from the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or Competent 
Authority (CA).  Each investigator will be responsible for enrolling only those patients who 
have met all of the protocol inclusion criteria and none of the exclusion criteria.
Before the first patient is entered into the study, aSponsorrepresentative will review and 
discuss the requirements of the Clinical StudyProtocol and related documents with the 
investigational staff and also train them in any study specific procedures and the PRA Data 
Labs Electronic Data Capture (EDC) system utilized.
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).
9.2.Monitoring of the study
During the study, the Sponsorrepresentative will have regular contacts with the study site, 
conducted in accordance with current ICH E6Good Clinical Practice (GCP) guidelines, and 
the respective United States or foreign regulations and guidelines, as applicable.  Contacts will 
include visits to:
Provide information and support to the investigator(s)
Confirm that facilities remain acceptable
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating patients.  This will 
require direct access to all original records for each patient (eg, clinic charts)  
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Ensurewithdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, 
and the action is documented, and reported to the patient.
The Sponsorrepresentative will also be able to review query status remotely, which may 
warrant additional communication with the investigator and the study centre
's personnel.  The 
investigator will make available to the Sponsorrepresentative source documents, signed ICFs, 
and all other study related documents.  The Sponsorrepresentative will be available between 
visits if the investigator(s) or other staff at the centre needs information and advice about the 
study conduct
9.2.1.Source data
Refer to the CSA for location of source data.
Source documents may include, but are not limited to, study progress notes, study-or 
patient-specific e-mail correspondence, computer printouts, laboratory data, and recorded data 
from automated instruments.  In most cases, the source documents are the hospital or the 
physician subject chart.  In these cases, data collected on the CRFs must match the data in 
those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and atthe Sponsorthat clearly identifies those data 
that will be recorded on the CRF, and for which the CRF will stand as the source document.
The original signed ICF for each participating patient shall be filed with records kept by the 
investigator.  Alldocuments produced in this study will be maintained by the investigator and 
made available for inspection by the Sponsor or Sponsor representative and applicable 
regulatory authorities.
9.2.2.Study agreements
The PI at each/the centre should comply with all theterms, conditions, and obligations of the 
CSA, or equivalent, for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to 
the conduct of the study and the treatment of patients and in all other respects, not relating to 
study conduct or treatment of patients, the terms of the CSA shall prevail.
Agreements between the Sponsorand the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3.Archiving of study documents
The investigator follows the principles outlined in the CSA.
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To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consentdocuments, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local regulations, 
or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The study 
records must be transferred to a designee acceptable to Pfizer, such as another investigator, 
another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer
's written permission before disposing of any records, even 
if retention requirements have been met.
9.2.3.1.Data handlingand record keeping
Training sessions; monitoring of the investigative centre by the Sponsor or Sponsor 
representative; instruction manuals; and data verification, crosschecking, and auditing will be 
provided or performed to ensure quality of all study data.  One or more investigator meetings 
will be held to prepare the investigator and other study personnel for appropriate collection of 
study data.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the source documents 
must be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. 
The Sponsor or Sponsor representative will review and validate study data as defined in the 
monitoring plan.
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The Sponsorwill provide the PI with a file in which to organize and retain all study-related 
documents.  All study documents (including letters from the Sponsor or its representatives) 
should be retained in this file by the PI.  The monitor will regularly check the file to ensure 
that all relevant documents are retained.  The contents of the file may be audited/inspected by 
the Sponsor’s auditor, regulatory authorities, or IRB.
It will be the responsibility of the investigator to ensure that the essential documents are 
available in the investigator’s files or at the institutional centre.  Any or all of these documents 
should be available for monitoring by the Sponsor or Sponsor representative and inspection by 
the regulatory authorities as defined in the monitoring plan.
9.3.Study timetable and end of study
The end of the study in all participating countries is defined as ‘the last visit of the last patient 
undergoing the study’or date of study closure in the case of early study termination, 
whichever date is later.
9.3.1.Study completion
The Sponsor requires the following data and materials before a study can be considered 
complete or terminated, including, but not limited to:
Laboratory findings, clinical data, and all special test results from screening through 
SFU
CRFs properly completed by appropriate study personnel and signed and dated by the 
investigator within the EDC system.  This approval method will include applying an 
electronic signature, a uniquely assigned user name, and a password that together will 
represent a traditional handwritten signature.
Copies of complete study drug accountability records (eg, study drug inventory logs 
and shipment and return records)
Copies of all IRB/IEC or CA approvals and acknowledgements
A summary of the study prepared by the investigator (an IRB/IEC or CA summary 
letteris acceptable)
9.3.2.Guidance to investigators on when to end study therapy
Patients who are improving clinically will receive at least 48hours, but no more than 14days, 
of study therapy.  Before ending study therapy, patients should demonstrate improvement in 
the clinical assessment of their infection from Baseline as follows:
Resolution of all acute signs and symptoms of LOS or improvement to such an extent 
that no further antibacterial therapy is necessary
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Microbiological eradication (confirmed or presumed).
An assessment of clinical outcome will be made by the investigator at the end of study therapy 
as defined in Section 4.2.5.
If signs and symptoms have not resolved or improvedafter 14days,refer to Section 3.9.1.
9.3.3.Study termination by Sponsor and termination criteria
The Sponsor reserves the right to terminate an investigational site or this study at any time.  
Reasons for termination may include, but are not limited to, the following:
The incidence or severity of AEs in this or other studies of ceftaroline indicates a 
potential health hazard to patients
Serious or persistent noncompliance by the investigator with the protocol, clinical 
research agreement, Form FDA 1572, or applicable regulatory guidelines in 
conducting the study
IRB/IEC or CA decision to terminate or suspend approval for the investigation or the 
investigator
Investigator request to withdraw from participation
Patient enrolment is unsatisfactory.
Regulatory authority decision to terminate study
Sponsor discontinues development of ceftaroline
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within a reasonable timeframe (ie, two weeks).  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
9.4.Data management 
Data management will be performed by PRA according to the Clinical Informatics Plan.  
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the MedDRA.  Medications will be classified according to the Sponsor
Drug Dictionary.  Classification coding will be performed by the PRA Coding Group.
Data collection will involve the use of the PRA Data Labs EDC system, to which only 
authorized personnel will have access.  Electronic CRFs will be usedto capture study data in 
an EDC system.  Entering of CRFs should be handled in accordance with instructions from 
the Sponsor or Sponsor representative.  All CRFs must be completed by qualified study centre 
personnel.  Each investigator is responsible for ensuring that accurate data are entered into the 
EDC system in a timely manner.
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Before the first patient is dosed at the investigational site, the Sponsor or Sponsor 
representative will meet with the investigator and the study centre
's personnel to train them on 
recording the data on the CRFs using the EDC system.  The investigator or designee will be 
responsible for reviewing CRFs, resolving data queries generated by the Sponsor via the 
system, providing missing or corrected data, approving all changes performed on the patient 
data, and endorsing these data within the EDC system.  This approval method will include 
applying an electronic signature, a uniquely assigned user name, and a password that together 
will represent a traditional handwritten signature.
The data collected through third party sources will be obtained and reconciled against study 
data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of MedDRA.  Medications will be classifiedaccording to the SponsorDrug 
Dictionary.  All coding will be performed by the PRA Coding Group.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.  Queries maybe issued electronically to the 
clinical study centre and answered electronically by that study centre
's personnel.  The 
identifying information (assigned user name, date, and time) for both the originator of the 
query and the originator of the data change (if applicable) will be collected.
The data will be validated as defined in the Clinical Informatics Plan and Edit Specifications 
Document.  Quality control procedures will be applied to each stage of data handling to ensure 
that all data are reliable and have been processed correctly.  The Clinical Informatics Plan will 
also clarify the roles and responsibilities of the various functions and personnel involved in 
the data management process.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation between safety data and clinical data will be performed by PRA.  The 
frequency depends on the expected volume of SAE reports and will be defined in the AE/SAE 
Reconciliation Plan.
10.ETHICAL AND REGULATORY REQUIREMENTS
10.1.Ethical conduct of the study
The study will be conductedin accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guidelines for Good Clinical Practices, and the Declaration of 
Helsinki.
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10.2.Patientdata protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numericalcodes based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
10.3.Ethics and regulatory review
An IRB/IEC should approve the final study protocol, including the final version of the 
Informed Consent Form and any other written information and/or materials to be provided to 
the patients.  The investigator will ensure the distribution of these documents to the applicable 
IRB/IEC, and to the study site staff.  All correspondence with the IRB/EC should be retained 
in the investigator file.  Copies of IRB/EC approvals should be forwarded to Pfizer or its 
representative.
The opinion of the IRB/IEC should be given in writing.  The investigator should submit the 
written approval to the Sponsorbefore enrolment of any patient into the study. 
The IRB/IEC should approve all advertising used to recruit patients for the study.
The Sponsorshould approve any modifications to the Informed Consent Form that are needed 
tomeet local requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.  The 
IRB/IEC or CA must approve any recruiting materials before use; and subsequent amended 
protocols and corresponding ICFs, before instituting amendment-specified changes to the 
study, unless required for patient safety.  The only circumstance in which an amendment may 
be initiated prior to IRB/EC approval is where the change is necessary to eliminate apparent 
immediate hazards to the subjects.  In that event, the investigator must notify the IRB/EC and 
Pfizer in writing immediately after the implementation.
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The Sponsoror its representativewill handle the distribution of any of these documents to the 
national regulatory authorities.
The Sponsor or its representativewill provide Regulatory Authorities, Ethics Committees and 
PIs with safety updates/reports according to local requirements.
The investigator is responsible for informing the IRB/IEC or CA of any changes made to the 
protocol, and for advisingthe IRB/IEC or CA, at least once a year, about the progress of the 
study. 
Each PI is responsible for providing the IRB/IEC with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the IP.  The Sponsor or its 
representativewill provide this information to the PI so that he/she can meet these reporting 
requirements.
10.4.Informed consent
This study will be conducted in compliance with current ICH E6GCP pertaining to informed 
consent, the current CFR (Title 21, Parts 50Subparts B and D, 56and 312).  The informed 
consentdocuments and any subject recruitment materials must be in compliance with ICH 
GCP, local regulatory requirements, and legal requirements, including applicable privacy 
laws.  The Principal Investigator(s) at each centrewill:
Ensure each patient
's parent(s) or legally-acceptable representative(s) is given full and 
adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study
Ensure each patient
's parent(s) or legally-acceptable representative(s) is notified that 
their child is free to discontinue from the study at any time
Ensure each patient
's parent(s) or legally-acceptable representative(s) is given the 
opportunity to askquestions and allowed time to consider the information provided
Ensure each patient
's parent(s) or legally-acceptable representative(s) provides signed 
and dated informed consent before conducting any procedure specifically for the study
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
investigator’s Study File and is available for verification by the Sponsor or Sponsor 
representative at any time
Ensure a copy of the signed Informed Consent Form is given to the patient
's parent(s) 
or legally-acceptable representative(s)
If applicable, the ICF will be provided in certified translation for non-English-speaking 
parent(s) or other legally-acceptable representative(s)
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Ensure that any reimbursement for study visitsas well as any provisions for patients 
harmed as a consequence of study participation are described in the informed consent 
form that is approved by an Ethics Committee.
10.5.Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International 
Co-ordinating Investigator and the Sponsor.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment, and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and, if applicable, the 
national regulatory authority before implementation.  Local requirements are to be followed 
for revised protocols.
Pfizer or its representativewill distribute any subsequent amendments and new versions of the 
protocol to each PI(s).  For distributionto Ethics Committee see Section 10.3.
If a protocol amendment requires a change to a centre
's Informed Consent Form, the Sponsor 
or its representativeand the centre
's Ethics Committee are to approve the revised Informed 
Consent Form before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6.Audits and inspections
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, authorized representatives of Pfizer, or 
companies working on behalf of Pfizer, a regulatory authority, or anIRB/ECmay perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements.  The investigator(s)will notify Pfizer or its agents
immediately if contacted by a regulatoryagency about an inspection at the centre.  
Furthermore, the investigator will cooperate with Pfizer or its agents to prepare the 
investigator site for the inspection and will allow Pfizer or its agent, whenever feasible, to be 
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present during the inspection.  The investigator site and investigator will promptly resolve any 
discrepancies that are identified between the study data and the subject
's medical records.  The 
investigator will promptly provide copies of the inspection findings to Pfizer or its agent.  
Before response submission to the regulatory authorities, the investigator will provide Pfizer 
or its agents with an opportunity to review and comment on responses to any such findings.
The investigator will allow the Sponsor or Sponsor representative and applicable regulatory 
authorities to inspect facilities and records relevant to this study.  It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
10.7.Reporting of safety issues and serious breaches of the protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
10.8.Publication of study results
10.9.Communication of results by the Sponsor
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1year of the primary completion date (PCD) 
for studies in adult populations or within 6months of the PCD for studies in pediatric 
populations.
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PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocolor was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1year of the PCD for studies in adult populations or within 6months of the 
PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data that 
could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
10.9.1.Publications by investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected inventions, 
the investigator will provide Pfizer an opportunity to review any proposed publication or other 
type of disclosure of the results of the study (collectively, “publication”) before it is submitted 
or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60days.
The investigator will, on request, remove any previously undisclosed confidential information 
before disclosure, except for any study-or Pfizer product-related information necessary to the 
appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is to 
be a joint publication covering all investigator sites, and that any subsequent publications by 
the PIwill reference that primary publication.  However, if a joint manuscript has not been 
submitted for publication within 12months of completion or termination of the study at all 
participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
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For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II -“Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the institution.  
In this section entitled Publications by Investigators, the defined terms shall have the 
meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.
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11.LIST OF REFERENCES
1.
BlackRE, Cousens S, Johnson HL, et al.  Global, regional, and national causes of child 
mortality in 2008: a systematic analysis.  Lancet 2010;375:1969-87.
2.
Bradley JS, Nelson JD, Barnett ED, et al, editors.  2016Nelson’s pediatric antimicrobial 
therapy.  22nded.  United States: American Academy of Pediatrics; 2016.p 21-43.
3. European Commission.  Ethical considerations for clinical trials on medicinal products 
conducted with the paediatric population: Recommendations of the ad hoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to good 
clinical practice in the conduct of clinical trials on medicinal products for human use.  
2008.  Available from: http://ec.europa.eu/health/files/eudralex/vol-
10/ethical_considerations_en.pdf.  Accessed 2013 May 20.
4.
Fisher RG, Boyce TG.  Perinatal syndromes.  Moffet’s pediatric infectious diseases: a 
problem-oriented approach.  4th Ed.  Philadelphia, PA: Lippincott Williams & Wilkins; 
2005.  p 645-51.
5.
Flamm RK, Sader HS, Farrell DJ, et al.  Summary of ceftaroline activity against 
pathogens in the United States, 2010: report from the Assessing Worldwide 
Antimicrobial Resistance Evaluation (AWARE) surveillance program.  Antimicrob 
Agents Chemother 2012;56:2933-40
6.
Howie SR.  Blood sample volumes in child health research: review of safe limits.  Bull 
World Health Organ 2011;89:46-53.
7.
Kuczmarski RJ, Ogden C, Grummer-Strawn L, et al. CDC Growth Charts: United States. 
Advance Data Report No. 314. Vital and Health Statistics of the Centers for Disease 
Control and Prevention, National Center for Health Statistics, 2000
8.
Lukacs SL, Schrag SJ.  Clinical sepsis in neonates and young infants, United States, 
1988 2006.  J Pediatr 2012;160:960-5.
9.
Lutsar I, Trafojer UM, Heath PT, et al.  Meropenem vs standard of care for treatment of 
late onset sepsis in children of less than 90 days of age: study protocol for a randomised 
controlled trial.  Trials 2011;12:215.
10. Muller-Pebody B, Johnson AP, Heath PT, et al.  Empirical treatment of neonatal sepsis: 
are the current guidelines adequate? Arch Dis Child Fetal Neonatal Ed 2011;96:F4-8.
11. Nizet V, Klein JO.  Bacterial sepsis and meningitis.  In: Remington JS, Klein JO, Wilson 
CB, et al, editors.  Infectious diseases of the fetus and newborn infant.  7th ed.  
Philadelphia, PA: Elsevier; 2011.  p 226-78.
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12. OlsenIE, GrovemanSA, LawsonML, ClarkRH, ZemelBS.New Intrauterine Growth 
Curves Based on United States Data. Pediatrics 2010;125(2):e214-24
13. Riccobene TA, Khariton T, Knebel W, Das S, Li J,  Jandourek A, Carrothers TJ, Bradley 
JS. Population PK Modeling and Target Attainment Simulations to Support Dosing of 
Ceftaroline Fosamil in Pediatric Patients with ABSSSI and CABP. J Clin Pharmacol. 
2016 Aug 11. doi: 10.1002/jcph.809. [Epub ahead of print] PubMed PMID: 27510635.
14. Rivera AM, Boucher HW.  Current concepts in antimicrobial therapy against select gram 
positive organisms: methicillin-resistant Staphylococcus aureus, penicillin-resistant 
pneumococci, and vancomycin-resistant enterococci [review].  Mayo Clin Proc 
2011;86:1230-43.
15. Rubin LG, Sanchez PJ, Siegel J, et al.  Evaluation and treatment of neonates with 
suspected late-onset sepsis: a survey of neonatologists
' practices.  Pediatrics 
2002;110:e42.
16. Sivanandan S, Soraisham AS, Swarnam K.  Choice and duration of antimicrobial therapy 
for neonatal sepsis and meningitis.  Int J Pediatr 2011;2011:712150.
17. Smith PB, Benjamin DK Jr.  Clinical approach to the infected neonate.  In: Long SS, 
Pickering LK, Prober CG, editors.  Principles and practice of pediatric infectious 
diseases.  4th ed.  Philadelphia, PA: Elsevier; 2012.  p 536-8.
18. Teflaro®(ceftaroline fosamil) [prescribing information].  Allegan; 2016.  Available from: 
http://www.allergan.com/assets/pdf/teflaro_pi.  Accessed 17 Aug 2016.
19. Zinforo™(ceftaroline fosamil) [summary of product characteristics].  Bedfordshire, 
United Kingdom: AstraZeneca UK Limited; 2016.  Available from: 
https://www.medicines.org.uk/emc/medicine/26988.  Accessed 17Aug 2016.
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Version 5.0
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APPENDIXA
INTERNATIONAL AIRLINE TRANSPORTATION 
ASSOCIATION (IATA) 6.2GUIDANCE DOCUMENT
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3categories.  For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category AInfectious Substancesare infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substancesare infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1and 2.  They are assigned the following UN 
number and proper shipping name:
UN 3373–Biological Substance, Category B
are to be packed in accordance with UN3373and IATA 650
Exempt -all other materials with minimal risk of containing pathogens
Clinical trial samples will fall into Category B or exempt under IATA regulations
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650compliant packaging 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
Samples routinely transported by road or rail are subject to local regulations which require 
that they are also packed and transported in a safe and appropriate way to contain any risk of 
infection or contamination by using approved couriers and packaging / containment materials 
at all times.  The IATA 650biological sample containment standards are encouraged 
wherever possible when road or rail transport is used.
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SAP_001.pdf: 
Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
 
1 
 
Statistical Analysis Plan 
Study Code 
C2661002 
Edition Number 
2.7 
Date 
22 March 2018 
Open-label, Multicentre Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Ceftaroline in Neonates and Young Infants 
with Late-Onset Sepsis 
 
 
 
