Conditions: Hematogenously Acquired Staphylococcus Aureus Osteomyelitis Bone Infection Osteomyelitis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
This research study is looking at an antibiotic medicine, Ceftaroline Fosamil (Ceftaroline), which fights infections like the one the subject has. Ceftaroline is effective against S.aureus germs including those that are called Methicillin Resistant Staphylococcus aureus (MRSA.)

Ceftaroline has been approved by the U.S. Food and Drug Administration (FDA) for use in adults and children with Community-Acquired Bacterial Pneumonia \[a type of lung infection\] and Acute Bacterial Skin and Skin Structure Infections. Ceftaroline is not yet approved for treatment in subjects with hematogenous osteomyelitis, therefore, the use of Ceftaroline in this research study is considered "investigational".

The goal of this research study is to find out what side effects there may be when children are taking Ceftaroline and to study how effective Ceftaroline is in treating bone infections due to Staphylococcus aureus in children. The investigators are also studying what the body does to the study drug, Ceftaroline, and if the doses the investigators use result in blood levels that the investigators think are going to be effective against bone infections in children. This is called pharmacokinetics (PK).

Detailed description:
This is a Phase 1/2, open-label, single-center study to determine safety and tolerability of Ceftaroline in pediatric subjects 1 to 17 years of age (inclusive) with signs and symptoms of acute hematogenous osteomyelitis at the end of intravenous therapy. After informed consent/assent is obtained, Ceftaroline will be administered intravenously. After the subject has been afebrile for at least 48 hours, has negative blood cultures, is clearly improving in general, is able to eat and drink, and is able to use or move the involved extremity, the subject may be switched to oral antibiotic administration.

The duration of subject participation from signing the informed consent form will be up to 14 months \[(includes screening period (1 Day), study IV drug administration (approximately 2-14 Days), Standard of Care Oral Drug Administration (4-5 weeks) (the total maximum treatment period is typically 6 weeks), and a follow-up visit 12 months after the last dose of study drug)\]. Baseline assessments for study eligibility will occur within 24 hours before the first dose of study drug. A minimum of 2 days (48 hours) of study drug administration is required.

Some of the tests and procedures completed during this study may be part of regular care for the subject's condition. Some tests and procedures will be done only for study purposes. Some regular procedures may also be completed more often as part of the research study.

Study assessments:

1. Past and Current Medical History: A detailed review of the subject's medical history, including demographics, concomitant medication review, medical/surgical history will be performed.
2. Vital Signs: Weight, height, blood pressure, pulse rate, and body temperature, will be recorded.
3. Physical Exam: Physical exam will include, evaluation of subject's overall health, examination site of infection, and assessment of subject's ability to move affected limb.
4. Safety Laboratory Assessments: Routine laboratory monitoring including liver function tests will be done 24 hours prior to enrollment and weekly during Ceftaroline treatment, and the completion of Ceftaroline treatment and at the follow-up visit. Isolate susceptibility testing will be done at baseline visit.
5. Pregnancy testing: For females of child-bearing potential, urine pregnancy will be performed prior to and after completing antibiotic treatment.
6. Pharmacokinetics Assessment: One PK blood sample will be obtained from all subjects who receive Ceftaroline fosamil.

Arms:
arm 1: IV Ceftaroline fosamil 15 mg/kg (or 600 mg if \> 40 kg) infused over 120 (± 10) minutes q8h (± 1 hour). The dose may vary with age.

Interventions: intervention 1: Ceftaroline Fosamil
Intervention descriptions: intervention 1: IV Ceftaroline fosamil 15 mg/kg (or 600 mg if \> 40 kg) infused over 120 (± 10) minutes q8h (± 1 hour) for children 2 years of age - 17 years of age (inclusive). IV Ceftarloine Fosamil 10 mg/kg infused 120 (± 10) minutes q8h (± 1 hour) for children 1 years of age - less than 2 years of age (inclusive).

Protocol document:
Prot_SAP_000.pdf: 
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Clinical Trial Protocol 
 
Study Drug: 
Ceftaroline Fosamil 
 
Study Title: 
Phase 1/2 Trial of Ceftaroline for the Treatment of Hematogenously Acquired 
Staphylococcus aureus Osteomyelitis in Children  
 
Phase: 
Phase 1/2 
 
Sponsor Investigator: 
Sheldon L. Kaplan 
1102 Bates Avenue, Suite1150 
Houston, TX 77030 
Telephone: 832-824-4330 
Fax: 
832-825-4347 
 
Funding: 
Allergan 
 
Research Nurse: 
Andrea Forbes, MS, BSN, RN 
Telephone: 832-824-4336 
Fax: 
832-825-4347 
E-mail:  aforbes@bcm.edu  
 
Version Date: 
v5.0 (08October2018) 
 


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1.   SUMMARY 
 
 
Sponsor Investigator: Sheldon L. Kaplan, MD 
Sponsor: Baylor College of Medicine 
Funding:  Allergan 
Product Name: Ceftaroline 
Protocol Title: Phase 1/2 Trial of Ceftaroline for the Treatment of Hematogenously Acquired 
Staphylococcus aureus Osteomyelitis in Children 
Clinical Phase: 1/2 
Objectives: 
Primary: 
• Evaluate the safety of ceftaroline in pediatric subjects 1 to 17 years of age (inclusive) with 
acute hematogenous osteomyelitis at the end of intravenous therapy. 
Secondary: 
• Evaluate efficacy of ceftaroline in pediatric subjects with acute hematogenous osteomyelitis 
at the end of IV therapy, at the end of total therapy (anticipated to be at 4 to 6 weeks after 
enrollment), and at one year after enrollment. 
• Evaluate clearance of S. aureus bacteremia if blood cultures initially positive. 
• Assess proportion of patients with plasma levels of ceftaroline that exceed 1 µg/mL for 
over 60% of a dosing interval. 
Study Design: This is a Phase 1/2, open-label, single-center study to determine safety and 
tolerability of ceftaroline in pediatric subjects 1 to 17 years of age (inclusive) with signs and 
symptoms of acute hematogenous osteomyelitis at the end of intravenous therapy. After 
informed consent/assent is obtained, ceftaroline will be administered intravenously. After the 
subject has been afebrile for at least 48 hours, has negative blood cultures, is clearly improving 
in general, is able to eat and drink, and is able to use or move the involved extremity, the subject 
may be switched to oral antibiotic administration. 
Number of Subjects: 18 Children 1 to 17 years of age, inclusive. Each subject will receive 
ceftaroline. 2 subjects above 5 years old will be enrolled before the younger subjects are 
enrolled. 
Planned Study Period: Approximately 60 months (funding approval to last subject last visit). 
6 subjects/year enrollment is anticipated. 
Treatment Duration with ceftaroline: Approximately 5 to 14 days. 
Subject Participation:  The duration of subject participation from signing the informed consent 
form will be up to 14 months (includes screening period, study drug administration, oral drug 
administration and a follow-up visit 12 months after the last dose of study drug).  Baseline 
assessments for study eligibility will occur within 24 hours before the first dose of study drug 
except for Alkaline Phosphatase, Bilirubin, AST/ALT which will be obtained prior to 
administration of ceftaroline but the results may not be available. A minimum of 2 days (48 
hours) of study drug administration is required to assess safety. 


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Test Product, Dosage, and Mode of Administration: IV ceftaroline fosamil 15 mg/kg (or 600 mg if > 
40 kg) infused over 120 (± 10) minutes q8h (± 1 hour) for children 2 years of age – 17 years of age 
(inclusive). IV ceftaroline fosamil 10 mg/kg infused over 120 (± 10) minutes q 8h (± 1 hour) for children 
from 1 year of age to < 2 years (inclusive). 
Isolate susceptibilities: The ceftaroline MIC of S. aureus isolates or other isolates such as Group A 
streptococcus, Streptococcus pneumoniae or Kingella kingae that are obtained from the patients 
with acute hematogenous osteomyelitis will be determined using Clinical and Laboratory Standards 
Institute (CLSI) methods. These will be performed in the CAP certified Infectious Disease Research 
Laboratory. CLSI interpretive breakpoints will be used to determine if the isolate is susceptible, 
intermediate or resistant to ceftaroline. 
Oral Switch: A switch to one of the following open-label PO drugs is expected/allowed on or after 
EOIV assessments are completed and if criteria in Section 9.2 are met: 
• PO clindamycin 13 mg/kg/dose q8h in subjects with proven MRSA infection due to clindamycin 
susceptible MRSA or if no pathogen is isolated. 
OR 
• PO cephalexin 25 to 33 mg/kg/dose q 8 hours in subjects with proven MSSA infection. 
OR 
• PO linezolid 600 mg q12h (Children > 12 years old) or 10 mg/kg q8h (children < 12 years old) in 
subjects with clindamycin-resistant MRSA pathogens or for patients with MRSA isolates who are 
unable to tolerate clindamycin. 
Inclusion Criteria: Subjects are required to meet the following inclusion criteria: 
1. Informed consent in writing from parent(s) or other legally acceptable representative(s) and 
assent from subject (if appropriate according to local requirements). 
2. Male or female 1 to 17 years of age. 
3. Suspected hematogenous SA osteomyelitis in a large bone (upper or lower extremities, pelvis) 
based on clinical findings and radiology results. 
4. One to three sites of osteomyelitis with expectation that transition to oral antibiotics will be 
likely prior to discharge to complete IV therapy (The second or third site might be contiguous 
like a proximal tibia and distal femur but could also be at sites unrelated such as a distal femur 
and pelvic bone). 
5. Female subjects who have reached menarche must have a negative urine pregnancy test. 
6. Female subjects who have reached menarche and are sexually active must be willing to practice 
sexual abstinence or dual methods of birth control (eg, condom or diaphragm with spermicidal 
foam or gel) during treatment and for at least 28 days after the last dose of any study drug. 
7. Sufficient IV access to receive medication. 