 
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Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
4 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................ 1 
SIGNATURE OF STUDY STATISTICIAN ........................................................................... 2 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .................................................... 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF ABBREVIATIONS .................................................................................................. 6 
AMENDMENT HISTORY ...................................................................................................... 8 
1. 
STUDY DETAILS ................................................................................................. 11 
1.1 
Study objectives ..................................................................................................... 11 
1.1.1 
Primary objective ................................................................................................... 11 
1.1.2 
Secondary objectives ............................................................................................. 11 
1.1.3 
Exploratory objectives (Not applicable) ................................................................ 11 
1.2 
Study design ........................................................................................................... 11 
1.3 
Number of patients ................................................................................................. 17 
2. 
ANALYSIS SETS ................................................................................................. 17 
2.1 
Definition of analysis sets ...................................................................................... 17 
2.1.1 
Intent-to-treat Analysis Set .................................................................................... 17 
2.1.2 
Safety Analysis Set ................................................................................................ 18 
2.1.3 
Modified Intent-to-Treat Analysis Set ................................................................... 18 
2.1.4 
Microbiological Intent-to-Treat Analysis Set ........................................................ 18 
2.1.5 
Pharmacokinetic (PK) Analysis Set ....................................................................... 18 
2.2 
Protocol deviations ................................................................................................. 18 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 18 
3.1 
Primary outcome variables..................................................................................... 19 
3.1.1 
Safety variables ...................................................................................................... 19 
3.1.1.1 
Adverse events (AE) variables ............................................................................... 19 
3.1.1.2 
Death ...................................................................................................................... 20 
3.1.1.3 
Clinical laboratory variables .................................................................................. 20 
3.1.1.4 
Vital signs variables ............................................................................................... 21 
3.1.1.5 
Other safety variables............................................................................................. 22 
3.2 
Secondary outcome variables................................................................................. 22 
3.2.1 
Efficacy variables ................................................................................................... 22 
3.2.1.1 
Clinical response variable at EOT and TOC .......................................................... 22 
3.2.1.2 
Per-pathogen and per-patient microbiological response variables at 
EOT and TOC ........................................................................................................ 25 
3.2.2 
Pharmacokinetic variables ..................................................................................... 26 
3.3.1 
Demographic and baseline characteristic variables ............................................... 27 
3.3.1.1 
Demographic variables .......................................................................................... 27 
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3.3.1.2 
Surgical and medical history variables including antepartum/ 
peripartum period ................................................................................................... 27 
3.3.1.3 
Baseline microbiological assessment variables for blood, CSF, urine, 
and other specimens ............................................................................................... 27 
3.3.2 
Definition of prior and concomitant medication .................................................... 28 
3.3.3 
Exposure and Compliance variable........................................................................ 28 
4. 
ANALYSIS METHODS ....................................................................................... 29 
4.1 
General principles .................................................................................................. 29 
4.1.1 
Data quality ............................................................................................................ 29 
4.2 
Analysis methods ................................................................................................... 29 
4.2.1 
Patient disposition .................................................................................................. 29 
4.2.2 
Protocol deviations ................................................................................................. 30 
4.2.3 
Demographics and baseline characteristics............................................................ 30 
4.2.4 
Prior and concomitant medications ........................................................................ 30 
4.2.5 
Study therapy exposure and compliance ................................................................ 31 
4.2.6 
Safety analysis ....................................................................................................... 31 
4.2.6.1 
Analysis of adverse events, serious adverse events, and deaths ............................ 31 
4.2.6.2 
Clinical laboratory safety assessment .................................................................... 32 
4.2.6.3 
Weight, vital signs, and oxygen saturation results ................................................. 32 
4.2.6.4 
Other safety results ................................................................................................ 32 
4.2.7 
Efficacy analysis .................................................................................................... 32 
4.2.7.1 
Clinical response .................................................................................................... 32 
4.2.7.2 
Microbiological response ....................................................................................... 33 
4.2.8 
Pharmacokinetics analysis ..................................................................................... 33 
5. 
APPENDICES ....................................................................................................... 33 
 
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Date 22 March 2018 
6 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
AESI 
Adverse event of special interest 
BE 
Base excess 
BLQ 
Below limit of quantification 
CBC 
Complete blood count 
CI 
Confidence interval 
CRF 
Case report form 
CRP 
C-reactive protein 
CSF 
Cerebrospinal fluid 
CT 
Computed tomography 
CTMS 
Clinical Trials Management System 
CV 
Coefficient of variation 
CXR 
Chest radiograph 
DSMB 
Data Safety Monitoring Board 
EOT 
End-of-therapy 
ICF 
Informed consent form 
ITT 
Intent-to-treat 
IV 
Intravenous 
LLN 
Lower limit of normal 
LOS 
Late-onset sepsis 
LOQ 
Limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
MITT 
Modified intent-to-treat 
MRI 
Magnetic resonance imaging 
NC 
Not calculable 
NQ 
Non quantifiable 
OAE 
Other significant AE 
PCS 
Potentially clinically significant 
PD 
Protocol deviation 
PK 
Pharmacokinetic 
q8h 
Every 8 hours 
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Date 22 March 2018 
7 
Abbreviation or 
special term 
Explanation 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SFU 
Safety follow-up 
SMQ 
Standard MedDRA Query 
SOC 
System organ class 
TFL 
Tables, Figures and Listings 
TOC 
Test-of-cure 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
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Statistical Analysis Plan  
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Edition Number 2.7  
Date 22 March 2018 
8 
AMENDMENT HISTORY 
Date 
Brief description of change 
9 Dec 2014 
V0.1  
Initial Statistical Analysis Plan (SAP) for client review. 
7 Jan 2015 
V0.2 
Version incorporating client review comments on V0.1. 
21 Jan 2015 
V1.0 
Signed version approved for programming commencement incorporating 
client review comments on V0.2. 
8 June 2016 
V2.0 
Updated version of the SAP incorporating Protocol Amendment changes as 
outlined below: 
 
Change in definition of study day from “Study Day 1 is defined as the first 
day of study therapy administration.” to “Study Day 1 will start at the onset 
of study therapy and will end 24 hours later.”. 
Change in definition of cohort 2 from “Cohort 2: term neonates (defined as 
gestational age ≥38 weeks) aged 7 to ≤28 days”. to “Cohort 2: term neonates 
(defined as gestational age ≥37 weeks) aged 7 to ≤28 days”. 
Change in definition of cohort 3 from “Cohort 3: preterm neonates (defined 
as gestational age ≥34 to <38 weeks) aged 7 to ≤28 days” to “Cohort 3: 
preterm neonates (defined as gestational age ≥34 to <37 weeks) aged 7 to 
≤28 days”. 
Change in dose from “Ceftaroline fosamil will be given at a dose of 4 mg/kg 
IV over 60 (± 10) minutes every 8 hours (q8h) (± 1 hour).” to “Ceftaroline 
fosamil will be given at a dose of 6 mg/kg IV over 60 (± 10) minutes every 
8 hours (q8h) (± 1 hour).”.]. 
Change in requirements for administration of IV ampicillin and optional 
aminoglycoside from “IV ampicillin and optional aminoglycoside will be 
given as per standard of care.” to “IV ampicillin and optional aminoglycoside 
will be given as per standard of care. If the presence of an organism that 
requires treatment with ampicillin cannot be excluded, then the use of IV 
ampicillin for the first 48 hours is mandatory. If the result of additional 
microbiology, polymerase chain reaction or other investigations, indicate that 
ampicillin during the first 48 hours of treatment is not required, then its use is 
at the discretion of the investigator.”. 
 
In addition to the changes in relation to protocol amendments, additional 
tables were added for the duration of different Investigational Products (IP) 
[Ceftaroline, Ampicillin and Aminoglycoside]. 
Some additional programming notes were added to the shells to assist with 
the definition of variables within the derived/analysis datasets.  
An additional appendix was added to the SAP to list the criteria for 
potentially clinically significant laboratory tests. 
An additional appendix was added to the SAP to indicate the TFLs required 
for the Data Safety Monitoring Board (DSMB). 
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Date 
Brief description of change 
12 July 2016 
V2.1 
Updated to incorporate client review comments on V2.0. 
Updated to incorporate protocol amendment 2 changes: study medication 
dose changed from 4mg/kg to 6mg/kg. 
23 August 2016 
V2.2 
Updated to incorporate client review comments on V2.1: 
In section 3.1.1.1, if the intensity of an Adverse Event (AE) is missing, the 
AE will be regarded as having missing rather than severe intensity; 
If the relationship of an AE to IMP is missing, the AE will be regarded as 
having a missing relationship to IMP rather than being related to IMP; and  
an additional table for the duration of prior medication was added. 
Updated to incorporate protocol amendment 3 changes: inclusion criteria 3, 4 
and 5 were revised so that patients must meet at least 1 of the listed 
laboratory criteria, rather than 2 of the criteria and justification provided for 
the dose increase to 6mg/kg in the previous protocol amendment.  
5 September 2016 
V2.3 
Additional details added to the amendment history for V2.2 of the SAP. 
The text of SAP Appendix A was clarified. 
Listing was replaced with Appendix in the “Source: …” footnote of Tables. 
Listing xx.x.xx was removed from the footnotes of the TFL appendix shells, 
as not required. 
6 December 2017 
V2.4 
Updated to incorporate protocol amendment 4. 
Version of protocol and CRF updated.  
Additional Tables and Listings added further to receipt of Pfizer review 
comments. 
Unnecessary appendices removed and cross-references within the SAP 
updated. 
Details in relation to the DSMB modified and DSMB Tables and Listings 
removed as no further DSMBs to occur. 
12 January 2018 
V2.5 
Updated to incorporate final Pfizer review comments on V2.4 SAP and TFL 
shells. 
Additional Tables and Listings added. 
Further TFL numbering changes incorporated. 
Additional Microbiological ITT population added. 
Further clarification of non-eligible organisms provided in Appendix A. 
16 March 2018 
V2.6 
Incorporate final changes to the SAP ahead of database lock. 
Update to include list of AESIs. 
Update to Micro-ITT population definition. 
Post Data Review Meeting changes incorporated. 
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Date 22 March 2018 
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Date 
Brief description of change 
22 March 2018 
V2.7 
Appendix A updated to move Enterococcus species from never to sometimes 
a pathogen based on investigator determination. 
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1. 
STUDY DETAILS 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Pfizer Protocol C2661002. This version of 
the plan has been developed using the protocol dated 25 May 2017 and case report form 
(CRF) dated 17 November 2017. Any further changes to the protocol or CRF may 
necessitate updates to the SAP and will be captured in an amendment. 
1.1 
Study objectives 
1.1.1 
Primary objective 
The primary objective is to evaluate the safety and tolerability of ceftaroline for the 
treatment of late-onset sepsis (LOS) in neonates and young infants aged 7 to <60 days. 
1.1.2 
Secondary objectives 
The secondary objectives are: 
• To evaluate the pharmacokinetic (PK) profile of ceftaroline in neonates and young 
infants aged 7 to <60 days with LOS 
• To evaluate the efficacy of ceftaroline for the treatment of LOS in neonates and 
young infants aged 7 to <60 days. 
1.1.3 
Exploratory objectives (Not applicable) 
1.2 
Study design 
This open label, multicentre, multinational, single treatment arm study will evaluate the 
safety, tolerability, PK, and efficacy of ceftaroline fosamil and ampicillin, plus an optional 
aminoglycoside of choice, in hospitalized neonates and young infants with LOS. The study 
will be conducted in approximately 30 centres worldwide. Eligible pediatric patients (7 to 
<60 days) with suspected or confirmed LOS will be enrolled in this study. At least 24 
patients with LOS will be enrolled and treated within three age cohorts of 8 patients: 
• Cohort 1: young infants aged >28 days to <60 days (n=8) 
• Cohort 2: term neonates (defined as gestational age ≥37 weeks) aged 7 to ≤28 days 
(n=8) 
• Cohort 3: preterm neonates (defined as gestational age ≥34 to <37 weeks) aged 7 to 
≤28 days (n=8). 
This study is not randomized, but patients will be stratified by age cohort and randomly 
assigned (1:1) at the time of enrolment to 1 of the PK sample collection schedules: 
• PK Schedule 1: at the end of the ceftaroline fosamil infusion (± 5 minutes, i.e. 
within 5 minutes of the end of the ceftaroline infusion) and 3 to 4 hours after the 
end of the infusion 
• PK Schedule 2: 15 minutes to 2 hours after the end of the ceftaroline fosamil 
infusion and 5 to 7 hours after the end of the infusion (before the start of the next 
infusion). 
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Study therapy will consist of standard of care ampicillin plus an optional aminoglycoside 
of choice, with the addition of intravenous (IV) ceftaroline fosamil, and will be given to all 
patients. Ceftaroline fosamil will be given at a dose of 6 mg/kg IV over 60 (± 10) minutes 
every 8 hours (q8h) (± 1 hour).  If the presence of an organism that requires treatment with 
ampicillin cannot be excluded, then the use of IV ampicillin for the first 48 hours is 
mandatory.  If the result of additional microbiology, polymerase chain reaction or other 
investigations, indicate that ampicillin during the first 48 hours of treatment is not 
required, then its use is at the discretion of the investigator. 
The study design is described in the Study Diagram (Figure 1). Patient participation will 
require up to 49 days (up to 14 days of treatment plus up to 35 days of safety follow-up). 
The total duration of study therapy is 48 hours (minimum) to 14 days (maximum). 
Hospitalization is required during IV study therapy. Baseline assessments for study 
eligibility will occur within 36 hours before the first dose of study therapy. 
Procedures will be performed according to the Study Plan in Table 1. Safety assessments 
will be done throughout the study. Between Day 2 and Day 14, 2 blood samples will be 
collected for PK analysis. The efficacy of ceftaroline fosamil will be evaluated based on 
the clinical outcome (clinical cure, clinical failure or indeterminate) at end of therapy 
(EOT; within 24 hours after completion of last infusion) and test-of-cure (TOC; 8 to 15 
days after the last dose of study therapy) assessments. The Safety Follow-up (SFU) 
assessments will occur 28 to 35 days after the last dose of study therapy. Adverse events 
(AEs) will be followed up in the study until SFU. 
A patient who is prematurely discontinued from study therapy administration for any 
reason will have EOT assessments conducted and undergo subsequent safety assessments 
at TOC and SFU per protocol. 
• If a patient is prematurely discontinued from study therapy due to an adverse event 
and the clinical signs and symptoms of sepsis have resolved completely or 
improved such that no further antibacterial therapy is necessary, the patient will be 
assessed as a clinical cure at EOT and reassessed at TOC. 
• If a patient is prematurely discontinued from study therapy due to a study therapy-
related AE and requires alternative non-study antibacterial for treatment for LOS, 
the patient will be assessed as a clinical failure (or indeterminate, if the patient 
discontinued before minimum treatment duration) at EOT and TOC. 
• If a patient is prematurely discontinued from study therapy administration (at any 
time after the required minimum treatment duration of 48 hours) due to insufficient 
therapeutic effect, the patient will be assessed as a clinical failure on the day of 
discontinuation (ie, EOT) and at all subsequent evaluation time points. 
A patient who is withdrawn completely from this study will undergo, if possible, EOT 
assessments per protocol on the day of withdrawal. Patients withdrawn from the study will 
not undergo subsequent TOC efficacy assessments. Patients who are withdrawn from the 
study and have not been assessed as clinical failure will be assessed as indeterminate for 
all remaining scheduled clinical assessments. Patients withdrawn from therapy and 
assessed as a clinical cure at EOT will undergo subsequent TOC efficacy assessments, if 
possible. 
An external Data Safety Monitoring Board (DSMB) will review data on a regular basis to 
assess the safety of all patients enrolled in this and other ongoing pediatric studies of 
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ceftaoline fosamil. The scope of the DSMB and the data to be provided to them is 
documented in a separate DSMB charter. 
 
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Date 22 March 2018 
 
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15 
 
Table 1 
Study Plan  
Assessment or Procedure 
Baseline 
Treatment period 
Follow-up 
Study Days* 
 
 
 
1 2 3 4-14 
EOT
b 
TOCc 
SFUd 
 
Written informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteriae 
X 
 
 
 
 
 
 
 
Clinical 
Medical history (including 
antepartum/peripartum period) 
X 
 
 
 
 
 
 
 
Adverse event review (AEs and SAEs) 
X 
X X X 
X 
X 
X 
X 
Prior and concomitant medicationsf 
X 
X X X 
X 
X 
X 
X 
Length 
X 
 
 
 
 
 
 
 
Weight 
X 
X X X 
X 
X 
X 
X 
Physical examination 
X 
X X X 
X 
X 
X 
 
Vital signs and oxygen saturationg 
X 
X X X 
X 
X 
X 
X 
Clinical outcome 
 
 
 
 
 
X 
X 
 
Record adjunctive therapeutic 
procedures (if performed) 
 
X X X 
X 
X 
X 
 
CXR, CT scan, or other imaging testsh 
Xj 
 
Laboratory 
CBC with differentiali 
X 
Xj 
X 
Xj 
Xj 
Chemistry paneli 
X 
Xj 
X 
Xj 
Xj 
Base excess 
Xj 
 
 
CRP and Procalcitonini 
Xj 
 
 
Urinalysis 
X 
Xj 
X 
Xj 
 
Urine output 
Xk 
X X X 
Xj 
 
CSF 
Xj 
 
PK 
Assignment to PK schedulel 
X 
 
 
 
 
 
 
 
PK blood samplem 
 
 
X 
 
 
 
CSF sample (if collected per standard of 
care) & matching blood samplen 
 
X 
 
 
 
Micro 
Blood culture 
Xj 
 
Urine culture 
Xj 
 
CSF culture 
Xj 
 
Other specimen or tissue cultures 
Xj 
 
 
Administration of study therapy 
 
X X X 
X 
X 
 
 
Abbreviations: AEs=adverse events; CBC=complete blood count; CRP=C-reactive protein; CSF=cerebrospinal 
fluid; CT=computed tomography; CXR=chest radiograph; EOT=End-of-Therapy; MRI=magnetic resonance 
imaging; PK=pharmacokinetic; SAEs=serious adverse events; SFU=Safety Follow-up; TOC=Test-of-Cure. 
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a. Conduct Baseline assessments within 36 hours before first dose of study therapy. 
b. Conduct EOT assessments within 24 hours after the last dose of study therapy.  Study therapy may or may 
not be given on the same calendar day as EOT assessments; administration should be as for days 4-14. 
c. Conduct TOC assessments 8 to 15 days after the last dose of study therapy. 
d. Conduct SFU assessments, preferably in person, 28 to 35 days after the last dose of study therapy.  The 
SFU may be conducted via telephone for any patient who has not experienced clinical relapse, did not have 
ongoing AEs or SAEs at TOC, or did not develop AEs or SAEs since TOC.  If symptoms of relapse or new 
AEs or SAEs are noted, or at the discretion of the investigator, the patient should be immediately scheduled 
for an in-person visit.  If the visit is in-person, weight, vital signs and oxygen saturation should be recorded.  
If a patient was previously assessed as a clinical failure, only safety assessments will be performed. 
e. Refer to the inclusion criteria (Section 3.1 of the study protocol) for the recommended definitions of clinical 
and laboratory inclusion criteria. 
f. For patients who are being breast fed, record all medications taken by the lactating mother for 3 days before 
first dose of study therapy through SFU. 
g. Postbaseline, record highest and lowest postdose temperature measurements. 
h. At baseline, record results of CXR, CT scan, or other imaging tests (eg, echocardiogram, CT, MRI, 
sonography) if performed within 72 hours before first dose of study therapy. 
i. Refer to the inclusion criteria (Section 3.1 of the study protocol) for list of tests.  Recommended to repeat at 
least every 7 days.  If immature neutrophils are available, calculate I/T neutrophil ratio using the formula: 
I/T ratio=Immature cells/Total (mature+immature). 
j. If clinically indicated. 
k. For patients who have been hospitalized for ≥8 hours, calculate urine output over the last 8 hour period. 
l. Patients will be randomly assigned (1:1) to one of the following PK sample collection schedules collected 
after any dose between the end of the 4th infusion of ceftaroline fosamil and before EOT or Study Day 14 
(whichever is earlier): 
 
PK Schedule 1: at the end of the ceftaroline fosamil infusion (± 5 minutes) and 3 to 4 hours after the end of 
the infusion 
 
PK Schedule 2: 15 minutes to 2 hours after the end of the ceftaroline fosamil infusion and 5 to 7 hours after 
the end of the infusion (before the start of the next infusion). 
m. PK blood samples are NOT to be drawn if the patient received a blood or blood component transfusion 
within the past 24 hours.  For patients who are at risk from additional blood loss, collection of PK samples 
will require assessment by the investigator. 
n. Matching blood sample to be collected only if 2 PK blood samples have not been collected already. The 
matching blood sample replaces one of the PK samples, so that the total number of PK samples does not 
exceed 2. 
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1.3 
Number of patients 
The primary objective of this study is to evaluate safety and tolerability of ceftaroline fosamil 
in neonates and young infants aged 7 to <60 days with LOS and the study is not powered for 
inferential statistical analysis. The sample size (24 patients; 3 cohorts of 8 patients) is 
considered adequate to evaluate the safety of ceftaroline fosamil in neonates and young infants 
with LOS. 
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
Figure 2 shows the relationship among different analysis sets graphically. The analysis of data 
will be based on different analysis sets according to the purpose of analysis, ie, for safety, 
efficacy, etc. 
 