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Exclusion Criteria: Subjects must NOT meet any of the following exclusion criteria. Septic arthritis 
contiguous to the site of osteomyelitis is not an exclusion criterion. 
1. Received more than 24 hours of IV antibiotics prior to enrollment. 
2. More than three bones infected. 
3. Disseminated infection or is admitted to the pediatric intensive care unit. 
4. Underlying condition (excludes mild eczema or reactive airways disease). 
5. Suspected or proven venous thrombosis or concern for endocarditis. 
6. Requirement for other reasons for another antibiotic potentially active against organisms 
commonly causing osteomyelitis in children. 
7. Creatinine clearance < 50 mL/min/1.73m2 (calculated by the Schwartz formula). 
8. AST or ALT > 3 times the upper limit of normal. 
9. Neutropenia (<500 neutrophils/mm3). 
10. Thrombocytopenia (<50,000 platelets/mm3). 
11. Females who are currently pregnant or breast feeding. 
12. Hypersensitivity reaction to any Beta-lactam antibiotic. 
13. Has had an allergic reaction to ceftaroline in the past. 
Safety: Adverse event and serious adverse event monitoring, vital signs and laboratory tests 
(CBC,BUN, Creatinine, Alkaline Phosphatase, Bilirubin, AST and ALT will be obtained within 24 hours 
prior to enrollment and weekly during ceftaroline treatment and at the completion of ceftaroline 
treatment).  The Alkaline Phosphatase, Bilirubin, AST/ALT results may not be available prior to 
enrollment of the patient. We do not anticipate that the AST/ALT concentrations will be > 3 UNL but 
if they were to be this elevated, the subject will be dropped from the study immediately. 
Efficacy: 
• Clinical response by subject and by baseline pathogen at the conclusion of IV ceftaroline. 
• Clinical outcome at the completion of total therapy (IV plus oral) 
• Clinical outcome at one year after enrollment into study-long-term follow-up. 
Pharmacokinetics:  The pharmacokinetic (PK) outcome measures will include concentrations of 
ceftaroline, ceftaroline fosamil (prodrug), and ceftaroline M-1 (inactive metabolite) in plasma in 
subjects on days 2 to 5 of treatment (only one PK sample collected on days 2-5) 4 hours (+/- 30 
minutes) after the end of the infusion (before the start of the next infusion). Efforts will be made to 
obtain 1 PK blood sample (approximately 0.6 mL) at steady state from all subjects who receive 
ceftaroline fosamil. PK samples may be collected after any infusion of ceftaroline fosamil on those 
days and before oral switch. 
If purulent material is being obtained from bone or subperiosteal abscesses at surgery or via 
drainage by interventional radiology, we will attempt to obtain specimens for measurement of 
ceftaroline concentrations. 
Statistics: 
• 
Descriptive statistical methods will be used to summarize the demographic characteristics of the 
subjects as well as selected clinical features such as duration of fever or positive blood cultures, 
time until normalization of ESR and CRP. 
• 
The proportion of children with plasma concentrations of ceftaroline that exceed 1µg/mL at 4 
hours following a 2 hour infusion of ceftaroline dose will be determined. 
• 
Safety analyses will be conducted on all subjects who received at least one dose of ceftaroline. 
The occurrence of adverse events especially diarrhea, rash and evidence of bone marrow 
suppression which are the most common adverse effects associated with cephalosporin 
antibiotics will be evaluated. 


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Table 1.1 - Schedule of Assessments and Procedures 
 
Assessment or Procedure 
1 
Baseline 
Treatment 
Follow-up 
Day 1 
Days 2-14 
End of IV 
Treatment 
(EOIV) 
Week 2, Week 4, 
and Week 6 After 
Discharge14 
End of 
Antibiotic 
Treatment 
(EOT) 
Month 12 
  Obtain Informed Consent/Assent 
X 
  Verify Inclusion/Exclusion Criteria 
X 
Demographic Data 
X 
 
 
 
 
 
 
Medical and Surgical History 
X 
 
 
 
X 
X 
X 
Complete Physical Examination3 
X 
 
 
 
 
 
 
Brief Physical Exam4 
X 
X 
X 
X 
X 
X 
X 
Ambulatory/Movement Status5 
X 
X 
X 
X 
 
 
 
   Height and Weight 
X 
X 
X 
   Peak Temperature 
X 
X 
X 
X 
   Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
   Vital signs 
X 
X 
X 
X 
X 
X 
X 
   Record adjunctive therapeutic procedures (if   
  performed i.e. Surgery)6 
 
X 
Standard of Care Radiology Results 
X 
Clinical outcome 
X 
X 
X 
AEs and SAEs 
X 
X 
X 
X 
X 
X 
CBC with differential 7 
X 
X 
X 
Chemistries (BUN, Creatinine, Alkaline 
Phosphatase, Bilirubin, AST, ALT) 7 
X 
X 
X 
CRP and ESR8 
X 
X 
X 
X 
X 
X 
Direct Coombs test 
X 
X 
Urine pregnancy test9 
X 
X 
CrCl calculation 
X 
If Clinically Indicated 
Standard of Care Blood Culture10 
X 
Blood for PKanalyses11 
X 
Standard of Care Purulent Material From Bone12 
X 
Drug administration13 
 
X 
X 
X 
X 
 
 


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Abbreviations: AE = adverse event; CBC = complete blood count; CrCl = creatinine clearance; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; SAE = serious adverse event. 
1 
Perform baseline assessments within 24 hours before first dose of IV study drug. 
2 
Interval history focusing on the use of the involved extremity. On Month 12 follow up interval problems such as pathologic fractures and growth disturbances will be evaluated only. 
3 
The presence of warmth, tenderness, swelling, erythema, and movement of the infected extremity will be recorded specifically. The circumference of the infected extremity taken at the location of 
point tenderness will be determined. 
4 
Involved extremity will be assessed as at enrollment, if possible. Most of the subjects are expected to have surgical incision and drainage procedures and thus assessing the extremity for swelling, 
erythema, warmth and tenderness may not be possible because of drains in place and large surgical dressings that cannot be removed. 
5 
The degree of the subject’s ability to ambulate will be assessed if the osteomyelitis is in the lower extremity-i.e. walks unaided, able to bear weight, can walk aid using a walker, etc. The use of upper and 
lower extremities will be assessed in terms of movement and range of motion. 
6 
Any surgical procedures will be documented and the findings described. 
7 
CBC and chemistries . If not done for SOC, collect samples for research if clinically indicated. 
8 
CRP and ESR will be collected typically  as part of standard of care.  If not performed for SOC, collect samples for research if clinically indicated. 
9 
Perform test if subject is a female who has reached menarche. If a pregnancy test is positive post baseline, follow reporting requirements in Section 11.1.4. 
10 
Isolate susceptibilities will be performed on samples obtained from Pathology as per section 10.8.1. 
11 
Refer to section 10.9. PK samples may be collected 4 hours (+/- 30 minutes) after any infusion of ceftaroline fosamil (before the start of the next infusion) on days 2-5 and before oral switch. 
12 
If purulent material is being obtained from bone or subperiosteal abscesses at surgery or via drainage by interventional radiology, we will attempt to obtain specimens for measurement of ceftaroline 
concentrations. 
13 
Administer drug per Section 9. 
14 
Week 2 visit will occur only if the subject has been discharged prior to Week 2. 


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2.   TABLE OF CONTENTS 
1.   SUMMARY ...................................................................................................................................... 2 
Table 1.1 - Schedule of Assessments and Procedures ............................................................................... 5 
 
2.   TABLE OF CONTENTS ....................................................................................................................... 7 
 
3. 
LIST OF ABREVIATIONS AND DEFINITIONS OF TERMS ............................................................... 10 
 
4. 
BACKROUND AND RATIONALE ............................................................................................... 12 
4.1. 
Indication ............................................................................................................................. 12 
4.2. 
Ceftaroline Fosamil ............................................................................................................... 13 
4.3. 
Rationale for Present Study ................................................................................................... 19 
4.4. 
Rationale for Ceftaroline Fosamil Dosage Regimen ......................................................... 20 
4.5. 
Outpatient Parenteral Antimicrobial Therapy .......................................................................... 20 
4.6. 
Oral Drugs ............................................................................................................................ 20 
 
5. 
STUDY OBJECTIVES ............................................................................................................... 21 
5.1. 
Primary Objectives ................................................................................................................ 21 
5.2. 
Secondary Objectives ............................................................................................................ 21 
 
6. 
STUDY DESIGN ...................................................................................................................... 21 
6.1. 
Outcome Measures............................................................................................................... 21 
6.2. 
Number of Subjects .............................................................................................................. 22 
6.3. 
Expected Duration of Subject Participation ............................................................................. 22 
6.4. 
Data Review Committee ........................................................................................................ 22 
 
7. 
SELECTION, DISCONTINUATION AND WITHDRAWAL OF STUDY SUBJECTS ................................. 22 
7.1. 
Inclusion Criteria ................................................................................................................... 22 
7.2. 
Exclusion Criteria .................................................................................................................. 23 
7.3. 
Prior and Concomitant Treatment and Medications ................................................................ 23 
7.4. 
Permitted Treatment and Medications ................................................................................... 23 
7.5. 
Prohibited Medications and Therapies ................................................................................... 24 
7.6. 
Screening Failures ................................................................................................................. 24 
7.7. 
Subject Discontinuation or Withdrawal .................................................................................. 24 
7.8. 
Premature Discontinuation From Study Drug Administration ................................................... 24 
7.9. 
Replacement of Subjects ....................................................................................................... 26 
7.10. 
Stopping Rules ................................................................................................................... 26 
 
8. 
STUDY DRUGS ...................................................................................................................... 26 
8.1. 
Ceftaroline Fosamil Intravenous Study Drug............................................................................ 26 
8.2. 
Directions for Use ................................................................................................................. 26 
8.3. 
Storage ................................................................................................................................ 26 
8.4. 
Criteria for Switching to Oral Drug .......................................................................................... 26 
8.5. 
Dose Adjustments ................................................................................................................. 27 
8.6. 
Adjunctive Surgical Procedures .............................................................................................. 27 
8.7. 
Treatment Compliance .......................................................................................................... 28 
8.8. 
Accountability Procedures ..................................................................................................... 28 