 
2.1.1 
Intent-to-treat Analysis Set 
The Intent-to-treat (ITT) Analysis Set will consist of all enrolled patients for whom informed 
consent form (ICF) was signed. 
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2.1.2 
Safety Analysis Set 
The Safety Analysis Set will be a subset of the ITT Analysis Set and will include all patients 
who received any amount of ceftaroline fosamil. 
2.1.3 
Modified Intent-to-Treat Analysis Set 
The Modified Intent-to-treat (MITT) Analysis Set will include all patients who received any 
amount of ceftaroline fosamil and who met minimal disease criteria of LOS as described in 
the protocol inclusion criteria (diagnosis of sepsis within 36 hours before enrolment, defined 
as the presence of at least 2 clinical criteria and at least 1 laboratory criteria in the presence of 
or as a result of suspected or proven bacterial infection that requires IV antibiotic therapy). 
Patients with confirmed infection at baseline with a pathogen known to be resistant by CLSI 
methodologies and interpretive criteria (M100-S-28) to the study therapy received will be 
excluded. Patients with a confirmed fungal, parasitic, or viral pathogen as the sole cause of 
infection will also be excluded (Appendix A). 
2.1.4 
Microbiological Intent-to-Treat Analysis Set 
The Microbiological Intent-to-treat (Micro-ITT) Analysis Set will include all ITT subjects 
who have one or more potentially causative baseline pathogens identified. 
2.1.5 
Pharmacokinetic (PK) Analysis Set 
The PK Analysis Set will include all patients who received a known amount of ceftaroline 
fosamil, were randomized to a PK sample collection schedule, and had at least 1 PK sample 
collected.  
2.2 
Protocol deviations 
Per PRA processes all important protocol deviations (PDs) as identified in the protocol 
deviation guidance document will be tracked and entered into the Clinical Trials Management 
System (CTMS). The study team will conduct ongoing reviews of PD data from CTMS 
throughout the study.  Protocol deviations that the study team considers not to be important 
will not be tabulated or listed. Important protocol deviations will be verified as part of the 
final data review before database lock. 
3. 
PRIMARY AND SECONDARY VARIABLES 
For the calculation or derivations of the variables in this section, baseline will be defined as 
the last non-missing value before the start of study therapy. Change from baseline variables 
will be calculated for clinical laboratory tests and vital signs parameters as the post-treatment 
value minus the value at baseline. The visit windows for EOT, TOC, and SFU are defined in 
Table 2 for efficacy analyses. 
Study days are to be calculated starting from the onset of the first dose of study therapy, in 
24-hour increments. If a date is prior to the first study therapy dose date (eg, date of LOS 
diagnosis, prior medication start date) then the study day will be calculated as (past date – first 
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study therapy dose date); if the assessment date is on or after the first study therapy dose date 
then the study day will be calculated as (assessment date – first study therapy dose date + 1). 
Durations in days will be calculated as (end date – start date +1). 
Table 2 
Visit Windows for EOT, TOC, and SFU 
Visit 
Protocol-defined Window 
End of IV therapy (EOT) 
Within 24 hours of completion of the last infusion of study drug 
Test of cure (TOC) 
8 to 15 days after the last dose of study drug 
Safety follow-up (SFU) 
28 to 35 days after the last dose of study drug 
NB. Since there is no per protocol population defined for this study, scheduled visits will be used for MITT 
analyses and derived analysis windows will not be evaluated. 
For analyses purposes, nominal visit data was used. 
3.1 
Primary outcome variables 
3.1.1 
Safety variables 
The safety analysis will be performed using the Safety Analysis Set. Safety parameters 
include AEs, serious adverse events (SAEs), deaths, clinical laboratory parameters (eg, 
complete blood count [CBC] with differential, chemistry panel), and vital signs.  
No imputation on missing data will be undertaken for safety parameters. 
3.1.1.1 
Adverse events (AE) variables 
An AE is the development of any new undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver), or the 
abnormal results of an investigation (eg, laboratory findings). In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, even if no study therapy has 
been administered. All AEs will be classified using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 12.0 or higher. 
The term AE is used to include both serious and nonserious AEs. Each AE will be graded for 
intensity (mild, moderate, severe). If intensity is missing it will be presented as such in the 
corresponding Tables. Each AE will be assessed for relationship to the study therapy (yes, no) 
as well. If relationship to study therapy is missing it will be presented as such in the 
corresponding Tables. 
Adverse events will be collected from the time the parent(s)/legal guardian/legally acceptable 
representative provides informed consent throughout the treatment period up to and including 
the SFU visit in the study. AEs occurring after the start of administration of the first dose of 
study therapy or AEs that started prior to treatment and worsened on treatment up to and 
including the SFU visit will be summarised. 
Adverse events of special interest (AESI) will be selected by subsetting MedDRA preferred 
terms from Pseudomembranous colitis Standard MedDRA Query (SMQ narrow) , 
Anaphylactic reaction (SMQ narrow), Angioedema (SMQ narrow), and Malignancies (SMQ 
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narrow). The MedDRA preferred terms identifying the AESI were provided by Pfizer, see 
Appendix C.  
Serious adverse events variables 
A SAE is an AE occurring during any study phase (ie, treatment, follow-up), that fulfils one or 
more of the following criteria: 
• Results in death 
• Is immediately life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
• Is any suspected transmission via a medicinal product of an infectious agent. 
SAEs will be collected from baseline throughout the treatment period up to and including the 
SFU visit in the study. SAEs occurring in a subject after the active collection period has ended 
are reported to Pfizer Safety if the investigator becomes aware of them; at a minimum, all 
SAEs that the investigator believes have at least a reasonable possibility of being related to 
investigational product must be reported to Pfizer Safety. SAEs reported after the active 
collection period will be reported in the Pfizer Safety database only, not in the clinical 
database. 
Analysis of SAEs will focus on treatment-emergent SAEs which will be those occurring after 
the start of administration of the first dose of study therapy or SAEs that started prior to 
treatment and worsened on treatment. 
3.1.1.2 
Death 
For any patients who die during the study, date and time of death, autopsy yes/no, and primary 
and secondary cause of death will be collected. 
3.1.1.3 
Clinical laboratory variables 
The safety laboratory parameters presented in Table 3 will be measured. 
 
 
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Table 3 
Laboratory safety variables 
Chemistry panel 
CBC and differential 
Urinalysis 
Albumin 
Haematocrit 
Bilirubin 
Alkaline phosphatase 
Haemoglobin 
Blood  
Alanine aminotransferase 
Red Blood Cell count 
Glucose 
Aspartate aminotransferase 
White Blood Cell count 
Protein 
Bilirubin, total and direct 
Eosinophilsc 
pH 
Blood urea nitrogen 
Lymphocytesc 
Specific Gravity 
Urea 
Monocytesc 
Colour 
Calcium 
Neutrophilsc 
Appearance 
Chloride 
Platelets 
Nitrite 
Creatininea 
Immature granulocytesc 
Urobilinogen 
Glucose, nonfastinga 
Metamyelocytesc 
Leukocyte esterase 
Potassium 
Myelocytesc 
 
Sodium 
Promyelocytesc 
 
Bicarbonate (HCO3)b 
Blastsc 
 
Lactate Dehydrogenaseb 
 
 
pHb 
 
 
C-reactive proteinb 
 
 
Procalcitoninb 
 
 
a Required for eligibility. 
b Test not mandatory for eligibility if other eligibility criteria are met. 
c Absolute count and/or %. 
Hematology and chemistry will be performed at every visit or as clinically indicated. 
Urinalysis, 8-hour urine output if available, and CSF samples will be collected through the 
TOC visit. If available, base excess (BE) will be calculated from blood gases, and C-reactive 
protein (CRP) and procalcitonin will be assessed during the treatment period only. 
Système International units will be reported for all analytes. Local laboratory upper limit of 
the normal range (ULN) and lower limit of the normal range (LLN) values for laboratory 
parameters will be applied for safety data in this study. No ULN or LLN are defined for vital 
signs parameters in the pediatric setting. Selected potentially clinically significant (PCS) 
laboratory results will be defined; see Appendix B for a list of PCS laboratory results. 
3.1.1.4 
Vital signs variables 
Vital signs variables include weight, heart rate, blood pressure (systolic and diastolic), 
respiratory rate, and temperature will be assessed at every scheduled clinical visit. Highest and 
lowest daily temperature will be monitored as well. In addition, length will be collected at 
baseline only. 
For heart rate and blood pressure measurements at baseline, at least 2 measurements will be 
taken during a 30 minute period; the mean of all measurements will be utilized for analysis.  
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3.1.1.5 
Other safety variables 
Other safety variables include: 
• Physical exam by body system (general appearance, skin, head and neck, lymph nodes, 
musculoskeletal/extremities, cardiovascular, respiratory, abdomen, and neurological) 
through TOC, with specification of baseline and new/aggravated abnormalities 
• Imaging study results (chest radiograph [CXR], computed tomography [CT] scan, or 
other radiology) through TOC including location, type of examination, result 
normal/abnormal, and description of abnormal findings  
• Adjunctive therapeutic procedures related to infections variables through TOC 
including procedure, procedure type, other (specify), start date and time, stop date and 
time, and reason for procedure. 
3.2 
Secondary outcome variables 
3.2.1 
Efficacy variables 
3.2.1.1 
Clinical response variable at EOT and TOC 
Efficacy outcome measures will include clinical response at EOT and TOC. The clinical 
outcome categories at EOT are defined in Table 4 below and the clinical outcome categories 
at TOC as defined in Table 5 below. A favourable outcome is clinical cure.  
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Table 4 
Clinical outcome categories at End-of-Therapy 
Outcome 
Definition 
Clinical Cure 
Resolution of all acute signs and symptoms of LOS or improvement to 
such an extent that no further antibacterial therapy is required 
Clinical Failure 
Subjects who received ≥48 hours of study treatment and meet any of the 
following: 
• Discontinuation of study therapy due to insufficient therapeutic 
effect, including persistence, incomplete clinical resolution, 
worsening in signs and symptoms of LOS, or isolation of a resistant 
pathogen that requires alternative nonstudy antibacterial therapy 
• Discontinuation of study therapy due to a study therapy-related AE 
and requirement for alternative nonstudy antibacterial therapy for 
LOS 
• Death in which LOS is contributory 
Indeterminate 
Study data are not available for evaluation of efficacy for any reason, 
including: 
• Death in which LOS is clearly noncontributory 
• Lost to follow-up 
• Extenuating circumstances precluding classification as a cure or 
failure 
• Diagnosis of CNS infection, osteomyelitis, endocarditis, or NEC at 
any time after enrolment 
• Received <48 hours of study therapy 
Abbreviations: AE=adverse event; CNS=central nervous system; LOS=late-onset sepsis; NEC=necrotizing 
enterocolitis. 
 
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Table 5 
Clinical outcome categories at Test-of-Cure 
Outcome 
Definition 
Clinical Cure 
Resolution of all acute signs and symptoms of LOS or improvement to 
such an extent that no further antibacterial therapy is required 
Clinical Failure 
Subjects who received ≥48 hours of study treatment and meet either of the 
following criteria: 
• Incomplete resolution or worsening of LOS signs or symptoms or 
development of new signs or symptoms, or isolation of a resistant 
pathogen requiring alternative nonstudy antibacterial therapy 
• Death in which LOS is contributory 
Indeterminate 
Study data are not available for evaluation of efficacy for any reason,  
including: 
• Death in which LOS is clearly noncontributory 
• Lost to follow-up 
• Extenuating circumstances precluding classification as a cure or 
failure 
• Diagnosis of CNS infection, osteomyelitis, endocarditis, or NEC at 
any time after enrolment 
• Received <48 hours of study therapy 
Abbreviations: CNS=central nervous system; LOS=late-onset sepsis; NEC=necrotizing enterocolitis. 
Per-patient clinical response at TOC will be derived from clinical outcome (ie, investigator 
assessment) of clinical cure, clinical failure, or indeterminate at EOT and TOC as shown in 
Table 6 below. 
Missing values may occur due to failure to record a response at TOC due to earlier clinical 
failure. An outcome of clinical failure at EOT will be carried forward to TOC. Missing values 
may occur due to premature discontinuation from study therapy administration. Patients who 
were prematurely discontinued from study therapy administration for any reason will have 
EOT assessments conducted (see Section 1.2) and will have per-patient clinical response at 
TOC derived according to the rules in Table 6. Unrelated deaths will be assessed as 
indeterminate for all remaining scheduled clinical assessments. Deaths occurring after TOC 
will not retrospectively change the TOC outcome (ie, if a patient was a clinical cure at TOC 
but died after TOC their clinical response at TOC remains clinical cure). 
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Table 6 
Derivation of clinical response at TOC 
EOT Outcome 
TOC Outcome 
Clinical Response at TOC 
Clinical Cure 
Clinical Cure 
Clinical Cure 
 
Clinical Failure 
Clinical Failure 
 
Indeterminate 
Indeterminate 
 
Missing 
Indeterminate 
Clinical Failure 
Clinical Cure 
Clinical Failure 
 
Clinical Failure 
Clinical Failure 
 
Indeterminate 
Clinical Failure 
 
Missing 
Clinical Failure 
Indeterminate 
Clinical Cure 
Clinical Cure 
 
Clinical Failure 
Clinical Failure 
 
Indeterminate 
Indeterminate 
 
Missing 
Indeterminate 
 
The proportion of MITT Analysis Set patients with a clinical cure will be defined using the 
following formula:  
Number of patients with clinical response at TOC=clinical cure 
(Number of patients with clinical cure + Number of patients with clinical failure + Number of 
patients with indeterminate) 
The proportion of MITT Analysis Set patients with clinical failure and with indeterminate 
clinical response will be calculated analogously. For proportion of patients with clinical cure, 
clinical failure, and indeterminate, indeterminate or missing assessments will be included in 
the denominator for calculation of the proportions for the MITT Analysis Set. 
3.2.1.2 
Per-pathogen and per-patient microbiological response variables at EOT and 
TOC 
The per-pathogen microbiological outcome categories for pathogens identified at baseline are 
defined in Table 7. Local microbiology data will only be used when central data is not 
available, for example, samples were not sent to the central laboratory for processing.  Please 
see section 3.3.1.3 for further details. 
 