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9. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................................ 28 
9.1. 
Baseline ............................................................................................................................... 28 
9.2. 
Study Day 1 .......................................................................................................................... 30 
9.3. 
Study Days 2-14 .................................................................................................................... 31 
9.4. 
Study Day 15 (End of IV Treatment-EOIV) ................................................................................ 32 
9.5. 
Week 2, Week 4, and Week 6 After Discharge ......................................................................... 33 
9.6. 
End of Antibiotic Therapy (EOT)/Week 4/ OR Week 6 ............................................................... 34 
9.7. 
Follow Up ............................................................................................................................. 35 
9.8. 
Safety Lab Tests .................................................................................................................... 36 
9.9. 
Diagnostic Imaging and Non-Pharmacological Assessments ...................................................... 36 
 
10. 
SAFETY ASSESSMENTS ........................................................................................................... 37 
10.1. 
Adverse Events ..................................................................................................................... 37 
10.2. 
Causality and Severity Assessments ........................................................................................ 37 
10.3. 
Serious Adverse Events/Suspected Adverse Reaction ............................................................... 38 
10.4. 
Follow Up of Serious Adverse Events....................................................................................... 39 
10.5. 
Collecting and Reporting Adverse Events and Serious Adverse Events ........................................ 39 
10.6. 
Other Reportable Events – Pregnancy ..................................................................................... 40 
10.7. 
IND Safety Reports ................................................................................................................ 40 
10.8. 
Other Clinical Assessments .................................................................................................... 41 
10.9. 
Laboratory Assessments ........................................................................................................ 41 
 
11. 
DATA MANAGEMENT ............................................................................................................ 41 
 
12. 
STATISTICAL ASSUMPTIONS ................................................................................................... 42 
12.1. 
Statistical Methods and Planned Analysis ................................................................................ 42 
12.2. 
Primary End Points ................................................................................................................ 42 
12.3. 
Secondary Endpoints ............................................................................................................. 42 
12.4. 
Safety Analysis ...................................................................................................................... 42 
12.5. 
Efficacy Analysis .................................................................................................................... 43 
12.6. 
Interim Analysis .................................................................................................................... 43 
12.7. 
PK Analysis ........................................................................................................................... 43 
12.8. 
Handling of Dropouts and Missing Data .................................................................................. 43 
 
13. 
ADMINISTRATIVE ASPECTS ..................................................................................................... 43 
13.1. 
Compliance with Regulatory Requirements ............................................................................. 43 
13.2. 
Institutional Review Board ..................................................................................................... 44 
13.3. 
Informed Consent ................................................................................................................. 44 
13.4. 
Confidentiality ...................................................................................................................... 44 
13.5. 
Compensation, Insurance, and Indemnity ............................................................................... 44 
13.6. 
Protocol Amendments .......................................................................................................... 44 
13.7. 
Case Report Forms ................................................................................................................ 44 
13.8. 
Source Document Maintenance ............................................................................................. 45 
13.9. 
Study Monitoring/Quality Assurance ...................................................................................... 45 
13.10. 
Study File Management ......................................................................................................... 45 
13.11. 
Study Completion ................................................................................................................. 46 
13.12. 
Audits .................................................................................................................................. 46 


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13.13. 
Retention of Records ............................................................................................................ 46 
13.14. 
Publication Policy .................................................................................................................. 47 
 
14. 
REFERENCES ......................................................................................................................... 48 
 
 
 


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3. LIST OF ABREVIATIONS AND DEFINITIONS OF TERMS 
 
ABSSSI 
acute bacterial skin and skin structure infection 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
CA 
Competent Authority 
CABP 
community-acquired bacterial pneumonia 
CA-MRSA 
community-acquired methicillin-resistant Staphylococcus aureus 
CBC 
complete blood count 
CE 
clinically evaluable 
CFR 
Code of Federal Regulations 
CHEOPS 
Children’s Hospital of Eastern Ontario Pain Scale 
Cmax 
maximum plasma drug concentration 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CRP 
C-reactive protein 
cSSSI 
complicated skin and skin structure infection 
CT 
computed tomography 
CXR 
chest radiograph 
CYP 
cytochrome P450 enzyme 
DRC 
Data Review Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOIV 
End-of-Intravenous Study Drug 
EOT 
End-of-Therapy 
FDA 
US Food and Drug Administration 
FLACC 
Faces, Legs, Activity, Crying, and Consolability 
FPS-R 
Hicks Faces Pain Scale-Revised 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HA-MRSA 
hospital-acquired methicillin-resistant Staphylococcus aureus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
ICF 
informed consent form 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
intent to treat 
IV 
intravenous 
LFU 
Late Follow-up 
MDRSP 
multidrug-resistant Streptococcus pneumoniae 
ME 
microbiologically evaluable 
MIC 
minimum inhibitory concentration 


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MIC90 
minimum concentration required to inhibit the growth of 90% of 
organisms 
MITT 
modified intent-to-treat 
mMITT 
microbiological modified intent-to-treat 
MRSA 
methicillin-resistant Staphylococcus aureus 
MSSA 
methicillin-susceptible Staphylococcus aureus 
NOAEL 
no-observable-adverse-effect level 
OPAT 
outpatient parenteral antimicrobial therapy 
PBP 
penicillin-binding protein 
PCS 
potentially clinically significant 
PCV7 
pneumococcal conjugate vaccine 
PCV13 
pneumococcal 13-valent conjugate vaccine 
PD 
pharmacodynamic 
PISP 
penicillin-intermediate Streptococcus pneumoniae 
PK 
pharmacokinetic 
PK/PD 
pharmacokinetic/pharmacodynamic 
PNSSP 
penicillin-nonsusceptible Streptococcus pneumoniae 
PO 
by mouth (per os) 
PRSP 
penicillin-resistant Streptococcus pneumoniae 
PVL 
Panton-Valentine leukocidin 
q6h 
every 6 hours 
q8h 
every 8 hours 
q12h 
every 12 hours 
QTcB 
 QT interval corrected for heart rate using the Bazett formula       
                                   (QTcB = QT/(RR)½) 
QTcF 
 QT interval corrected for heart rate using the Fridericia formula   
                               (QTcF = QT/(RR)½) 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
study day or standard deviation 
TEAE 
treatment-emergent adverse event 
TOC 
Test-of-Cure 
ULN 
upper limit of normal 
US/USA 
United States/United States of America 
USP 
United States Pharmacopeia 
VATS 
video-assisted thoracic surgery 
VISA 
vancomycin-intermediate Staphylococcus aureus 
WBC 
white blood cell 


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4. BACKROUND AND RATIONALE 
4.1. Indication 
 
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates are now an 
important cause of systemic infections in children and has to be considered among the pathogens for any 
child presenting with a bone or joint infection depending on the local epidemiology. (1) (2)  In Houston, 
TX CA-MRSA was the pathogen in 56 of 89 (63%) children with S.aureus osteomyelitis seen from August 
2001 to July 2004.(3) In extending these findings, we found over the 10 year period from 2001 to 2010, 
195 of 376 (52%) of S. aureus isolates from children with acute community acquired osteomyelitis were 
MRSA.  In the United States and in a growing number of countries around the world, the USA300 clone 
is the most common or an emerging CA-MRSA pulsotype identified in invasive infections, including bone 
and joint infections.(4, 5) 
Kingella kingae is a relatively common etiology of osteoarticular infection, primarily septic arthritis in 
children under 5 years of age.(6) The exact frequency of K. kingae bone and joint infections is difficult to 
determine because the organism is somewhat difficult to isolate using routine techniques. When 
polymerase chain reaction (PCR) techniques are applied to culture negative specimens from patients with 
presumed septic arthritis or acute osteomyelitis, K. kingae has been identified in a high percentage of 
cases for younger children.(7) 
Streptococcus pneumoniae has been a relatively uncommon cause of bone and joint infections but does 
occur in children generally less than 24 months of age. Over a three-year period from September 1993 
through August 1996, 42 children with pneumococcal bone or joint infections were identified at 8 
children’s hospitals.(8) In these same hospitals, 25 cases were identified over the three-year period 2007 
through 2009. In 2010 and 2011, 2 and 4 cases occurred, respectively.(9) Thus, following the introduction 
of the 13-valent pneumococcal conjugate vaccine, pneumococcal bone and joint infection is likely to be 
even less common in young children. 
In areas where CA-MRSA isolates account for > 10% of community S.aureus isolates, an antibiotic effective 
against CA-MRSA isolates is recommended to be included in the initial empiric antibiotic regimen for 
treating children with suspected acute hematogenous osteomyelitis and/or septic 
arthritis.(10) 
Vancomycin is considered the antibiotic of first choice in the treatment of invasive CA- MRSA infections 
including musculoskeletal infections and is the agent to administer empirically for moderately to severely 
ill children. Nafcillin or oxacillin is also recommended along with vancomycin for severely ill children 
because these agents are superior to vancomycin for CA-MSSA bacteremic illness. Clindamycin is an option 
for empiric therapy in patients who are not very ill and in whom bacteremia is not suspected. Once an 
organism is isolated and antibiotic susceptibilities known, antibiotic therapy is modified.  Clindamycin is 
an effective agent for clindamycin susceptible isolates.(11) Linezolid is quite active against CA-MRSA in 
vitro and can be administered orally with excellent bioavailability for treating CA-MRSA osteomyelitis in 
children and is considered an option, especially for clindamycin resistant isolates. Linezolid has been used 
most extensively for this indication in children in Taiwan where the CA- MRSA clone is typically resistant 
to clindamycin. (12) Daptomycin has been employed for treatment of osteomyelitis in adults but very little 
has been published regarding its use for this indication in children.(13) Trimethoprim-sulfamethoxazole 
may be very useful for treating acute osteomyelitis caused by Kingella kingae or in patients with culture-
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Multiple studies have demonstrated that completing therapy with an oral agent following an initial 
duration of parenteral administration compared with parenteral therapy alone results in equivalent 
outcomes for treating musculoskeletal infections.(14, 15) In other studies, a high rate of complications 
was noted in children being treated for acute osteomyelitis who have parenteral antibiotics administered 
through a peripherally placed central catheter.(16)  Thus, switching to oral administration                         of 
appropriate antibiotics to complete treatment of acute osteomyelitis is an important option for many, if 
not, most patients. The recommended duration of total treatment for acute osteomyelitis is at least three 
weeks depending on the clinical response of the patient. 
 