 
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Table 7 
Per-pathogen microbiological response categories 
Microbiological 
Responsea 
Definition 
Response 
Category 
Eradication 
Source specimen demonstrated absence of the 
original baseline pathogen 
Favorable 
Presumed 
eradication 
Source specimen was not available to culture and 
the patient was assessed as a clinical cure 
Favorable 
Persistence 
Source specimen demonstrates continued presence 
of the original baseline pathogen 
Unfavorable 
Presumed 
persistence 
Source specimen was not available to culture and 
the patient was assessed as a clinical failure 
Unfavorable 
Indeterminate 
Source specimen was not available to culture and 
the patient’s clinical outcome was assessed as 
indeterminate 
Indeterminate 
a For patients who were clinical failures before TOC, the microbiological outcome will be carried forward to 
TOC and will be determined based on the cultures and/or clinical outcome at the time of the early clinical failure 
determination. 
Similarly, per-patient microbiological response will be categorized as favorable, unfavorable, 
or indeterminate as follows. Per-patient microbiological response at EOT and TOC will be 
derived programmatically based on individual outcomes for each baseline pathogen. In order 
for a patient to have a favorable per-patient microbiological response, the outcome for each 
baseline pathogen must be favorable (eradicated or presumed eradicated) at that time point. 
This includes results of blood cultures, urine cultures, CSF cultures or other specimen cultures 
at the time point. If the outcome for any baseline pathogen from any culture is unfavorable 
(persistence or presumed persistence) at that time point, the patient will be considered to have 
an unfavorable per-patient microbiological response. If there is an indeterminate per-pathogen 
microbiological response at the time point (ie, no culture result available and patient’s clinical 
outcome was indeterminate), the patient will be considered to have an indeterminate 
per-patient microbiological response. For per-patient microbiological response at TOC visit, 
the above definition is only applicable to patients who are not clinical failures at EOT. 
Patients who are clinical failures at EOT will have the corresponding per-patient 
microbiological outcome determined from EOT cultures and carried forward to TOC. If no 
EOT culture is available for patients who are clinical failures at EOT, then the microbiological 
outcome at TOC will be presumed persistence. Otherwise, the microbiological outcome at 
TOC will be determined from cultures obtained within the TOC visit window. If no culture is 
available in the TOC window, then the microbiological outcome at TOC will be presumed 
from the clinical response at TOC (if clinical cure, the microbiological outcome will be 
presumed eradication; if clinical failure, the microbiological outcome will be presumed 
persistence; if clinically indeterminate, the microbiological outcome will be indeterminate). 
3.2.2 
Pharmacokinetic variables 
Two PK samples will be obtained at steady state from at least 20 patients to determine the 
population pharmacokinetics of ceftaroline fosamil, ceftaroline, and ceftaroline M-1 in this 
patient population. If CSF sample collection is expected per standard of care, PK blood 
samples should be collected at the time of CSF collection as a matching sample (see section 
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5.4.1 of the protocol). The total number of PK blood samples will not exceed 2. After the 2 
PK blood samples have been collected, any portion of a CSF sample (collected as part of 
standard of care) not required for the patient’s medical care should be retained for PK 
analysis. 
Pharmacokinetic variables include actual sample collection times and plasma concentrations 
of ceftaroline fosamil, ceftaroline, and ceftaroline M-1 at each time point. If available, 
concentrations of ceftaroline and ceftaroline M-1 in cerebrospinal fluid (CSF) will be 
reported.  
Plasma concentrations of ceftaroline fosamil, ceftaroline and ceftaroline M-1 will be listed by 
age cohort. 
Covance Laboratories, using appropriate bioanalytical methods will determine plasma 
concentrations of ceftaroline fosamil, ceftaroline, and ceftaroline M-1. 
3.3.1 
Demographic and baseline characteristic variables 
3.3.1.1 
Demographic variables 
Demographic variables include age (days), sex, race, and ethnicity. Age (days) will be 
calculated as (date of informed consent - date of birth + 1). 
3.3.1.2 
Surgical and medical history variables including antepartum/ peripartum 
period 
Surgical history variables include procedures, study day of procedure start date, and current 
medication yes/no. Medical history variables include diagnosis, study day of condition start 
date and duration of condition (see Section 3 for calculation of study day and duration), status 
(past or current), and any current medication yes/no. Surgical and medical histories will be 
coded using MedDRA Version 12.0 or higher. 
3.3.1.3 
Baseline microbiological assessment variables for blood, CSF, urine, and other 
specimens 
Identification of pathogens and susceptibility results will be recorded by both the local 
microbiology laboratory and the central reference laboratory. The identification and 
susceptibility results of the central microbiology reference laboratory will be regarded as 
definitive, if after re-testing, any discrepancies noted are not resolved. In the circumstance that 
the central lab could not isolate any organism from the submitted specimen, the local lab 
result will be used for organism identification (not including a result of “No Growth” at the 
central laboratory, which should be reported). 
Microbiological assessments at baseline include collection data, culture data, antibiotic 
susceptibility data, and gram stain data: 
• Collection data: specimen collected yes/no, type of specimen, reason for no specimen, 
specify if attempt made but unable to obtain, collection date and time and specimen 
acquisition method 
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• Culture data: specimen work up performed by, culture outcome, culture source 
location, laboratory name and identifier, pathogen type, isolate identification, isolate 
classification, isolate quantitation for 1 µL, 5 µL, 10 µL plates (for urine specimens 
only), isolate sent to central lab yes/no, reason if no specimen sent to central 
laboratory, accession identifier primary and secondary 
• Antibiotic susceptibility data: local susceptibility tested yes/no, isolate identification, 
antibiotics tested, susceptibility, susceptibility criteria and susceptibility method 
• Gram stain data: gram stain done yes/no, specify if no gram stain done and gram stain 
results, for example, epithelial cell results, etc. 
3.3.2 
Definition of prior and concomitant medication 
Any medications (non-antimicrobial, antimicrobial, parenteral nutrition and 
blood/blood-component transfusions) taken by the patient between 7 days prior to study entry 
(or taken by the lactating mother of breast fed patients within 3 days prior to study entry) and 
prior to the first dose date of study therapy received will be considered prior medication. Any 
medication taken by the patient (or by the lactating mother of breast fed patients) at any time 
between dates of the first dose (including the date of the first dose) of study therapy through 
the TOC visit, inclusive, will be considered concomitant medication. Any medication started 
prior to the study entry and ended/ongoing up to the TOC will be considered as both prior and 
concomitant medication. 
If any medications reported are not able to be determined as prior medications or concomitant 
medications due to missing or partial start dates and/or stop dates, the following imputation 
rules will be implemented: 
• If the year is present but the month and day are missing, then 01JAN will be imputed 
for the start date and 31DEC for the stop date. 
• If the year and month are present but the day is missing, then 01 will be imputed for 
the start date and the last day of the month for the stop date. 
If both stop/start years are missing or both stop/start dates otherwise cannot be imputed, then 
the date will be treated as missing and the medication will be treated as both prior and 
concomitant medications. 
3.3.3 
Exposure and Compliance variable 
Exposure to the study therapy will be calculated as the difference between the last study 
therapy date and the first study therapy date converted to days plus 1 day. Any partial infusion 
will be considered as a complete infusion for the purpose of exposure, and the relevant details 
will be listed. 
Compliance will be calculated as the sum of the actual infusions over all doses/expected 
infusions over all doses)*100. 
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4. 
ANALYSIS METHODS 
4.1 
General principles 
All analyses will use SAS® version 9.1.3 or higher. Summary tables will be organized by age 
cohort and overall. All available data for each analysis set will be used in the analyses, and a 
subset of key safety, efficacy, and PK data will be included in listings. No statistical 
hypothesis testing will be performed. Confidence intervals (CI) will be two-sided 95% CIs. 
Unless otherwise noted, categorical data will be presented using counts and percentages with 
the denominator for percentages being the number of patients in the analysis set by age cohort. 
Percentages will be rounded to one decimal place; except 0% and 100% will be displayed 
without any decimal places and percentages will not be displayed for zero counts. Continuous 
variables will be summarized using the number of observations (n), mean, SD, median, 
minimum, and maximum. The minimum and maximum values will be displayed to the same 
level of precision as the raw data, the mean and median to a further decimal place and the SD 
to two additional decimal places. 
Imputation of missing data will be performed as described within this document (see Section 
3.2.1 for imputation of efficacy data at EOT and TOC and Section 3.3.2 for imputation of 
partial dates for prior and concomitant medication). Visit windowing will be performed as 
described in Section 3. 
Baseline summaries will utilize the ITT and MITT Analysis Sets. Study therapy exposure, 
concomitant medication, and safety analyses will utilize the Safety Analysis Set. Efficacy 
analyses of clinical outcome and microbiological response will utilize the MITT and Micro-
ITT Analysis Sets. PK analyses will utilize the PK Analysis Set. All data will be listed. 
4.1.1 
Data quality 
The clinical database will be cleaned prior to analysis; see PRA Clinical Informatics Plan for 
details. Beyond the data screening built into the PRA Clinical Informatics Plan, the PRA 
programming of analysis datasets, tables, figures, and listings (TFLs) will provide additional 
data screening. 
Review of a pre-freeze TFL run on clean patients and a post-freeze TFL run on the frozen 
database will allow for further data screening prior to lock. The post-freeze TFL will be 
discussed with Pfizer in a data review meeting to identify any final data issues and seek 
corrections prior to database lock. The PRA statistician and Pfizer must approve database 
lock. 
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. Our 
quality control procedures will be documented separately in the study-specific clinical 
programming quality control plan. 
4.2 
Analysis methods 
4.2.1 
Patient disposition 
The number and percentage of patients enrolled and treated with study therapy, along with the 
number and percentage of treatment completers, premature discontinuations from study 
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therapy administration, and withdrawals from the study will be provided overall and within 
each age cohort based for all patients, ie, all subjects who signed informed consent. 
Disposition details for subjects who discontinued from the study and from study therapy; and 
those who completed the study will be listed for all patients. 
The number of patients in each analysis set and the reasons for exclusion from analysis sets 
will be listed and summarized for the ITT Analysis Set. 
4.2.2 
Protocol deviations 
A table of important PDs will be presented overall and by age cohort for the ITT Analysis Set. 
See Section 2.2 for details, including determination of importance. 
Important PDs will be displayed in a data listing by age cohort and patient. 
4.2.3 
Demographics and baseline characteristics 
Demographics data defined in Section 3.3.1 will be summarized for the ITT, MITT and 
Micro-ITT Analysis Set by age cohort and overall. Baseline length (cm) and weight (kg) will 
be tabulated. 
Relevant surgical and medical history (past and current) including antepartum/ peripartum 
period will be summarized by MedDRA System Organ Class and preferred term, both by age 
cohort and overall for the ITT Analysis Set. 
The number and percentage of patients with baseline pathogens (Genus and species) by 
specimen type (blood, CSF, urine, and other specimens) will be summarized by age cohort 
and overall for the ITT, MITT and Micro-ITT Analysis Set. 
Demographics and baseline characteristics, and relevant medical and surgical history data will 
be listed by age cohort and patient. Baseline culture data including susceptibility (susceptible, 
intermediate, resistant) and gram stain testing results will be listed by age cohort and patient 
for the ITT Analysis Set. 
4.2.4 
Prior and concomitant medications 
See Section 3.3.3 for definitions of prior and concomitant medications. 
Medications received concomitantly with study therapy, categorized by anatomical 
therapeutic chemical classification and generic name according to the World Health 
Organization Drug Dictionary Enhanced (WHODDE, Version 20.0), will be summarized. The 
number and percentage of patients using at least one medication within each ATC Group and 
Generic Term will be displayed by age cohort and overall for the Safety Analysis Set. Prior 
medications will be summarized in an identical fashion. For lactating mothers, maternal prior 
and concomitant medications will be included in these summaries. 
The duration of prior medications defined as the end date – start date +1, will also be 
summarized for each ATC Group and Generic Term and displayed by age cohort and overall 
for the ITT Analysis Set.  In the event that prior medications had partial dates no imputation 
will be undertaken and consequently the duration of prior medication will be missing for any 
such records. 
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Prior and concomitant medication data will be listed for the ITT Analysis Set by age cohort 
and patient. 
4.2.5 
Study therapy exposure and compliance 
Duration of study therapy exposure in days for ceftaroline fosamil, optional ampicillin and 
optional aminoglycoside will be tabulated by age cohort and overall for the Safety Analysis 
Set and MITT population. In addition to standard summary statistics, quartiles for each patient 
and total treatment days for all patients will be shown.  
Following protocol amendment 2 the dose of ceftaroline fosamil was changed from 4mg/kg to 
6mg/kg. No summaries will be provided by the different ceftaroline fosamil doses, under the 
different versions of the protocol to which patients were enrolled. 
Treatment compliance will be summarized as continuous data and categorically (<80%, 80-
120%, >120% compliance) by age cohort and overall for the Safety Analysis Set and MITT 
population. 
Ceftaroline fosamil exposure data, compliance data and administration details will be listed by 
age cohort and patient for the Safety Analysis Set. 
4.2.6 
Safety analysis 
4.2.6.1 
Analysis of adverse events, serious adverse events, and deaths 
The number and percentage of patients with AEs occurring after the start of administration of 
the first dose of study therapy, or AEs that started prior to treatment and worsened on 
treatment, up to the SFU visit will be summarized, i.e. treatment emergent(TE) AEs. The 
following summaries will be presented for the Safety Analysis Set: 
• Overall summary of TEAEs by category (overall and by age cohort) 
• Incidence of TEAEs by system organ class (SOC) and preferred term 
• Incidence of TEAEs by SOC, preferred term, and maximum intensity 
• Incidence of TEAEs by SOC, preferred term, and relationship to ceftaroline 
• Incidence of TEAEs of special interest by SOC and preferred term 
• Incidence of non-serious TEAEs by SOC and preferred term  
• Incidence of TEAEs with fatal outcome by SOC and preferred term 
• Incidence of all deaths 
• Incidence of Serious TEAEs by SOC and preferred term 
• Incidence of TEAEs leading to discontinuation of investigational product by SOC and 
preferred term 
All AEs occurring prior to the first intake of ceftaroline will be listed for the Safety Analysis 
Set. 
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4.2.6.2 
Clinical laboratory safety assessment 
Clinical laboratory data include hematology, chemistry, CRP, CSF, blood gas and base excess, 
urinalysis, and urine output. Descriptive statistics (including n, mean, SD, minimum, median, 
and maximum) of observed results and change from baseline will be presented for continuous 
clinical laboratory results by age cohort and overall for the Safety Analysis Set. 
In addition, the following summaries at each applicable visit will also be provided by age 
cohort and overall: 
• Shift tables showing the number of patients with changes from low, normal, or high 
values from baseline 
• Shift tables showing the number of patients with urinalysis changes from baseline to 
each category (negative, trace, positive) 
• The number and percentage of patients with abnormal values using the PCS criteria in 
Appendix B 
Listings of values for each patient will be presented by age cohort with abnormal or out-of-
range values flagged. All laboratory results for each patient will be listed for the Safety 
Analysis Set. 
4.2.6.3 
Weight, vital signs, and oxygen saturation results 
Weight, vital signs (heart rate, blood pressure, respiratory rate, temperature) and oxygen 
saturation (measured by oximeter) will be summarized. Descriptive statistics (including n, 
mean, SD, minimum, median, and maximum) of observed results and change from baseline 
will be presented for continuous results by age cohort and overall for the Safety Analysis Set. 
Listings of values for each patient will be presented by age cohort for the Safety Analysis Set. 
4.2.6.4 
Other safety results 
Data for physical examination by body system, imaging study results, and adjunctive 
therapeutic procedures related to infections will be included in ADaM datasets and presented 
in listings for the Safety Analysis Set. 
4.2.7 
Efficacy analysis 
4.2.7.1 
Clinical response 
The number and percentage of patients with a clinical cure, clinical failure, and indeterminate 
clinical response at EOT and TOC will be tabulated overall and by baseline pathogen, overall 
and within each age cohort for the ITT, MITT and Micro-ITT Analysis Sets. A two-sided 95% 
CI for the observed clinical cure rate overall, within each cohort and overall will be 
constructed using the Jeffreys method. Sensitivity analyses will be conducted on the overall 
response excluding indeterminate responses. 
Clinical outcome and derived response data will be listed by age cohort and patient for the 
ITT Analysis Set. 
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4.2.7.2 
Microbiological response 
The number and percentage of patients with a favourable, unfavourable and indeterminate 
microbiological response at EOT and TOC will be tabulated overall, and by baseline pathogen 
(overall and within each age cohort) for the MITT and Micro-ITT Analysis Sets. A two-sided 
95% CI for the observed microbiological favourable rate overall within each cohort and 
overall will be constructed using the Jeffreys method.   
The number and percentage of pathogens with a favorable microbiological response 
(eradication, presumed eradication) at TOC will be tabulated by baseline pathogen and 
baseline ceftaroline MIC (overall and within each age cohort) for the MITT and Micro-ITT 
Analysis Sets. 
All other microbiological data including microbiological responses by pathogen and by 
patient, susceptibility testing and gram staining will be listed by age cohort and patient for the 
ITT Analysis Set. 
4.2.8 
Pharmacokinetics analysis 
Ceftaroline plasma concentration data, along with other information including demographic 
data, will be combined with appropriate data from other clinical studies and analyzed using a 
population PK approach and reported separately. 
PK schedule assignment data, sample collection data and plasma concentration data will be 
listed by age cohort and patient for the PK Analysis Set. 
5. 
APPENDICES 
APPENDIX A 
Non-eligible pathogens 
APPENDIX B  
Criteria for potentially clinically significant laboratory results 
APPENDIX C  
Adverse Events of Special Interest 
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Appendix A 
Non-eligible pathogens 
 
Table 2 
Pathogen Classifications for Study 
Always 
Never  
Sometimes 
Enterobacteriaceae 
 
Staphylococcus aureus 
 
Streptococcus spp. 
 
Coagulase-negative 
staphylococci 
 
Streptococcus spp. 
(except viridans Streptococci) 
 
 
ESBL phenotype positive 
Enterobacteriaceae 
 
Other Enterobacteriaceae not 
susceptible to study drug received 
 
Other non-Enterobacteriaceae 
Gram negative bacteria  
 
Non-fermentative Gram-negative 
bacteria including Pseudomonas 
spp.  
 
viridans Streptococci 
 
Anaerobes 
 
Fungal pathogens (including yeast) 
 
Parasitic pathogens 
 
Viral pathogens 
Enterococcus spp.* 
 
 
Table 1 represents the latest known list for pathogens susceptible to ceftaroline.  If more data 
become available during the course of this study, then this list will be updated appropriately. 
* Based on investigator determination. 
 
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Appendix B 
Criteria for Potentially Clinically Significant Laboratory Tests 
Category 
               
Category 
              Parameter 
Lower 
Limit 
Upper 
Limit 
Percent 
decrease from 
baseline 
Percent 
increase from 
baseline 
Haematology 
Haematocrit 
< 0.6 x LLN 
> 1.3 x ULN 
> 25% 
> 30%  
 
Haemoglobin 
< 0.6 x LLN 
> 1.3 x ULN 
> 25% 
> 30% 
 
Red Blood Cell 
count 
< 0.8 x LLN 
> 1.3 x ULN 
> 20% 
> 30%  
 
White Blood Cell 
count 
< 0.5 x LLN 
> 2.0 x ULN 
> 60% 
> 100%  
 
Eosinophils 
N/A 
> 4.0 x ULN 
N/A 
> 400%  
 
Lymphocytes 
(absolute count)  
< 0.2 x LLN 
> 2.2 x ULN 
> 70%  
> 100%  
 
Neutrophils 
(absolute count)  
< 0.5 x LLN 
> 2.2 x ULN 
> 70%  
> 100%  
 
Platelets 
< 0.4 x LLN 
> 2.0 x ULN 
> 40%  
> 100%  
Haematology/   
Coagulation 
International 
normalized ratio 
< 0.5 x LLN 
> 2.0 x ULN 
> 50%  
> 100%  
 
Partial 
thromboplastin time  
< 0.5 x LLN 
> 2.0 x ULN 
> 50%  
> 100%  
 
Prothrombin Time  
< 0.5 x LLN 
> 2.0 x ULN 
> 50%  
> 100%  
Chemistry 
Albumin  
< 0.6 x LLN 
N/A 
> 60%  
N/A 
 
Alkaline 
phosphatase  
< 0.5 x LLN 
> 3.0 x ULN 
> 80% 
> 300%  
 
Alanine 
aminotransferase  
N/A 
> 3.0 x ULN 
N/A 
> 300%  
 
Aspartate 
aminotransferase  
N/A 
> 3.0 x ULN 
N/A 
> 300%  
 
Bilirubin, direct  
N/A 
> 2.5 x ULN 
N/A 
> 150%  
 
Bilirubin, total  
N/A 
> 2.5 x ULN 
N/A 
> 300%  
 
Bilirubin, indirect  
N/A 
> 2.5 x ULN 
N/A 
> 150%  
 
Blood urea 
nitrogen* 
N/A 
> 3 x ULN 
N/A 
> 300%  
 
Calcium 
< 0.7 x LLN 
> 1.3 x ULN 
> 30%  
 
> 30% 
 
Chloride 
< 0.8 x LLN 
> 1.2 x ULN 
> 20%  
 
> 20% 
 
Creatinine 
N/A 
> 2.0 x ULN 
N/A 
> 100%  
 
Glucose, nonfasting 
< 0.6 x LLN 
> 4.0 x ULN 
> 40%  
> 200% 
 
Potassium 
< 0.8 x LLN 
> 1.2 x ULN 
> 15%  
> 20%  
 
Sodium 
< 0.85 x 
LLN 
> 1.1 x ULN 
> 10%  
> 10%  
 
Lactate 
Dehydrogenase 
< 0.4 x LLN 
> 4.0 x ULN 
> 60%  
> 300%  
PCS are based on P903-21 Study and consistent with Division of AIDS (DAIDS) Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Version 2.0, November 2014 with grade 2 or greater laboratory 
abnormalities being considered PCS and Harriet Lane Handbook Version 19. 
* For sites that collect Urea instead of BUN, Urea will be converted to BUN using the following formula:  
   Urea [mg/dL]/2.14 = BUN [mg/dL]. 
 
 
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Appendix C 
Adverse Events of Special Interest 
SMQ PTs taken from Anaphylactic reaction (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactic transfusion reaction 
Anaphylactoid reaction 
Anaphylactoid shock 
Circulatory collapse 
Dialysis membrane reaction 
Kounis syndrome 
Shock 
Shock symptom 
Type I hypersensitivity 
 