4.2. Ceftaroline Fosamil 
Ceftaroline is a fifth generation cephalosporin with excellent in vitro activity against S. aureus isolates 
including methicillin resistant strains.(17) Ceftaroline is approved by the United States Food and Drug 
Administration for treatment of skin and soft tissue infections caused by MRSA in adults based on two 
large randomized trials. (18, 19)  In a rabbit model of MRSA osteomyelitis, ceftaroline and linezolid were 
significantly better than vancomycin in decreasing colony forming units in bone and joint fluid.(20) In 
seven of ten adult patients with deep seated MRSA infections, including osteomyelitis and septic arthritis 
in two patients each, ceftaroline treatment resulted in a microbiologic cure.(21)  Clinical trials of 
ceftaroline in children are being conducted and the role of ceftaroline in treating MRSA osteomyelitis will 
need to be determined. 
 
Seventeen clinical studies (3153 subjects in total) of ceftaroline fosamil have been conducted and 
completed to date. Eleven Phase 1 clinical pharmacology studies (305 subjects) have been completed, of 
which, 10 were conducted in adults. Two Phase 2 studies (242 subjects) were conducted in adult subjects 
with complicated skin and skin structure infection (cSSSI). Four Phase 3 studies (2606 subjects) have been 
completed. Studies P903-06 and P903-07 were conducted in adults with cSSSI (1378 subjects) and Studies 
P903-08 and P903-09 were conducted in adults with CAP (1228 subjects). The Phase 3 studies were 
multicenter, randomized, double-blind, comparative, safety and efficacy studies of ceftaroline fosamil (600 
mg every 12 hours [q12h] as a 60-minute IV infusion; or 400 mg q12h if the subject had renal impairment) 
versus IV comparators. Studies P903-06 and P903-07 in cSSSI were identical in design. The comparator was 
vancomycin plus aztreonam (1 g of each q12h as 60-minute IV infusions with aztreonam discontinued if a 
gram-negative pathogen [infection] was not identified or suspected). The duration of ceftaroline fosamil   
or vancomycin (with or without aztreonam) administration was 5 to 14 days (with extensions allowed up  
to 21 days with previous approval of the Medical Monitor). Studies P903-08 and P903-09 were similar in 
design; the only difference was that a single day of adjunctive macrolide therapy (clarithromycin) was 
administered to subjects in both treatment groups in Study P903-08 and not in Study P903-09. The 
comparator was ceftriaxone (1 g q12h as a 30-minute IV infusion). The duration of ceftaroline fosamil or 
ceftriaxone administration was 5 to 7 days. 
 
4.2.1. Summary of Toxicology Studies 
Ceftaroline was well tolerated in various animal species in studies compliant with Good Laboratory 
Practices (GLP). When given as a single dose, ceftaroline fosamil had a minimum lethal dose > 2000 mg/kg 
in rats and monkeys. In repeat-dose studies (up to 13 weeks), the no-observable-adverse-effect level 
(NOAEL) was 30 mg/kg/day in rats and 32 mg/kg/day in monkeys. At high doses (270 mg/kg in rats and 64 
mg/kg in monkeys), clinical signs or pathological observations (or both) revealed some treatment-related 


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abnormalities. The spleen and lymphoid organs (in 4-week studies only), and kidney were considered the 
potential targets for the toxicities of ceftaroline fosamil. These were typically reversible following a 
recovery period. Clonic/tonic convulsions were observed in rodents treated with high doses, similar to that 
observed following treatment with imipenem and other cephalosporins. No significant respiratory or 
cardiovascular toxicities were observed. 
 
Reproductive toxicity, genotoxicity, and juvenile dose range-finding studies were also conducted with 
ceftaroline fosamil. There was no evidence of developmental toxicity in rats where the NOAEL was 300 
mg/kg/day. In rabbits, the NOAEL was 100 mg/kg/day, and doses ≥ 50 mg/kg/day induced a statistically 
significant increase in the incidence of angulated hyoid alae, a common skeletal variation in this species. 
 
Ceftaroline fosamil was not considered mutagenic and had minimal antigenic potential. It did not induce 
local irritation in rabbits and was compatible with human plasma. 
 