SMQ PTs taken from Angioedema (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Allergic oedema 
Angioedema 
Circumoral oedema 
Conjunctival oedema 
Corneal oedema 
Epiglottic oedema 
Eye oedema 
Eye swelling 
Eyelid oedema 
Face oedema 
Gingival oedema 
Gingival swelling 
Gleich's syndrome 
Hereditary angioedema 
Idiopathic angioedema 
Idiopathic urticaria 
Intestinal angioedema 
Laryngeal oedema 
Laryngotracheal oedema 
Limbal swelling 
Lip oedema 
Lip swelling 
Mouth swelling 
Oculorespiratory syndrome 
Oedema mouth 
Oropharyngeal oedema 
Oropharyngeal swelling 
Palatal oedema 
Palatal swelling 
Periorbital oedema 
Pharyngeal oedema 
Scleral oedema 
Swelling face 
Swollen tongue 
Tongue oedema 
Tracheal oedema 
Urticaria 
Urticaria cholinergic 
Urticaria chronic 
Urticaria papular 
 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
5q minus syndrome 
Abdominal neoplasm 
Abdominal wall neoplasm 
Abdominal wall neoplasm malignant 
Acanthosis nigricans 
Acinar cell carcinoma of pancreas 
Acinic cell carcinoma of salivary gland 
Acquired thalassaemia 
Acral lentiginous melanoma 
Acral lentiginous melanoma stage I 
Acral lentiginous melanoma stage II 
Acral lentiginous melanoma stage III 
Acral lentiginous melanoma stage IV 
Acrokeratosis paraneoplastica 
ACTH-producing pituitary tumour 
Acute biphenotypic leukaemia 
Gestational trophoblastic tumour 
Gingival cancer 
Glioblastoma 
Glioblastoma multiforme 
Glioma 
Gliomatosis cerebri 
Glioneuronal tumour 
Gliosarcoma 
Glossectomy 
Glottis carcinoma 
Glucagonoma 
Good syndrome 
Granular cell tumour 
Granulosa cell tumour of the testis 
Growth hormone-producing pituitary 
tumour 
Ostectomy 
Osteosarcoma 
Osteosarcoma metastatic 
Osteosarcoma recurrent 
Otic cancer metastatic 
Ovarian cancer 
Ovarian cancer metastatic 
Ovarian cancer recurrent 
Ovarian cancer stage I 
Ovarian cancer stage II 
Ovarian cancer stage III 
Ovarian cancer stage IV 
Ovarian clear cell carcinoma 
Ovarian dysgerminoma stage I 
Ovarian dysgerminoma stage II 
Ovarian dysgerminoma stage III 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
37 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Acute leukaemia 
Acute leukaemia in remission 
Acute lymphocytic leukaemia 
Acute lymphocytic leukaemia (in 
remission) 
Acute lymphocytic leukaemia recurrent 
Acute lymphocytic leukaemia refractory 
Acute megakaryocytic leukaemia 
Acute megakaryocytic leukaemia (in 
remission) 
Acute monocytic leukaemia 
Acute monocytic leukaemia (in 
remission) 
Acute myeloid leukaemia 
Acute myeloid leukaemia (in remission) 
Acute myeloid leukaemia recurrent 
Acute myelomonocytic leukaemia 
Acute promyelocytic leukaemia 
Acute promyelocytic leukaemia 
differentiation syndrome 
Acute undifferentiated leukaemia 
Adenocarcinoma 
Adenocarcinoma gastric 
Adenocarcinoma of appendix 
Adenocarcinoma of colon 
Adenocarcinoma of salivary gland 
Adenocarcinoma of the cervix 
Adenocarcinoma pancreas 
Adenoid cystic carcinoma 
Adenoid cystic carcinoma of external 
auditory canal 
Adenoid cystic carcinoma of salivary 
gland 
Adenosquamous carcinoma of the cervix 
Adenosquamous carcinoma of vagina 
Adenosquamous cell carcinoma 
Adenosquamous cell lung cancer 
Adenosquamous cell lung cancer 
recurrent 
Adenosquamous cell lung cancer stage 0 
Adenosquamous cell lung cancer stage I 
Adenosquamous cell lung cancer stage 
II 
Adenosquamous cell lung cancer stage 
III 
Adenosquamous cell lung cancer stage 
IV 
Adrenal gland cancer 
Adrenal gland cancer metastatic 
Adrenal neoplasm 
Adrenocortical carcinoma 
Adult T-cell lymphoma/leukaemia 
Adult T-cell lymphoma/leukaemia 
recurrent 
Adult T-cell lymphoma/leukaemia 
refractory 
Haemangiopericytoma 
Haemangiopericytoma of meninges 
Haematological malignancy 
Haematopoietic neoplasm 
Haemorrhagic tumour necrosis 
Hairy cell leukaemia 
Hairy cell leukaemia recurrent 
Head and neck cancer 
Head and neck cancer metastatic 
Head and neck cancer stage I 
Head and neck cancer stage II 
Head and neck cancer stage III 
Head and neck cancer stage IV 
Hemicorporectomy 
Hemilaryngectomy 
Hemipelvectomy 
Hepatectomy 
Hepatic angiosarcoma 
Hepatic cancer 
Hepatic cancer metastatic 
Hepatic cancer recurrent 
Hepatic cancer stage I 
Hepatic cancer stage II 
Hepatic cancer stage III 
Hepatic cancer stage IV 
Hepatic neoplasm 
Hepatobiliary cancer 
Hepatobiliary cancer in situ 
Hepatobiliary neoplasm 
Hepatoblastoma 
Hepatoblastoma recurrent 
Hepatocellular carcinoma 
Hepatosplenic T-cell lymphoma 
HER-2 positive breast cancer 
HER-2 positive gastric cancer 
Hereditary leiomyomatosis renal cell 
carcinoma 
Hereditary papillary renal carcinoma 
Hidradenocarcinoma 
High frequency ablation 
High grade B-cell lymphoma Burkitt-
like lymphoma 
High grade B-cell lymphoma Burkitt-
like lymphoma recurrent 
High grade B-cell lymphoma Burkitt-
like lymphoma refractory 
High grade B-cell lymphoma Burkitt-
like lymphoma stage I 
High grade B-cell lymphoma Burkitt-
like lymphoma stage II 
High grade B-cell lymphoma Burkitt-
like lymphoma stage III 
High grade B-cell lymphoma Burkitt-
like lymphoma stage IV 
High intensity focused ultrasound 
High-grade B-cell lymphoma 
Ovarian dysgerminoma stage IV 
Ovarian dysgerminoma stage 
unspecified 
Ovarian embryonal carcinoma 
Ovarian endometrioid carcinoma 
Ovarian epithelial cancer 
Ovarian epithelial cancer metastatic 
Ovarian epithelial cancer recurrent 
Ovarian epithelial cancer stage I 
Ovarian epithelial cancer stage II 
Ovarian epithelial cancer stage III 
Ovarian epithelial cancer stage IV 
Ovarian germ cell cancer 
Ovarian germ cell cancer stage I 
Ovarian germ cell cancer stage II 
Ovarian germ cell cancer stage III 
Ovarian germ cell cancer stage IV 
Ovarian germ cell choriocarcinoma 
Ovarian germ cell choriocarcinoma 
stage I 
Ovarian germ cell choriocarcinoma 
stage II 
Ovarian germ cell choriocarcinoma 
stage III 
Ovarian germ cell choriocarcinoma 
stage IV 
Ovarian germ cell embryonal 
carcinoma stage I 
Ovarian germ cell embryonal 
carcinoma stage II 
Ovarian germ cell embryonal 
carcinoma stage III 
Ovarian germ cell embryonal 
carcinoma stage IV 
Ovarian germ cell endodermal sinus 
tumour 
Ovarian germ cell endodermal sinus 
tumour stage I 
Ovarian germ cell endodermal sinus 
tumour stage II 
Ovarian germ cell endodermal sinus 
tumour stage III 
Ovarian germ cell endodermal sinus 
tumour stage IV 
Ovarian germ cell polyembryoma 
Ovarian germ cell polyembryoma stage 
I 
Ovarian germ cell polyembryoma stage 
II 
Ovarian germ cell polyembryoma stage 
III 
Ovarian germ cell polyembryoma stage 
IV 
Ovarian germ cell teratoma 
Ovarian germ cell teratoma stage I 
Ovarian germ cell teratoma stage II 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
38 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Adult T-cell lymphoma/leukaemia stage 
I 
Adult T-cell lymphoma/leukaemia stage 
II 
Adult T-cell lymphoma/leukaemia stage 
III 
Adult T-cell lymphoma/leukaemia stage 
IV 
Aesthesioneuroblastoma 
Alcoholisation procedure 
Aleukaemic leukaemia 
Alpha 1 foetoprotein abnormal 
Alpha 1 foetoprotein increased 
Alpha interferon therapy 
Alpha-L-fucosidase increased 
Alveolar rhabdomyosarcoma 
Alveolar soft part sarcoma 
Alveolar soft part sarcoma metastatic 
Alveolar soft part sarcoma recurrent 
Anal cancer 
Anal cancer metastatic 
Anal cancer recurrent 
Anal cancer stage 0 
Anal cancer stage I 
Anal cancer stage II 
Anal cancer stage III 
Anal cancer stage IV 
Anal neoplasm 
Anal squamous cell carcinoma 
Anaplastic astrocytoma 
Anaplastic large cell lymphoma T- and 
null-cell types 
Anaplastic large cell lymphoma T- and 
null-cell types recurrent 
Anaplastic large cell lymphoma T- and 
null-cell types refractory 
Anaplastic large cell lymphoma T- and 
null-cell types stage I 
Anaplastic large cell lymphoma T- and 
null-cell types stage II 
Anaplastic large cell lymphoma T- and 
null-cell types stage III 
Anaplastic large cell lymphoma T- and 
null-cell types stage IV 
Anaplastic large-cell lymphoma 
Anaplastic meningioma 
Anaplastic oligodendroglioma 
Anaplastic thyroid cancer 
Androgen therapy 
Angiocentric glioma 
Angiocentric lymphoma 
Angiocentric lymphoma recurrent 
Angiocentric lymphoma refractory 
Angiocentric lymphoma stage I 
Angiocentric lymphoma stage II 
Angiocentric lymphoma stage III 
Histiocytic medullary reticulosis 
Histiocytic sarcoma 
Hodgkin's disease 
Hodgkin's disease lymphocyte 
depletion stage I site unspecified 
Hodgkin's disease lymphocyte 
depletion stage I subdiaphragm 
Hodgkin's disease lymphocyte 
depletion stage I supradiaphragm 
Hodgkin's disease lymphocyte 
depletion stage II site unspecified 
Hodgkin's disease lymphocyte 
depletion stage II subdiaphragm 
Hodgkin's disease lymphocyte 
depletion stage II supradiaphragm 
Hodgkin's disease lymphocyte 
depletion type recurrent 
Hodgkin's disease lymphocyte 
depletion type refractory 
Hodgkin's disease lymphocyte 
depletion type stage III 
Hodgkin's disease lymphocyte 
depletion type stage IV 
Hodgkin's disease lymphocyte 
depletion type stage unspecified 
Hodgkin's disease lymphocyte 
predominance stage I site unspec 
Hodgkin's disease lymphocyte 
predominance stage I subdiaphragm 
Hodgkin's disease lymphocyte 
predominance stage I supradiaphragm 
Hodgkin's disease lymphocyte 
predominance stage II site unspec 
Hodgkin's disease lymphocyte 
predominance stage II subdiaphragm 
Hodgkin's disease lymphocyte 
predominance stage II supradiaphragm 
Hodgkin's disease lymphocyte 
predominance type recurrent 
Hodgkin's disease lymphocyte 
predominance type refractory 
Hodgkin's disease lymphocyte 
predominance type stage III 
Hodgkin's disease lymphocyte 
predominance type stage IV 
Hodgkin's disease lymphocyte 
predominance type stage unspecified 
Hodgkin's disease mixed cellularity 
recurrent 
Hodgkin's disease mixed cellularity 
refractory 
Hodgkin's disease mixed cellularity 
stage I site unspecified 
Hodgkin's disease mixed cellularity 
stage I subdiaphragmatic 
Hodgkin's disease mixed cellularity 
Ovarian germ cell teratoma stage III 
Ovarian germ cell teratoma stage IV 
Ovarian germ cell tumour 
Ovarian germ cell tumour mixed 
Ovarian granulosa cell tumour 
Ovarian granulosa-theca cell tumour 
Ovarian low malignant potential 
tumour 
Ovarian neoplasm 
Ovarian Sertoli-Leydig cell tumour 
Ovarian stromal cancer 
Ovarian theca cell tumour 
 
Paget's disease of nipple 
Paget's disease of penis 
Paget's disease of the vulva 
Palliative care 
Pancoast's tumour 
Pancreastatin abnormal 
Pancreastatin increased 
Pancreatectomy 
Pancreatic carcinoma 
Pancreatic carcinoma metastatic 
Pancreatic carcinoma recurrent 
Pancreatic carcinoma stage 0 
Pancreatic carcinoma stage I 
Pancreatic carcinoma stage II 
Pancreatic carcinoma stage III 
Pancreatic carcinoma stage IV 
Pancreatic neoplasm 
Pancreatic neuroendocrine tumour 
Pancreatic neuroendocrine tumour 
metastatic 
Pancreatic sarcoma 
Pancreaticoduodenectomy 
Pancreaticosplenectomy 
Pancreatoblastoma 
Papillary renal cell carcinoma 
Papillary serous endometrial carcinoma 
Papillary thyroid cancer 
Paraganglion neoplasm 
Paraganglion neoplasm malignant 
Paranasal biopsy abnormal 
Paranasal sinus and nasal cavity 
malignant neoplasm 
Paranasal sinus and nasal cavity 
malignant neoplasm recurrent 
Paranasal sinus and nasal cavity 
malignant neoplasm stage 0 
Paranasal sinus and nasal cavity 
malignant neoplasm stage I 
Paranasal sinus and nasal cavity 
malignant neoplasm stage II 
Paranasal sinus and nasal cavity 
malignant neoplasm stage III 
Paranasal sinus and nasal cavity 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
39 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Angiocentric lymphoma stage IV 
Angiogenesis biomarker increased 
Angioimmunoblastic T-cell lymphoma 
Angioimmunoblastic T-cell lymphoma 
recurrent 
Angioimmunoblastic T-cell lymphoma 
refractory 
Angioimmunoblastic T-cell lymphoma 
stage I 
Angioimmunoblastic T-cell lymphoma 
stage II 
Angioimmunoblastic T-cell lymphoma 
stage III 
Angioimmunoblastic T-cell lymphoma 
stage IV 
Angiosarcoma 
Angiosarcoma metastatic 
Angiosarcoma non-metastatic 
Angiosarcoma recurrent 
Antiandrogen therapy 
Anti-NMDA antibody positive 
Antioestrogen therapy 
Anti-VGCC antibody positive 
Apocrine breast carcinoma 
Appendix cancer 
APUDoma 
Astroblastoma 
Astrocytoma 
Astrocytoma malignant 
Atypical fibroxanthoma 
Atypical teratoid/rhabdoid tumour of 
CNS 
Autologous bone marrow 
transplantation therapy 
Axillary lymphadenectomy 
B precursor type acute leukaemia 
Basal cell carcinoma 
Basosquamous carcinoma 
Basosquamous carcinoma of skin 
B-cell depletion therapy 
B-cell lymphoma 
B-cell lymphoma recurrent 
B-cell lymphoma refractory 
B-cell lymphoma stage I 
B-cell lymphoma stage II 
B-cell lymphoma stage III 
B-cell lymphoma stage IV 
B-cell prolymphocytic leukaemia 
B-cell small lymphocytic lymphoma 
B-cell small lymphocytic lymphoma 
recurrent 
B-cell small lymphocytic lymphoma 
refractory 
B-cell small lymphocytic lymphoma 
stage I 
B-cell small lymphocytic lymphoma 
stage I supradiaphragmatic 
Hodgkin's disease mixed cellularity 
stage II subdiaphragmatic 
Hodgkin's disease mixed cellularity 
stage II supradiaphragmatic 
Hodgkin's disease mixed cellularity 
stage III 
Hodgkin's disease mixed cellularity 
stage IV 
Hodgkin's disease mixed cellularity 
stage unspecified 
Hodgkin's disease nodular sclerosis 
Hodgkin's disease nodular sclerosis 
recurrent 
Hodgkin's disease nodular sclerosis 
refractory 
Hodgkin's disease nodular sclerosis 
stage I 
Hodgkin's disease nodular sclerosis 
stage II 
Hodgkin's disease nodular sclerosis 
stage III 
Hodgkin's disease nodular sclerosis 
stage IV 
Hodgkin's disease recurrent 
Hodgkin's disease refractory 
Hodgkin's disease stage I 
Hodgkin's disease stage II 
Hodgkin's disease stage III 
Hodgkin's disease stage IV 
Hodgkin's disease unclassifiable 
Hormone refractory breast cancer 
Hormone suppression therapy 
Hormone therapy 
Hormone-dependent prostate cancer 
Hormone-refractory prostate cancer 
Hormone-secreting ovarian tumour 
Huerthle cell carcinoma 
Human chorionic gonadotropin 
increased 
Human chorionic gonadotropin 
positive 
Human epidermal growth factor 
receptor increased 
Hypercalcaemia of malignancy 
Hyperleukocytosis 
Hyperthermia therapy 
Hypopharyngeal cancer 
Hypopharyngeal cancer recurrent 
Hypopharyngeal cancer stage 0 
Hypopharyngeal cancer stage I 
Hypopharyngeal cancer stage II 
Hypopharyngeal cancer stage III 
Hypopharyngeal cancer stage IV 
Hypopharyngeal neoplasm 
Hypophysectomy 
malignant neoplasm stage IV 
Paranasal sinus neoplasm 
Paraneoplastic arthritis 
Paraneoplastic dermatomyositis 
Paraneoplastic dermatosis 
Paraneoplastic encephalomyelitis 
Paraneoplastic glomerulonephritis 
Paraneoplastic nephrotic syndrome 
Paraneoplastic neurological syndrome 
Paraneoplastic pemphigus 
Paraneoplastic pleural effusion 
Paraneoplastic rash 
Paraneoplastic syndrome 
Parathyroid scan abnormal 
Parathyroid tumour 
Parathyroid tumour malignant 
Parathyroidectomy 
Parotidectomy 
Pelvic neoplasm 
Penile cancer 
Penile neoplasm 
Penile squamous cell carcinoma 
Penis carcinoma metastatic 
Penis carcinoma recurrent 
Penis carcinoma stage I 
Penis carcinoma stage II 
Penis carcinoma stage III 
Penis carcinoma stage IV 
Pepsinogen test positive 
Percutaneous ethanol injection therapy 
Pericardial effusion malignant 
Pericardial mesothelioma malignant 
Pericardial mesothelioma malignant 
recurrent 
Pericardial neoplasm 
Pericarditis malignant 
Peripheral nerve sheath tumour 
malignant 
Peripheral nervous system neoplasm 
Peripheral neuroepithelioma of bone 
Peripheral neuroepithelioma of bone 
metastatic 
Peripheral neuroepithelioma of bone 
recurrent 
Peripheral neuroepithelioma of soft 
tissue 
Peripheral primitive neuroectodermal 
bone tumour 
Peripheral primitive neuroectodermal 
tumour of soft tissue 
Peripheral T-cell lymphoma 
unspecified 
Peripheral T-cell lymphoma 
unspecified recurrent 
Peripheral T-cell lymphoma 
unspecified refractory 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
40 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
stage II 
B-cell small lymphocytic lymphoma 
stage III 
B-cell small lymphocytic lymphoma 
stage IV 
B-cell type acute leukaemia 
B-cell unclassifiable lymphoma high 
grade 
B-cell unclassifiable lymphoma low 
grade 
Beta interferon therapy 
Bile duct adenocarcinoma 
Bile duct adenosquamous carcinoma 
Bile duct cancer 
Bile duct cancer recurrent 
Bile duct cancer stage 0 
Bile duct cancer stage I 
Bile duct cancer stage II 
Bile duct cancer stage III 
Bile duct cancer stage IV 
Bile duct squamous cell carcinoma 
Biliary cancer metastatic 
Biliary neoplasm 
Biopsy abdominal wall abnormal 
Biopsy adrenal gland abnormal 
Biopsy anus abnormal 
Biopsy artery abnormal 
Biopsy bile duct abnormal 
Biopsy bladder abnormal 
Biopsy blood vessel abnormal 
Biopsy bone abnormal 
Biopsy bone marrow abnormal 
Biopsy brain abnormal 
Biopsy breast abnormal 
Biopsy bronchus abnormal 
Biopsy cartilage abnormal 
Biopsy cervix abnormal 
Biopsy chest wall abnormal 
Biopsy chorionic villous abnormal 
Biopsy colon abnormal 
Biopsy conjunctiva abnormal 
Biopsy cornea abnormal 
Biopsy diaphragm abnormal 
Biopsy ear abnormal 
Biopsy endometrium abnormal 
Biopsy epididymis abnormal 
Biopsy eyelid abnormal 
Biopsy fallopian tube abnormal 
Biopsy foetal abnormal 
Biopsy gallbladder abnormal 
Biopsy heart abnormal 
Biopsy intestine abnormal 
Biopsy kidney abnormal 
Biopsy larynx abnormal 
Biopsy ligament abnormal 
Biopsy lip abnormal 
Hysterectomy 
Hysterosalpingectomy 
Hysterosalpingo-oophorectomy 
IDH differentiation syndrome 
Ileectomy 
Ileocolectomy 
Imaging procedure abnormal 
Immune enhancement therapy 
Immune reconstitution inflammatory 
syndrome associated Kaposi's sarcoma 
Immunoblastic lymphoma 
Immunochemotherapy 
In vivo gene therapy 
Infected neoplasm 
Inferior vena cava syndrome 
Inflammatory carcinoma of breast 
recurrent 
Inflammatory carcinoma of breast 
stage III 
Inflammatory carcinoma of breast 
stage IV 
Inflammatory carcinoma of the breast 
Inflammatory malignant fibrous 
histiocytoma 
Inflammatory myofibroblastic tumour 
Insulinoma 
Interleukin therapy 
Intestinal adenocarcinoma 
Intestinal metastasis 
Intestinal resection 
Intestinal T-cell lymphoma recurrent 
Intestinal T-cell lymphoma refractory 
Intestinal T-cell lymphoma stage I 
Intestinal T-cell lymphoma stage II 
Intestinal T-cell lymphoma stage III 
Intestinal T-cell lymphoma stage IV 
Intracranial germ cell tumour 
Intracranial meningioma malignant 
Intracranial tumour haemorrhage 
Intraductal papillary breast neoplasm 
Intraductal papillary-mucinous 
carcinoma of pancreas 
Intraductal proliferative breast lesion 
Intraocular melanoma 
Intraperitoneal hyperthermic 
chemotherapy 
Intratumoural aneurysm 
Invasive breast carcinoma 
Invasive ductal breast carcinoma 
Invasive lobular breast carcinoma 
Invasive papillary breast carcinoma 
Iris melanoma 
Iris neoplasm 
Jejunectomy 
Joint neoplasm 
Juvenile chronic myelomonocytic 
Peripheral T-cell lymphoma 
unspecified stage I 
Peripheral T-cell lymphoma 
unspecified stage II 
Peripheral T-cell lymphoma 
unspecified stage III 
Peripheral T-cell lymphoma 
unspecified stage IV 
Peritoneal carcinoma metastatic 
Peritoneal fluid protein increased 
Peritoneal mesothelioma malignant 
Peritoneal mesothelioma malignant 
recurrent 
Peritoneal neoplasm 
Peritoneal sarcoma 
Peritonectomy 
Peritumoural oedema 
Phaeochromocytoma 
Phaeochromocytoma crisis 
Phaeochromocytoma excision 
Phaeochromocytoma malignant 
Pharyngeal cancer 
Pharyngeal cancer metastatic 
Pharyngeal cancer recurrent 
Pharyngeal cancer stage 0 
Pharyngeal cancer stage I 
Pharyngeal cancer stage II 
Pharyngeal cancer stage III 
Pharyngeal cancer stage IV 
Pharyngeal neoplasm 
Pharyngectomy 
Philadelphia chromosome positive 
Photodynamic diagnostic procedure 
Photon radiation therapy 
Photon radiation therapy to bladder 
Photon radiation therapy to blood 
Photon radiation therapy to bone 
Photon radiation therapy to brain 
Photon radiation therapy to breast 
Photon radiation therapy to colon 
Photon radiation therapy to ear, nose, 
or throat 
Photon radiation therapy to liver 
Photon radiation therapy to lung 
Photon radiation therapy to pancreas 
Photon radiation therapy to pleura 
Photon radiation therapy to prostate 
Photon radiation therapy to skin 
Photon radiation therapy to soft tissue 
Photon radiation therapy to thyroid 
Photon radiation therapy to uterus 
Phyllodes tumour 
Pilomatrix carcinoma 
Pineal germinoma 
Pineal neoplasm 
Pineal parenchymal neoplasm 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
41 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Biopsy liver abnormal 
Biopsy lung abnormal 
Biopsy lymph gland abnormal 
Biopsy mucosa abnormal 
Biopsy muscle abnormal 
Biopsy oesophagus abnormal 
Biopsy ovary abnormal 
Biopsy palate abnormal 
Biopsy pancreas abnormal 
Biopsy parathyroid gland abnormal 
Biopsy penis abnormal 
Biopsy pericardium abnormal 
Biopsy peripheral nerve abnormal 
Biopsy peritoneum abnormal 
Biopsy pharynx abnormal 
Biopsy pleura abnormal 
Biopsy prostate abnormal 
Biopsy rectum abnormal 
Biopsy retina abnormal 
Biopsy salivary gland abnormal 
Biopsy sclera abnormal 
Biopsy seminal vesicle abnormal 
Biopsy site unspecified abnormal 
Biopsy skin abnormal 
Biopsy small intestine abnormal 
Biopsy spinal cord abnormal 
Biopsy spleen abnormal 
Biopsy stomach abnormal 
Biopsy tendon abnormal 
Biopsy testes abnormal 
Biopsy thymus gland abnormal 
Biopsy thyroid gland abnormal 
Biopsy tongue abnormal 
Biopsy trachea abnormal 
Biopsy urethra abnormal 
Biopsy uterus abnormal 
Biopsy vagina abnormal 
Biopsy vocal cord abnormal 
Biopsy vulva abnormal 
Biotherapy 
Biphasic mesothelioma 
Bladder adenocarcinoma recurrent 
Bladder adenocarcinoma stage 0 
Bladder adenocarcinoma stage I 
Bladder adenocarcinoma stage II 
Bladder adenocarcinoma stage III 
Bladder adenocarcinoma stage IV 
Bladder adenocarcinoma stage 
unspecified 
Bladder cancer 
Bladder cancer recurrent 
Bladder cancer stage 0, with cancer in 
situ 
Bladder cancer stage 0, without cancer 
in situ 
Bladder cancer stage I, with cancer in 
leukaemia 
Kaposi's sarcoma 
Kaposi's sarcoma AIDS related 
Kaposi's sarcoma classical type 
Keratinising squamous cell carcinoma 
of nasopharynx 
Keratoacanthoma 
Lacrimal duct neoplasm 
Langerhans' cell histiocytosis 
Langerhans cell sarcoma 
Large cell lung cancer 
Large cell lung cancer metastatic 
Large cell lung cancer recurrent 
Large cell lung cancer stage 0 
Large cell lung cancer stage I 
Large cell lung cancer stage II 
Large cell lung cancer stage III 
Large cell lung cancer stage IV 
Large granular lymphocytosis 
Large intestinal polypectomy 
Laryngeal cancer 
Laryngeal cancer metastatic 
Laryngeal cancer recurrent 
Laryngeal cancer stage 0 
Laryngeal cancer stage I 
Laryngeal cancer stage II 
Laryngeal cancer stage III 
Laryngeal cancer stage IV 
Laryngeal neoplasm 
Laryngeal squamous cell carcinoma 
Laryngopharyngectomy 
Laser brain ablation 
Leiomyosarcoma 
Leiomyosarcoma metastatic 
Leiomyosarcoma recurrent 
Lentigo maligna 
Lentigo maligna recurrent 
Lentigo maligna stage I 
Lentigo maligna stage II 
Lentigo maligna stage III 
Lentigo maligna stage IV 
Leptomeningeal myelomatosis 
Leukaemia 
Leukaemia basophilic 
Leukaemia cutis 
Leukaemia granulocytic 
Leukaemia in remission 
Leukaemia monocytic 
Leukaemia recurrent 
Leukaemic cardiac infiltration 
Leukaemic infiltration 
Leukaemic infiltration extramedullary 
Leukaemic infiltration gingiva 
Leukaemic infiltration hepatic 
Leukaemic infiltration ovary 
Leukaemic infiltration pulmonary 
malignant 
Pinealoblastoma 
Pinealoma 
Pituitary cancer metastatic 
Pituitary gland radiotherapy 
Pituitary neoplasm malignant recurrent 
Pituitary tumour 
Pituitary tumour recurrent 
Placental neoplasm 
Plasma cell leukaemia 
Plasma cell leukaemia in remission 
Plasma cell myeloma 
Plasma cell myeloma in remission 
Plasma cell myeloma recurrent 
Plasmablastic lymphoma 
Plasmacytoma 
Pleomorphic adenoma 
Pleomorphic liposarcoma 
Pleomorphic malignant fibrous 
histiocytoma 
Pleural mesothelioma 
Pleural mesothelioma malignant 
Pleural mesothelioma malignant 
recurrent 
Pleural neoplasm 
Pleural sarcoma 
Pleurectomy 
PML/RAR alpha expression 
Pneumonectomy 
POEMS syndrome 
Polyneuropathy in malignant disease 
Poorly differentiated thyroid carcinoma 
Porocarcinoma 
Portal vein embolisation 
Post breast therapy pain syndrome 
Post transplant lymphoproliferative 
disorder 
Postcricoid cancer 
Posterior fossa syndrome 
Precursor B-lymphoblastic lymphoma 
Precursor B-lymphoblastic lymphoma 
recurrent 
Precursor B-lymphoblastic lymphoma 
refractory 
Precursor B-lymphoblastic lymphoma 
stage I 
Precursor B-lymphoblastic lymphoma 
stage II 
Precursor B-lymphoblastic lymphoma 
stage III 
Precursor B-lymphoblastic lymphoma 
stage IV 
Precursor T-lymphoblastic 
lymphoma/leukaemia 
Precursor T-lymphoblastic 
lymphoma/leukaemia recurrent 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
42 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
situ 
Bladder cancer stage I, without cancer in 
situ 
Bladder cancer stage II 
Bladder cancer stage III 
Bladder cancer stage IV 
Bladder neck resection 
Bladder neoplasm 
Bladder neoplasm surgery 
Bladder squamous cell carcinoma 
recurrent 
Bladder squamous cell carcinoma stage 
0 
Bladder squamous cell carcinoma stage 
I 
Bladder squamous cell carcinoma stage 
II 
Bladder squamous cell carcinoma stage 
III 
Bladder squamous cell carcinoma stage 
IV 
Bladder squamous cell carcinoma stage 
unspecified 
Bladder transitional cell carcinoma 
Bladder transitional cell carcinoma 
metastatic 
Bladder transitional cell carcinoma 
recurrent 
Bladder transitional cell carcinoma stage 
0 
Bladder transitional cell carcinoma stage 
I 
Bladder transitional cell carcinoma stage 
II 
Bladder transitional cell carcinoma stage 
III 
Bladder transitional cell carcinoma stage 
IV 
Blast cell crisis 
Blast crisis in myelogenous leukaemia 
Blastic plasmacytoid dendritic cell 
neoplasia 
Blood chromogranin A increased 
Bone cancer 
Bone cancer metastatic 
Bone giant cell tumour 
Bone giant cell tumour malignant 
Bone marrow infiltration 
Bone marrow leukaemic cell infiltration 
Bone marrow reticulin fibrosis 
Bone marrow tumour cell infiltration 
Bone neoplasm 
Bone sarcoma 
Bone scan abnormal 
Borderline mucinous tumour of ovary 
Borderline ovarian tumour 
Leukaemic infiltration renal 
Leukaemic lymphoma 
Leukaemic retinopathy 
Leukostasis syndrome 
Leydig cell tumour of the testis 
Linitis plastica 
Lip and/or oral cavity cancer 
Lip and/or oral cavity cancer recurrent 
Lip and/or oral cavity cancer stage 0 
Lip and/or oral cavity cancer stage I 
Lip and/or oral cavity cancer stage II 
Lip and/or oral cavity cancer stage III 
Lip and/or oral cavity cancer stage IV 
Lip neoplasm 
Lip neoplasm malignant stage 
unspecified 
Lip squamous cell carcinoma 
Liposarcoma 
Liposarcoma metastatic 
Liposarcoma recurrent 
Liver ablation 
Liver carcinoma ruptured 
Liver scan abnormal 
Lobular breast carcinoma in situ 
Lung adenocarcinoma 
Lung adenocarcinoma recurrent 
Lung adenocarcinoma stage 0 
Lung adenocarcinoma stage I 
Lung adenocarcinoma stage II 
Lung adenocarcinoma stage III 
Lung adenocarcinoma stage IV 
Lung cancer metastatic 
Lung carcinoma cell type unspecified 
recurrent 
Lung carcinoma cell type unspecified 
stage 0 
Lung carcinoma cell type unspecified 
stage I 
Lung carcinoma cell type unspecified 
stage II 
Lung carcinoma cell type unspecified 
stage III 
Lung carcinoma cell type unspecified 
stage IV 
Lung infiltration malignant 
Lung lobectomy 
Lung neoplasm 
Lung neoplasm malignant 
Lung neoplasm surgery 
Lung squamous cell carcinoma 
metastatic 
Lung squamous cell carcinoma 
recurrent 
Lung squamous cell carcinoma stage 0 
Lung squamous cell carcinoma stage I 
Lung squamous cell carcinoma stage II 
Precursor T-lymphoblastic 
lymphoma/leukaemia refractory 
Precursor T-lymphoblastic 
lymphoma/leukaemia stage I 
Precursor T-lymphoblastic 
lymphoma/leukaemia stage II 
Precursor T-lymphoblastic 
lymphoma/leukaemia stage III 
Precursor T-lymphoblastic 
lymphoma/leukaemia stage IV 
Primary cardiac lymphoma 
Primary effusion lymphoma 
Primary gastrointestinal follicular 
lymphoma 
Primary mediastinal large B-cell 
lymphoma 
Primary mediastinal large B-cell 
lymphoma recurrent 
Primary mediastinal large B-cell 
lymphoma refractory 
Primary mediastinal large B-cell 
lymphoma stage I 
Primary mediastinal large B-cell 
lymphoma stage II 
Primary mediastinal large B-cell 
lymphoma stage III 
Primary mediastinal large B-cell 
lymphoma stage IV 
Primitive neuroectodermal tumour 
Primitive neuroectodermal tumour 
metastatic 
Proctectomy 
Proctocolectomy 
Progesterone receptor assay positive 
Prolactin-producing pituitary tumour 
Prolymphocytic leukaemia 
Prophylactic chemotherapy 
Prostate ablation 
Prostate cancer 
Prostate cancer metastatic 
Prostate cancer recurrent 
Prostate cancer stage 0 
Prostate cancer stage I 
Prostate cancer stage II 
Prostate cancer stage III 
Prostate cancer stage IV 
Prostate cryoablation 
Prostate interstitial hyperthermia 
therapy 
Prostatectomy 
Prostatic specific antigen abnormal 
Prostatic specific antigen increased 
Pseudoachalasia 
Pseudomyxoma peritonei 
Pseudosarcoma 
Pulmonary resection 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
43 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Borderline serous tumour of ovary 
Bowen's disease 
Brachytherapy 
Brachytherapy to eye 
Brachytherapy to penis 
Brachytherapy to tongue 
Brachytherapy to tonsil 
Brain cancer metastatic 
Brain neoplasm 
Brain neoplasm malignant 
Brain sarcoma 
Brain scan abnormal 
Brain stem glioma 
Brain teratoma 
Brain tumour operation 
Breast angiosarcoma 
Breast angiosarcoma metastatic 
Breast cancer 
Breast cancer female 
Breast cancer in situ 
Breast cancer male 
Breast cancer metastatic 
Breast cancer recurrent 
Breast cancer stage I 
Breast cancer stage II 
Breast cancer stage III 
Breast cancer stage IV 
Breast capsulotomy 
Breast conserving surgery 
Breast neoplasm 
Breast prosthesis implantation 
Breast reconstruction 
Breast sarcoma 
Breast sarcoma metastatic 
Breast sarcoma recurrent 
Breast tumour excision 
Brenner tumour 
Bronchial carcinoma 
Bronchial neoplasm 
Bronchioloalveolar carcinoma 
Burkitt's leukaemia 
Burkitt's lymphoma 
Burkitt's lymphoma recurrent 
Burkitt's lymphoma refractory 
Burkitt's lymphoma stage I 
Burkitt's lymphoma stage II 
Burkitt's lymphoma stage III 
Burkitt's lymphoma stage IV 
Buschke-Lowenstein's tumour 
Cancer hormonal therapy 
Cancer in remission 
Cancer pain 
Cancer staging 
Cancer surgery 
Carbohydrate antigen 125 increased 
Carbohydrate antigen 15-3 increased 
Lung squamous cell carcinoma stage 
III 
Lung squamous cell carcinoma stage 
IV 
Lymph nodes scan abnormal 
Lymphadenectomy 
Lymphangiosarcoma 
Lymphangiosis carcinomatosa 
Lymphatic mapping 
Lymphatic system neoplasm 
Lymphocyte adoptive therapy 
Lymphocytic leukaemia 
Lymphocytic lymphoma 
Lymphoid leukaemia (in remission) 
Lymphoma 
Lymphoma AIDS related 
Lymphoma cutis 
Lymphoma operation 
Lymphoma transformation 
Lymphoplasmacytoid 
lymphoma/immunocytoma 
Lymphoplasmacytoid 
lymphoma/immunocytoma recurrent 
Lymphoplasmacytoid 
lymphoma/immunocytoma refractory 
Lymphoplasmacytoid 
lymphoma/immunocytoma stage I 
Lymphoplasmacytoid 
lymphoma/immunocytoma stage II 
Lymphoplasmacytoid 
lymphoma/immunocytoma stage III 
Lymphoplasmacytoid 
lymphoma/immunocytoma stage IV 
Lymphoproliferative disorder 
Lymphoproliferative disorder in 
remission 
Male reproductive tract neoplasm 
Malignant anorectal neoplasm 
Malignant ascites 
Malignant blue naevus 
Malignant bowel obstruction 
Malignant connective tissue neoplasm 
Malignant cranial nerve neoplasm 
Malignant dysphagia 
Malignant exophthalmos 
Malignant fibrous histiocytoma 
Malignant fibrous histiocytoma 
metastatic 
Malignant fibrous histiocytoma of 
bone 
Malignant fibrous histiocytoma 
recurrent 
Malignant genitourinary tract 
neoplasm 
Malignant giant cell fibrous 
histiocytoma 
Pulmonary tumour thrombotic 
microangiopathy 
Pylorectomy 
Pyoderma gangrenosum 
Queyrat erythroplasia 
Radiation therapy to ear, nose, or throat 
Radical cystectomy 
Radical hysterectomy 
Radical mastectomy 
Radical neck dissection 
Radical prostatectomy 
Radioactive iodine therapy 
Radioembolisation 
Radioisotope scan abnormal 
Radiosensitisation therapy 
Radiotherapy 
Radiotherapy to abdomen 
Radiotherapy to adrenal gland 
Radiotherapy to blood 
Radiotherapy to bone 
Radiotherapy to brain 
Radiotherapy to breast 
Radiotherapy to colon 
Radiotherapy to ear 
Radiotherapy to eye 
Radiotherapy to gallbladder 
Radiotherapy to gastrointestinal tract 
Radiotherapy to head and neck 
Radiotherapy to joint 
Radiotherapy to kidney 
Radiotherapy to liver 
Radiotherapy to lung 
Radiotherapy to lymph nodes 
Radiotherapy to mediastinum 
Radiotherapy to nose 
Radiotherapy to oesophagus 
Radiotherapy to oral cavity 
Radiotherapy to ovary 
Radiotherapy to pancreas 
Radiotherapy to pleura 
Radiotherapy to prostate 
Radiotherapy to rectum 
Radiotherapy to skin 
Radiotherapy to soft tissue 
Radiotherapy to spleen 
Radiotherapy to stomach 
Radiotherapy to throat 
Radiotherapy to thymus 
Radiotherapy to thyroid 
Radiotherapy to urinary bladder 
Radiotherapy to uterus 
Radiotherapy to vagina 
Rectal adenocarcinoma 
Rectal cancer 
Rectal cancer metastatic 
Rectal cancer recurrent 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
44 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Carbohydrate antigen 19-9 increased 
Carbohydrate antigen 27.29 increased 
Carbohydrate antigen 549 increased 
Carcinoembryonic antigen decreased 
Carcinoembryonic antigen increased 
Carcinoid crisis 
Carcinoid heart disease 
Carcinoid syndrome 
Carcinoid tumour 
Carcinoid tumour of the appendix 
Carcinoid tumour of the caecum 
Carcinoid tumour of the duodenum 
Carcinoid tumour of the gastrointestinal 
tract 
Carcinoid tumour of the pancreas 
Carcinoid tumour of the prostate 
Carcinoid tumour of the small bowel 
Carcinoid tumour of the stomach 
Carcinoid tumour pulmonary 
Carcinoma ex-pleomorphic adenoma 
Carcinoma in situ 
Carcinoma in situ of eye 
Carcinoma in situ of penis 
Carcinoma in situ of skin 
Carcinoma in situ of trachea 
Carcinomatous polyarthritis 
Cardiac neoplasm malignant 
Cardiac neoplasm unspecified 
Cardiac teratoma 
Carotid body tumour 
Cartilage neoplasm 
CD20 antigen positive 
CD25 antigen positive 
CD30 expression 
Cell marker increased 
Cell-free and concentrated ascites 
reinfusion therapy 
Cementoplasty 
Central nervous system leukaemia 
Central nervous system lymphoma 
Central nervous system melanoma 
Central nervous system neoplasm 
Central nervous system neuroblastoma 
Cerebellar tumour 
Cerebellopontine angle tumour 
Cervical tumour excision 
Cervix cancer metastatic 
Cervix carcinoma 
Cervix carcinoma recurrent 
Cervix carcinoma stage 0 
Cervix carcinoma stage I 
Cervix carcinoma stage II 
Cervix carcinoma stage III 
Cervix carcinoma stage IV 
Cervix neoplasm 
Chemotherapy 
Malignant glioma 
Malignant haemangiopericytoma 
Malignant haemangiopericytoma 
metastatic 
Malignant haemangiopericytoma 
recurrent 
Malignant histiocytosis 
Malignant hydatidiform mole 
Malignant joint neoplasm 
Malignant lymphoid neoplasm 
Malignant lymphoma unclassifiable 
high grade 
Malignant lymphoma unclassifiable 
low grade 
Malignant mast cell neoplasm 
Malignant mediastinal neoplasm 
Malignant melanoma 
Malignant melanoma in situ 
Malignant melanoma of eyelid 
Malignant melanoma of sites other 
than skin 
Malignant melanoma stage I 
Malignant melanoma stage II 
Malignant melanoma stage III 
Malignant melanoma stage IV 
Malignant meningioma metastatic 
Malignant mesenchymoma 
Malignant mesenchymoma metastatic 
Malignant mesenchymoma recurrent 
Malignant mesenteric neoplasm 
Malignant middle ear neoplasm 
Malignant muscle neoplasm 
Malignant neoplasm of ampulla of 
Vater 
Malignant neoplasm of auricular 
cartilage 
Malignant neoplasm of choroid 
Malignant neoplasm of conjunctiva 
Malignant neoplasm of cornea 
Malignant neoplasm of eye 
Malignant neoplasm of eyelid 
Malignant neoplasm of islets of 
Langerhans 
Malignant neoplasm of lacrimal duct 
Malignant neoplasm of lacrimal gland 
Malignant neoplasm of orbit 
Malignant neoplasm of paraurethral 
glands 
Malignant neoplasm of placenta 
Malignant neoplasm of pleura 
Malignant neoplasm of pleura 
metastatic 
Malignant neoplasm of renal pelvis 
Malignant neoplasm of retina 
Malignant neoplasm of seminal vesicle 
Malignant neoplasm of spermatic cord 
Rectal cancer stage 0 
Rectal cancer stage I 
Rectal cancer stage II 
Rectal cancer stage III 
Rectal cancer stage IV 
Rectal neoplasm 
Rectosigmoid cancer 
Rectosigmoid cancer metastatic 
Rectosigmoid cancer recurrent 
Rectosigmoid cancer stage 0 
Rectosigmoid cancer stage I 
Rectosigmoid cancer stage II 
Rectosigmoid cancer stage III 
Rectosigmoid cancer stage IV 
Recurrent cancer 
Refractory cancer 
Regional chemotherapy 
Renal cancer 
Renal cancer metastatic 
Renal cancer recurrent 
Renal cancer stage I 
Renal cancer stage II 
Renal cancer stage III 
Renal cancer stage IV 
Renal cell carcinoma 
Renal cell carcinoma recurrent 
Renal cell carcinoma stage I 
Renal cell carcinoma stage II 
Renal cell carcinoma stage III 
Renal cell carcinoma stage IV 
Renal neoplasm 
Renal scan abnormal 
Renal tumour excision 
Respiratory tract carcinoma in situ 
Respiratory tract neoplasm 
Retinal melanoma 
Retinal neoplasm 
Retinal tumour excision 
Retinoblastoma 
Retro-orbital neoplasm 
Retroperitoneal cancer 
Retroperitoneal neoplasm 
Retroperitoneal neoplasm metastatic 
Retro-pubic prostatectomy 
Rhabdoid tumour 
Rhabdoid tumour of the kidney 
Rhabdomyosarcoma 
Rhabdomyosarcoma recurrent 
Richter's syndrome 
Round cell liposarcoma 
Salivary bypass tube insertion 
Salivary gland cancer 
Salivary gland cancer recurrent 
Salivary gland cancer stage 0 
Salivary gland cancer stage I 
Salivary gland cancer stage II 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
45 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Chemotherapy cardiotoxicity attenuation 
Chemotherapy cytokine prophylaxis 
Chemotherapy extravasation 
management 
Chemotherapy multiple agents systemic 
Chemotherapy neurotoxicity attenuation 
Chemotherapy sensitivity and resistance 
assay 
Chemotherapy single agent systemic 
Chemotherapy urothelial toxicity 
attenuation 
Chest wall tumour 
Chloroma 
Chloroma (in remission) 
Cholangiocarcinoma 
Cholangiosarcoma 
Chondrosarcoma 
Chondrosarcoma metastatic 
Chondrosarcoma recurrent 
Chordoma 
Choriocarcinoma 
Choroid melanoma 
Choroid neoplasm 
Choroid plexus carcinoma 
Choroid tumour excision 
Chronic eosinophilic leukaemia 
Chronic leukaemia 
Chronic leukaemia in remission 
Chronic lymphocytic leukaemia 
Chronic lymphocytic leukaemia (in 
remission) 
Chronic lymphocytic leukaemia 
recurrent 
Chronic lymphocytic leukaemia 
refractory 
Chronic lymphocytic leukaemia stage 0 
Chronic lymphocytic leukaemia stage 1 
Chronic lymphocytic leukaemia stage 2 
Chronic lymphocytic leukaemia stage 3 
Chronic lymphocytic leukaemia stage 4 
Chronic lymphocytic leukaemia 
transformation 
Chronic myeloid leukaemia 
Chronic myeloid leukaemia (in 
remission) 
Chronic myeloid leukaemia recurrent 
Chronic myeloid leukaemia 
transformation 
Chronic myelomonocytic leukaemia 
Chronic myelomonocytic leukaemia (in 
remission) 
C-kit gene negative 
Clear cell carcinoma of cervix 
Clear cell endometrial carcinoma 
Clear cell renal cell carcinoma 
Clear cell sarcoma of soft tissue 
Malignant neoplasm of spinal cord 
Malignant neoplasm of thorax 
Malignant neoplasm of thymus 
Malignant neoplasm of unknown 
primary site 
Malignant neoplasm of uterine adnexa 
Malignant neoplasm papilla of Vater 
Malignant neoplasm progression 
Malignant nervous system neoplasm 
Malignant nipple neoplasm 
Malignant nipple neoplasm female 
Malignant nipple neoplasm male 
Malignant oligodendroglioma 
Malignant ovarian cyst 
Malignant palate neoplasm 
Malignant pericardial neoplasm 
Malignant peritoneal neoplasm 
Malignant pituitary tumour 
Malignant pleural effusion 
Malignant polyp 
Malignant psoas syndrome 
Malignant respiratory tract neoplasm 
Malignant splenic neoplasm 
Malignant sweat gland neoplasm 
Malignant transformation 
Malignant urinary tract neoplasm 
Mantle cell lymphoma 
Mantle cell lymphoma recurrent 
Mantle cell lymphoma refractory 
Mantle cell lymphoma stage I 
Mantle cell lymphoma stage II 
Mantle cell lymphoma stage III 
Mantle cell lymphoma stage IV 
Marginal zone lymphoma 
Marginal zone lymphoma recurrent 
Marginal zone lymphoma refractory 
Marginal zone lymphoma stage I 
Marginal zone lymphoma stage II 
Marginal zone lymphoma stage III 
Marginal zone lymphoma stage IV 
Marjolin's ulcer 
Mastectomy 
Mastocytic leukaemia 
Mastoidectomy 
Maternal cancer in pregnancy 
Mature B-cell type acute leukaemia 
Maxillofacial sinus neoplasm 
Mediastinal biopsy abnormal 
Mediastinum neoplasm 
Medullary carcinoma of breast 
Medullary thyroid cancer 
Medulloblastoma 
Medulloblastoma recurrent 
Meigs' syndrome 
Melanoma recurrent 
Meningeal neoplasm 
Salivary gland cancer stage III 
Salivary gland cancer stage IV 
Salivary gland neoplasm 
Salivary gland resection 
Salivary gland scan abnormal 
Salpingectomy 
Salpingo-oophorectomy 
Salpingo-oophorectomy bilateral 
Salpingo-oophorectomy unilateral 
Sarcoma 
Sarcoma excision 
Sarcoma metastatic 
Sarcoma of skin 
Sarcoma uterus 
Sarcomatoid mesothelioma 
Sarcomatosis 
Scan abdomen abnormal 
Scan abnormal 
Scan adrenal gland abnormal 
Scan bone marrow abnormal 
Scan gallium abnormal 
Scan myocardial perfusion abnormal 
Scan with contrast abnormal 
Scrotal cancer 
Sebaceous carcinoma 
Second primary malignancy 
Secondary cerebellar degeneration 
Secretory adenoma of pituitary 
Seminoma 
Serous cystadenocarcinoma of 
pancreas 
Serous cystadenocarcinoma ovary 
Sertoli cell testicular tumour 
Sigmoidectomy 
Signet-ring cell carcinoma 
Simple mastectomy 
Sinus cancer metastatic 
Skin angiosarcoma 
Skin cancer 
Skin cancer metastatic 
Skin cryotherapy 
Skin neoplasm bleeding 
Skin neoplasm bleeding 
Skin neoplasm excision 
Skin squamous cell carcinoma 
metastatic 
Small cell carcinoma 
Small cell carcinoma of the cervix 
Small cell lung cancer 
Small cell lung cancer extensive stage 
Small cell lung cancer limited stage 
Small cell lung cancer metastatic 
Small cell lung cancer recurrent 
Small intestinal resection 
Small intestine adenocarcinoma 
Small intestine carcinoma 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
46 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Clear cell sarcoma of the kidney 
Clonal evolution 
CNS germinoma 
Colectomy 
Colectomy total 
Colon cancer 
Colon cancer metastatic 
Colon cancer recurrent 
Colon cancer stage 0 
Colon cancer stage I 
Colon cancer stage II 
Colon cancer stage III 
Colon cancer stage IV 
Colon neoplasm 
Colony stimulating factor therapy 
Colorectal adenocarcinoma 
Colorectal cancer 
Colorectal cancer metastatic 
Colorectal cancer recurrent 
Colorectal cancer stage I 
Colorectal cancer stage II 
Colorectal cancer stage III 
Colorectal cancer stage IV 
Colorectal carcinoma stage 0 
Composite lymphoma 
Computerised tomogram breast 
abnormal 
Computerised tomogram liver abnormal 
Congenital fibrosarcoma 
Congenital malignant neoplasm 
Congenital neoplasm 
Congenital retinoblastoma 
Congenital teratoma 
Conjunctival melanoma 
Conjunctival neoplasm 
Conjunctival primary acquired 
melanosis 
Connective tissue neoplasm 
Cutaneous lymphoma 
Cyclotron therapy 
Cystadenocarcinoma ovary 
Cystoprostatectomy 
Cytokeratin 18 increased 
Dedifferentiated liposarcoma 
Dermatofibrosarcoma protuberans 
Dermatofibrosarcoma protuberans 
metastatic 
Desmoplastic melanoma 
Desmoplastic mesothelioma 
Desmoplastic small round cell tumour 
Diaphragm neoplasm 
Diffuse large B-cell lymphoma 
Diffuse large B-cell lymphoma recurrent 
Diffuse large B-cell lymphoma 
refractory 
Diffuse large B-cell lymphoma stage I 
Meningioma malignant 
Mesenteric neoplasm 
Mesothelioma 
Mesothelioma malignant 
Mesothelioma malignant recurrent 
Metaplastic breast carcinoma 
Metastases to abdominal cavity 
Metastases to abdominal wall 
Metastases to adrenals 
Metastases to biliary tract 
Metastases to bladder 
Metastases to bone 
Metastases to bone marrow 
Metastases to breast 
Metastases to central nervous system 
Metastases to chest wall 
Metastases to diaphragm 
Metastases to Eustachian tube 
Metastases to eye 
Metastases to fallopian tube 
Metastases to gallbladder 
Metastases to gastrointestinal tract 
Metastases to heart 
Metastases to kidney 
Metastases to larynx 
Metastases to liver 
Metastases to lung 
Metastases to lymph nodes 
Metastases to meninges 
Metastases to mouth 
Metastases to muscle 
Metastases to nasal sinuses 
Metastases to neck 
Metastases to nervous system 
Metastases to oesophagus 
Metastases to ovary 
Metastases to pancreas 
Metastases to pelvis 
Metastases to penis 
Metastases to perineum 
Metastases to peripheral nervous 
system 
Metastases to peripheral vascular 
system 
Metastases to peritoneum 
Metastases to pharynx 
Metastases to pituitary gland 
Metastases to placenta 
Metastases to pleura 
Metastases to prostate 
Metastases to rectum 
Metastases to reproductive organ 
Metastases to retroperitoneum 
Metastases to salivary gland 
Metastases to skin 
Metastases to soft tissue 
Small intestine carcinoma metastatic 
Small intestine carcinoma recurrent 
Small intestine carcinoma stage 0 
Small intestine carcinoma stage I 
Small intestine carcinoma stage II 
Small intestine carcinoma stage III 
Small intestine carcinoma stage IV 
Small intestine leiomyosarcoma 
Smooth muscle cell neoplasm 
Soft tissue neoplasm 
Soft tissue sarcoma 
Solid pseudopapillary tumour of the 
pancreas 
Somatostatin receptor scan abnormal 
Somatostatinoma 
Spermatocytic seminoma 
Spinal cord neoplasm 
Spinal meningioma malignant 
Spindle cell sarcoma 
Spleen scan abnormal 
Splenectomy 
Splenic marginal zone lymphoma 
Splenic marginal zone lymphoma 
recurrent 
Splenic marginal zone lymphoma 
refractory 
Splenic marginal zone lymphoma stage 
I 
Splenic marginal zone lymphoma stage 
II 
Splenic marginal zone lymphoma stage 
III 
Splenic marginal zone lymphoma stage 
IV 
Splenic neoplasm malignancy 
unspecified 
Squamous cell breast carcinoma 
Squamous cell carcinoma 
Squamous cell carcinoma of head and 
neck 
Squamous cell carcinoma of lung 
Squamous cell carcinoma of pharynx 
Squamous cell carcinoma of skin 
Squamous cell carcinoma of the cervix 
Squamous cell carcinoma of the 
hypopharynx 
Squamous cell carcinoma of the oral 
cavity 
Squamous cell carcinoma of the tongue 
Squamous cell carcinoma of the vagina 
Squamous cell carcinoma of the vulva 
Squamous endometrial carcinoma 
Stauffer's syndrome 
Stem cell transplant 
Stewart-Treves syndrome 
Stomach scan abnormal 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
47 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Diffuse large B-cell lymphoma stage II 
Diffuse large B-cell lymphoma stage III 
Diffuse large B-cell lymphoma stage IV 
Diffuse uveal melanocytic proliferation 
Disseminated large cell lymphoma 
Double hit lymphoma 
Ductal adenocarcinoma of pancreas 
Duodenal neoplasm 
Duodenectomy 
Dysplastic naevus syndrome 
Ear neoplasm 
Ear neoplasm malignant 
Eastern Cooperative Oncology Group 
performance status improved 
Eastern Cooperative Oncology Group 
performance status worsened 
Eccrine carcinoma 
Ectopic ACTH syndrome 
Ectopic aldosterone secretion 
Ectopic antidiuretic hormone secretion 
Ectopic calcitonin production 
Ectopic chorionic gonadotrophin 
secretion 
Ectopic growth hormone secretion 
Ectopic hormone secretion 
Ectopic parathyroid hormone production 
Ectopic prolactin secretion 
Ectopic renin secretion 
Electron radiation therapy 
Electron radiation therapy to bladder 
Electron radiation therapy to blood 
Electron radiation therapy to bone 
Electron radiation therapy to brain 
Electron radiation therapy to breast 
Electron radiation therapy to colon 
Electron radiation therapy to ear, nose, 
or throat 
Electron radiation therapy to liver 
Electron radiation therapy to lung 
Electron radiation therapy to pancreas 
Electron radiation therapy to prostate 
Electron radiation therapy to skin 
Electron radiation therapy to soft tissue 
Electron radiation therapy to uterus 
Elephantiasis nostras verrucosa 
Embryonal rhabdomyosarcoma 
Endocrine neoplasm 
Endocrine neoplasm malignant 
Endometrial adenocarcinoma 
Endometrial cancer 
Endometrial cancer metastatic 
Endometrial cancer recurrent 
Endometrial cancer stage 0 
Endometrial cancer stage I 
Endometrial cancer stage II 
Endometrial cancer stage III 
Metastases to spinal cord 
Metastases to spine 
Metastases to spleen 
Metastases to stomach 
Metastases to testicle 
Metastases to the mediastinum 
Metastases to the respiratory system 
Metastases to thorax 
Metastases to thyroid 
Metastases to tonsils 
Metastases to trachea 
Metastases to urinary tract 
Metastases to uterus 
Metastases to vagina 
Metastasis 
Metastatic bronchial carcinoma 
Metastatic carcinoid tumour 
Metastatic carcinoma of the bladder 
Metastatic choriocarcinoma 
Metastatic gastric cancer 
Metastatic glioma 
Metastatic glucagonoma 
Metastatic lymphoma 
Metastatic malignant melanoma 
Metastatic neoplasm 
Metastatic nervous system neoplasm 
Metastatic ocular melanoma 
Metastatic pulmonary embolism 
Metastatic renal cell carcinoma 
Metastatic salivary gland cancer 
Metastatic squamous cell carcinoma 
Metastatic uterine cancer 
Microsatellite instability cancer 
Minimal residual disease 
Mismatch repair cancer syndrome 
Mixed adenoneuroendocrine 
carcinoma 
Mixed hepatocellular 
cholangiocarcinoma 
Mixed-type liposarcoma 
Modified radical mastectomy 
Monoclonal gammopathy 
Monocytic leukaemia in remission 
Mucinous adenocarcinoma of 
appendix 
Mucinous breast carcinoma 
Mucinous cystadenocarcinoma of 
pancreas 
Mucinous cystadenocarcinoma ovary 
Mucinous endometrial carcinoma 
Mucoepidermoid carcinoma 
Mucoepidermoid carcinoma of salivary 
gland 
Mueller's mixed tumour 
Multiple gated acquisition scan 
abnormal 
Superficial spreading melanoma stage I 
Superficial spreading melanoma stage 
II 
Superficial spreading melanoma stage 
III 
Superficial spreading melanoma stage 
IV 
Superficial spreading melanoma stage 
unspecified 
Superior vena cava occlusion 
Superior vena cava syndrome 
Suprapubic prostatectomy 
Synovial sarcoma 
Synovial sarcoma metastatic 
Synovial sarcoma recurrent 
Targeted cancer therapy 
T-cell chronic lymphocytic leukaemia 
T-cell lymphoma 
T-cell lymphoma recurrent 
T-cell lymphoma refractory 
T-cell lymphoma stage I 
T-cell lymphoma stage II 
T-cell lymphoma stage III 
T-cell lymphoma stage IV 
T-cell prolymphocytic leukaemia 
T-cell type acute leukaemia 
T-cell unclassifiable lymphoma high 
grade 
T-cell unclassifiable lymphoma low 
grade 
Tendon neoplasm 
Teratoma 
Testicular cancer metastatic 
Testicular choriocarcinoma 
Testicular choriocarcinoma recurrent 
Testicular choriocarcinoma stage I 
Testicular choriocarcinoma stage II 
Testicular choriocarcinoma stage III 
Testicular embryonal carcinoma 
Testicular embryonal carcinoma stage I 
Testicular embryonal carcinoma stage 
II 
Testicular embryonal carcinoma stage 
III 
Testicular germ cell cancer 
Testicular germ cell cancer metastatic 
Testicular germ cell tumour 
Testicular germ cell tumour mixed 
Testicular germ cell tumour mixed 
stage I 
Testicular germ cell tumour mixed 
stage II 
Testicular germ cell tumour mixed 
stage III 
Testicular leiomyosarcoma 
Testicular malignant teratoma 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
48 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Endometrial cancer stage IV 
Endometrial neoplasm 
Endometrial sarcoma 
Endometrial sarcoma metastatic 
Endometrial sarcoma recurrent 
Endometrial stromal sarcoma 
Endotheliomatosis 
Enteropathy-associated T-cell 
lymphoma 
Eosinophilic leukaemia 
Ependymoma 
Ependymoma malignant 
Epididymal cancer 
Epididymal neoplasm 
Epiglottic carcinoma 
Epiglottidectomy 
Epithelioid mesothelioma 
Epithelioid sarcoma 
Epithelioid sarcoma metastatic 
Epithelioid sarcoma recurrent 
Epstein Barr virus positive 
mucocutaneous ulcer 
Epstein-Barr virus associated lymphoma 
Epstein-Barr virus associated 
lymphoproliferative disorder 
Erythraemic myelosis (in remission) 
Erythroleukaemia 
Ewing's sarcoma 
Ewing's sarcoma metastatic 
Ewing's sarcoma recurrent 
Ex vivo gene therapy 
Exploratory operation 
Extended radical mastectomy 
Extradural neoplasm 
Extragonadal primary embryonal 
carcinoma 
Extragonadal primary germ cell tumour 
Extragonadal primary germ cell tumour 
mixed 
Extragonadal primary germ cell tumour 
mixed stage I 
Extragonadal primary germ cell tumour 
mixed stage II 
Extragonadal primary germ cell tumour 
mixed stage III 
Extragonadal primary malignant 
teratoma 
Extragonadal primary non-seminoma 
Extragonadal primary non-seminoma 
stage I 
Extragonadal primary non-seminoma 
stage II 
Extragonadal primary non-seminoma 
stage III 
Extragonadal primary non-seminoma 
stage IV 
Muscle neoplasm 
Musculoskeletal cancer 
Myasthenic syndrome 
Mycosis fungoides 
Mycosis fungoides recurrent 
Mycosis fungoides refractory 
Mycosis fungoides stage I 
Mycosis fungoides stage II 
Mycosis fungoides stage III 
Mycosis fungoides stage IV 
Myectomy 
Myeloblastoma 
Myeloid leukaemia 
Myeloid leukaemia in remission 
Myeloid metaplasia 
Myeloma cast nephropathy 
Myeloproliferative neoplasm 
Myxofibrosarcoma 
Myxoid liposarcoma 
Naevoid melanoma 
Nasal cavity cancer 
Nasal neoplasm 
Nasal sinus cancer 
Nasopharyngeal cancer 
Nasopharyngeal cancer metastatic 
Nasopharyngeal cancer recurrent 
Nasopharyngeal cancer stage 0 
Nasopharyngeal cancer stage I 
Nasopharyngeal cancer stage II 
Nasopharyngeal cancer stage III 
Nasopharyngeal cancer stage IV 
Natural killer-cell leukaemia 
Natural killer-cell lymphoblastic 
lymphoma 
Necrolytic migratory erythema 
Needle biopsy site unspecified 
abnormal 
Neoadjuvant therapy 
Neobladder surgery 
Neonatal leukaemia 
Neonatal neuroblastoma 
Neoplasm 
Neoplasm malignant 
Neoplasm of appendix 
Neoplasm of cornea unspecified 
malignancy 
Neoplasm of orbit 
Neoplasm of thymus 
Neoplasm progression 
Neoplasm prostate 
Neoplasm recurrence 
Neoplasm skin 
Neoplasm swelling 
Nephrectomy 
Nephroblastoma 
Nephroureterectomy 
Testicular malignant teratoma stage I 
Testicular malignant teratoma stage II 
Testicular malignant teratoma stage III 
Testicular neoplasm 
Testicular scan abnormal 
Testicular seminoma (pure) 
Testicular seminoma (pure) stage I 
Testicular seminoma (pure) stage II 
Testicular seminoma (pure) stage III 
Testicular yolk sac tumour 
Testicular yolk sac tumour stage I 
Testicular yolk sac tumour stage II 
Testicular yolk sac tumour stage III 
Testis cancer 
Testis cancer recurrent 
Throat cancer 
Thymic cancer metastatic 
Thymoma 
Thymoma malignant 
Thymoma malignant recurrent 
Thyroid B-cell lymphoma 
Thyroid cancer 
Thyroid cancer metastatic 
Thyroid cancer recurrent 
Thyroid cancer stage 0 
Thyroid cancer stage I 
Thyroid cancer stage II 
Thyroid cancer stage III 
Thyroid cancer stage IV 
Thyroid electron radiation therapy 
Thyroid gland scan abnormal 
Thyroid neoplasm 
Thyroid stimulating hormone-
producing pituitary tumour 
Thyroidectomy 
Tissue polypeptide antigen increased 
Tongue cancer metastatic 
Tongue cancer recurrent 
Tongue carcinoma stage 0 
Tongue carcinoma stage I 
Tongue carcinoma stage II 
Tongue carcinoma stage III 
Tongue carcinoma stage IV 
Tongue neoplasm 
Tongue neoplasm malignant stage 
unspecified 
Tonsil cancer 
Tonsil cancer metastatic 
Tonsillar neoplasm 
Total adrenalectomy 
Tracheal cancer 
Tracheal neoplasm 
Tracheal resection 
Transcatheter arterial 
chemoembolisation 
Transcranial electrical motor evoked 
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Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
49 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Extragonadal primary seminoma (pure) 
Extragonadal primary seminoma (pure) 
stage I 
Extragonadal primary seminoma (pure) 
stage II 
Extragonadal primary seminoma (pure) 
stage III 
Extragonadal primary seminoma (pure) 
stage IV 
Extramammary Paget's disease 
Extranodal marginal zone B-cell 
lymphoma (MALT type) 
Extranodal marginal zone B-cell 
lymphoma (MALT type) recurrent 
Extranodal marginal zone B-cell 
lymphoma (MALT type) refractory 
Extranodal marginal zone B-cell 
lymphoma (MALT type) stage I 
Extranodal marginal zone B-cell 
lymphoma (MALT type) stage II 
Extranodal marginal zone B-cell 
lymphoma (MALT type) stage III 
Extranodal marginal zone B-cell 
lymphoma (MALT type) stage IV 
Extraocular retinoblastoma 
Extra-osseous Ewing's sarcoma 
Extra-osseous Ewing's sarcoma 
metastatic 
Extra-osseous Ewing's sarcoma 
recurrent 
Extraskeletal chondrosarcoma metastatic 
Extraskeletal chondrosarcoma recurrent 
Extraskeletal myxoid chondrosarcoma 
Extraskeletal osteosarcoma 
Extraskeletal osteosarcoma metastatic 
Extraskeletal osteosarcoma recurrent 
Eyelid tumour 
Fallopian tube cancer 
Fallopian tube cancer metastatic 
Fallopian tube cancer stage I 
Fallopian tube cancer stage II 
Fallopian tube cancer stage III 
Fallopian tube cancer stage IV 
Fallopian tube neoplasm 
Familial medullary thyroid cancer 
Female reproductive neoplasm 
Female reproductive tract carcinoma in 
situ 
Fibrosarcoma 
Fibrosarcoma excision 
Fibrosarcoma metastatic 
Fiducial marker placement 
Fms-like tyrosine kinase 3 positive 
Follicle centre lymphoma diffuse small 
cell lymphoma 
Follicle centre lymphoma diffuse small 
Nervous system neoplasm 
Nervous system neoplasm surgery 
Neuroblastoma 
Neuroblastoma recurrent 
Neuroectodermal neoplasm 
Neuroendocrine breast tumour 
Neuroendocrine carcinoma 
Neuroendocrine carcinoma metastatic 
Neuroendocrine carcinoma of the 
bladder 
Neuroendocrine carcinoma of the skin 
Neuroendocrine tumour 
Neuroendocrine tumour of the lung 
Neuroendocrine tumour of the lung 
metastatic 
Neuroendoscopy 
Neurofibrosarcoma 
Neurofibrosarcoma metastatic 
Neurofibrosarcoma recurrent 
Neuromyotonia 
Neurotensinoma 
Nipple neoplasm 
Nipple resection 
NMP22 test abnormal 
Nodal marginal zone B-cell lymphoma 
Nodal marginal zone B-cell lymphoma 
recurrent 
Nodal marginal zone B-cell lymphoma 
refractory 
Nodal marginal zone B-cell lymphoma 
stage I 
Nodal marginal zone B-cell lymphoma 
stage II 
Nodal marginal zone B-cell lymphoma 
stage III 
Nodal marginal zone B-cell lymphoma 
stage IV 
Nodular lymphocyte predominant 
Hodgkin lymphoma 
Nodular melanoma 
Nongerminomatous germ cell tumour 
of the CNS 
Non-Hodgkin's lymphoma 
Non-Hodgkin's lymphoma metastatic 
Non-Hodgkin's lymphoma recurrent 
Non-Hodgkin's lymphoma refractory 
Non-Hodgkin's lymphoma stage I 
Non-Hodgkin's lymphoma stage II 
Non-Hodgkin's lymphoma stage III 
Non-Hodgkin's lymphoma stage IV 
Non-Hodgkin's lymphoma transformed 
recurrent 
Non-Hodgkin's lymphoma unspecified 
histology aggressive 
Non-Hodgkin's lymphoma unspecified 
histology aggressive recurrent 
potential monitoring abnormal 
Transformation to acute myeloid 
leukaemia 
Transitional cell cancer of renal pelvis 
and ureter metastatic 
Transitional cell cancer of the renal 
pelvis and ureter 
Transitional cell cancer of the renal 
pelvis and ureter localised 
Transitional cell cancer of the renal 
pelvis and ureter recurrent 
Transitional cell cancer of the renal 
pelvis and ureter regional 
Transitional cell carcinoma 
Transitional cell carcinoma metastatic 
Transitional cell carcinoma recurrent 
Transitional cell carcinoma urethra 
Transurethral bladder resection 
Transurethral prostatectomy 
Triple hit lymphoma 
Triple negative breast cancer 
Trousseau's syndrome 
Tubular breast carcinoma 
Tumour associated fever 
Tumour budding 
Tumour cavitation 
Tumour cell mobilisation 
Tumour compression 
Tumour embolism 
Tumour excision 
Tumour exudation 
Tumour fistulisation 
Tumour flare 
Tumour haemorrhage 
Tumour inflammation 
Tumour invasion 
Tumour lysis syndrome 
Tumour marker abnormal 
Tumour marker decreased 
Tumour marker increased 
Tumour necrosis 
Tumour obstruction 
Tumour of ampulla of Vater 
Tumour pain 
Tumour perforation 
Tumour pruritus 
Tumour pseudoprogression 
Tumour rupture 
Tumour thrombosis 
Tumour treating fields therapy 
Tumour ulceration 
Tumour vaccine therapy 
Ultrasound pancreas abnormal 
Ultrasound scan abnormal 
Ultrasound scan vagina abnormal 
Undifferentiated carcinoma of colon 
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Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
50 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
cell lymphoma recurrent 
Follicle centre lymphoma diffuse small 
cell lymphoma refractory 
Follicle centre lymphoma diffuse small 
cell lymphoma stage I 
Follicle centre lymphoma diffuse small 
cell lymphoma stage II 
Follicle centre lymphoma diffuse small 
cell lymphoma stage III 
Follicle centre lymphoma diffuse small 
cell lymphoma stage IV 
Follicle centre lymphoma, follicular 
grade I, II, III 
Follicle centre lymphoma, follicular 
grade I, II, III recurrent 
Follicle centre lymphoma, follicular 
grade I, II, III refractory 
Follicle centre lymphoma, follicular 
grade I, II, III stage I 
Follicle centre lymphoma, follicular 
grade I, II, III stage II 
Follicle centre lymphoma, follicular 
grade I, II, III stage III 
Follicle centre lymphoma, follicular 
grade I, II, III stage IV 
Follicular dendritic cell sarcoma 
Follicular thyroid cancer 
Free prostate-specific antigen increased 
Free prostate-specific antigen positive 
Fungating wound 
Gallbladder adenocarcinoma 
Gallbladder adenosquamous carcinoma 
Gallbladder cancer 
Gallbladder cancer metastatic 
Gallbladder cancer recurrent 
Gallbladder cancer stage 0 
Gallbladder cancer stage I 
Gallbladder cancer stage II 
Gallbladder cancer stage III 
Gallbladder cancer stage IV 
Gallbladder neoplasm 
Gallbladder squamous cell carcinoma 
Gamma interferon therapy 
Gamma radiation therapy 
Gamma radiation therapy to bladder 
Gamma radiation therapy to blood 
Gamma radiation therapy to bone 
Gamma radiation therapy to brain 
Gamma radiation therapy to breast 
Gamma radiation therapy to colon 
Gamma radiation therapy to ear, nose, or 
throat 
Gamma radiation therapy to liver 
Gamma radiation therapy to lung 
Gamma radiation therapy to pancreas 
Gamma radiation therapy to pleura 
Non-Hodgkin's lymphoma unspecified 
histology aggressive refractory 
Non-Hodgkin's lymphoma unspecified 
histology aggressive stage I 
Non-Hodgkin's lymphoma unspecified 
histology aggressive stage II 
Non-Hodgkin's lymphoma unspecified 
histology aggressive stage III 
Non-Hodgkin's lymphoma unspecified 
histology aggressive stage IV 
Non-Hodgkin's lymphoma unspecified 
histology indolent 
Non-Hodgkin's lymphoma unspecified 
histology indolent stage I 
Non-Hodgkin's lymphoma unspecified 
histology indolent stage II 
Non-Hodgkin's lymphoma unspecified 
histology indolent stage III 
Non-Hodgkin's lymphoma unspecified 
histology indolent stage IV 
Nonkeratinising carcinoma of 
nasopharynx 
Non-renal cell carcinoma of kidney 
Non-secretory adenoma of pituitary 
Non-small cell lung cancer 
Non-small cell lung cancer metastatic 
Non-small cell lung cancer recurrent 
Non-small cell lung cancer stage 0 
Non-small cell lung cancer stage I 
Non-small cell lung cancer stage II 
Non-small cell lung cancer stage III 
Non-small cell lung cancer stage IIIA 
Non-small cell lung cancer stage IIIB 
Non-small cell lung cancer stage IV 
NUT midline carcinoma 
Ocular cancer metastatic 
Ocular haemangiopericytoma 
Ocular lymphoma 
Ocular neoplasm 
Oesophageal adenocarcinoma 
Oesophageal adenocarcinoma 
recurrent 
Oesophageal adenocarcinoma stage 0 
Oesophageal adenocarcinoma stage I 
Oesophageal adenocarcinoma stage II 
Oesophageal adenocarcinoma stage III 
Oesophageal adenocarcinoma stage IV 
Oesophageal cancer metastatic 
Oesophageal carcinoma 
Oesophageal carcinoma recurrent 
Oesophageal carcinoma stage 0 
Oesophageal neoplasm 
Oesophageal prosthesis insertion 
Oesophageal squamous cell carcinoma 
Oesophageal squamous cell carcinoma 
metastatic 
Undifferentiated nasopharyngeal 
carcinoma 
Undifferentiated sarcoma 
Ureteral neoplasm 
Ureteric cancer 
Ureteric cancer local 
Ureteric cancer metastatic 
Ureteric cancer recurrent 
Ureteric cancer regional 
Urethral cancer 
Urethral cancer metastatic 
Urethral cancer recurrent 
Urethral melanoma metastatic 
Urethral neoplasm 
Urethrectomy 
Urinary bladder sarcoma 
Urinary cystectomy 
Urinary tract carcinoma in situ 
Urinary tract neoplasm 
Uterine cancer 
Uterine carcinoma in situ 
Uterine leiomyosarcoma 
Uterine neoplasm 
Uterine tumour excision 
Uvulectomy 
Vaginal adenocarcinoma 
Vaginal cancer 
Vaginal cancer metastatic 
Vaginal cancer recurrent 
Vaginal cancer stage 0 
Vaginal cancer stage I 
Vaginal cancer stage II 
Vaginal cancer stage III 
Vaginal cancer stage IVA 
Vaginal cancer stage IVB 
Vaginal neoplasm 
Vaginectomy 
Vascular neoplasm 
Vipoma 
Vocal cord neoplasm 
Vocal cordectomy 
Vulval cancer 
Vulval cancer metastatic 
Vulval cancer recurrent 
Vulval cancer stage 0 
Vulval cancer stage I 
Vulval cancer stage II 
Vulval cancer stage III 
Vulval cancer stage IV 
Vulval neoplasm 
Vulvar adenocarcinoma 
Vulvectomy 
Waldenstrom's macroglobulinaemia 
Waldenstrom's macroglobulinaemia 
recurrent 
Waldenstrom's macroglobulinaemia 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)


Statistical Analysis Plan  
Study Code C2661002 
Edition Number 2.7  
Date 22 March 2018 
51 
SMQ PTs taken from Malignancies (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Gamma radiation therapy to prostate 
Gamma radiation therapy to skin 
Gamma radiation therapy to soft tissue 
Gamma radiation therapy to thyroid 
Gamma radiation therapy to uterus 
Gammopathy 
Ganglioglioma 
Ganglioneuroblastoma 
Garcin syndrome 
Gastrectomy 
Gastric cancer 
Gastric cancer recurrent 
Gastric cancer stage 0 
Gastric cancer stage I 
Gastric cancer stage II 
Gastric cancer stage III 
Gastric cancer stage IV 
Gastric neoplasm 
Gastric sarcoma 
Gastric stent insertion 
Gastrinoma 
Gastrinoma malignant 
Gastroenteropancreatic neuroendocrine 
tumour disease 
Gastrointestinal cancer metastatic 
Gastrointestinal carcinoma 
Gastrointestinal carcinoma in situ 
Gastrointestinal lymphoma 
Gastrointestinal melanoma 
Gastrointestinal neoplasm 
Gastrointestinal stromal cancer 
Gastrointestinal stromal tumour 
Gastrointestinal submucosal tumour 
Gastrooesophageal cancer 
Genital cancer male 
Genital cancer male in situ 
Genital neoplasm malignant female 
Genitourinary melanoma 
Genitourinary tract neoplasm 
Germ cell cancer 
Germ cell cancer metastatic 
Germ cell neoplasm 
Oesophageal squamous cell carcinoma 
recurrent 
Oesophageal squamous cell carcinoma 
stage 0 
Oesophageal squamous cell carcinoma 
stage I 
Oesophageal squamous cell carcinoma 
stage II 
Oesophageal squamous cell carcinoma 
stage III 
Oesophageal squamous cell carcinoma 
stage IV 
Oesophagectomy 
Oesophagogastrectomy 
Oestrogen receptor assay positive 
Oestrogen receptor positive breast 
cancer 
Oligoastrocytoma 
Oligodendroglioma 
Omentectomy 
Oncogenic osteomalacia 
Oncologic complication 
Oophorectomy 
Oophorectomy bilateral 
Optic glioma 
Optic nerve neoplasm 
Oral cavity cancer metastatic 
Oral cavity neoplasm surgery 
Oral neoplasm 
Orchidectomy 
Orchidotomy 
Oropharyngeal cancer 
Oropharyngeal cancer recurrent 
Oropharyngeal cancer stage 0 
Oropharyngeal cancer stage I 
Oropharyngeal cancer stage II 
Oropharyngeal cancer stage III 
Oropharyngeal cancer stage IV 
Oropharyngeal lymphoepithelioma 
Oropharyngeal neoplasm 
Oropharyngeal squamous cell 
carcinoma 
refractory 
Waldenstrom's macroglobulinaemia 
stage I 
Waldenstrom's macroglobulinaemia 
stage II 
Waldenstrom's macroglobulinaemia 
stage III 
Waldenstrom's macroglobulinaemia 
stage IV 
X-ray therapy to bladder 
X-ray therapy to blood 
X-ray therapy to bone 
X-ray therapy to brain 
X-ray therapy to breast 
X-ray therapy to colon 
X-ray therapy to ear, nose, or throat 
X-ray therapy to joint 
X-ray therapy to liver 
X-ray therapy to lung 
X-ray therapy to pancreas 
X-ray therapy to pleura 
X-ray therapy to prostate 
X-ray therapy to skin 
X-ray therapy to soft tissue 
X-ray therapy to thyroid 
X-ray therapy to uterus 
X-ray treatment 
Yolk sac tumour site unspecified 
 
SMQ PTs taken from Pseudomembranous colitis (SMQ) narrow 
MedDRA v20.1 Preferred Term (PT) 
Clostridial infection 
Clostridial sepsis 
Clostridium bacteraemia 
Clostridium colitis 
Clostridium difficile colitis 
Clostridium difficile infection 
Clostridium test positive 
Gastroenteritis clostridial 
Pseudomembranous colitis 
 
090177e18e706e22\0.1\Draft\Versioned On:28-May-2018 06:16 (GMT)