A juvenile toxicity dose range-finding study was conducted with ceftaroline fosamil in rats. The NOAEL was 
270 mg/kg, which represents a human exposure margin of 2 for ceftaroline (based on area under the plasma 
concentration versus time curve [AUC]). 
 
From a preclinical perspective, ceftaroline fosamil has a comparable safety profile similar to other 
cephalosporins. The margins of exposure were 1 to 2 times the maximum recommended human dose. 
 
4.2.2. Summary of Microbiological and Pharmacology Studies 
Ceftaroline displays broad antibacterial activity against aerobic and anaerobic gram-positive and gram- 
negative bacteria. Like other β-lactams, ceftaroline is bactericidal and targets PBPs to inhibit bacterial cell 
wall biosynthesis. Ceftaroline binds with high affinity to PBPs from MSSA with additional ability to bind 
efficiently to PBP2a, the PBP present in MRSA responsible for methicillin resistance. Ceftaroline also retains 
activity against contemporary resistant organisms including both hospital-acquired methicillin- resistant S. 
aureus (HA-MRSA) and CA-MRSA, including S. aureus isolates resistant to clindamycin, in addition to 
vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus. 
 
The minimum concentration required to inhibit the growth of 90% of organisms (MIC90) for S. aureus 
isolates is typically 1 mg/L (Study NSR-P903-M-071). Ceftaroline also has potent activity against isolates of 
streptococci, including Streptococcus viridans species, with MIC90 values typically < 0.12 mg/L. 
Erythromycin resistance in the streptococci has not been associated with increased MICs to ceftaroline. 
Against the Enterobacteriaceae, MIC90 values for ceftazidime-susceptible isolates (ie, presumed non- 
extended-spectrum ß-lactamase-producing, non-AmpC β-lactamase-overexpressing) are typically ≤ 1 mg/L, 
as seen with Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, K. oxytoca, and Proteus 
mirabilis isolates. Ceftazidime-resistant strains had elevated MIC values to ceftaroline. Ceftaroline is less 
active against the indole-positive Proteae, including Morganella morganii and Providencia spp. (MIC90 > 32 
mg/mL). Ceftaroline has little in vitro activity against Pseudomonas aeruginosa. 


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Resistance to ceftaroline develops at low frequency in vitro. For S. aureus, spontaneous resistant mutants 
to 4 times MIC of ceftaroline have not been observed (≤ 10-10). In various animal models of infection caused 
by either gram-positive or -negative bacteria, including MRSA and VISA, ceftaroline was shown to be highly 
effective. 
 
In common with most β-lactams, free drug percentage of time above the minimum inhibitory concentration 
(%T > MIC) is the most appropriate parameter to predict efficacy of ceftaroline. The 
pharmacokinetic/pharmacodynamic (PK/PD) relationship for ceftaroline was initially evaluated in the 
murine neutropenic thigh infection model with several organisms including S. aureus (Andes and Craig, 
2006). The mean free-drug %T > MIC required for stasis was 26% for S. aureus, regardless of the resistance 
phenotype. 
 
The efficacy of ceftaroline against aerobic gram-positive and gram-negative microorganisms has been 
established in a variety of animal models of infection, including mouse peritonitis, sepsis, thigh infection, 
and pneumonia; and in rabbit models of endocarditis, pneumonia, osteomyelitis and meningitis. In the 
mouse pneumonia model, the efficacy of ceftaroline fosamil was compared with that of vancomycin and 
linezolid (Study TAK-599/00063). The activity of ceftaroline against MRSA was better than that of 
vancomycin and linezolid in a neutropenic murine pneumonia model in which 20 mg/kg doses of each drug 
were administered subcutaneously three times daily for 
2 days beginning 1 day after intranasal inoculation. Ceftaroline reduced viable bacterial counts in infected 
lungs by 4 log units compared to the untreated control (p < 0.01), while both vancomycin and linezolid 
failed to reduce the bacterial counts. When the study was performed by administering the first dose only 
2 hours after inoculation, all 3 drugs exhibited bactericidal activity, perhaps because the bacteriostatic 
agents, vancomycin and linezolid, were only effective during the early stage of infection when the bacterial 
counts were low, while ceftaroline, being bactericidal, was active even later during the infection. 
 
A dose-fractionation study (P903-M-097) was conducted in a neutropenic murine lung infection model 
using various clinical isolates of S. aureus isolates (MSSA and MRSA, with ceftaroline MICs ranging from 0.5 
to 4 mg/L) to define the required magnitude of ceftaroline exposure (ie, free drug concentration above the 
MIC [f T > MIC]) that reliably results in efficacy. Additionally, the efficacy of a human simulated regimen    of 
ceftaroline 600 mg every 12 hours (q12h) administered as a 1-hour intravenous (IV) infusion was evaluated. 
 
Bronchopulmonary penetration of ceftaroline was also assessed in the murine pneumonia model by 
collecting epithelial lining fluid (ELF) via bronchoalveolar lavage (BAL) at various time points after dosing in 
both infected and uninfected animals. Ceftaroline concentrations in the ELF of infected, neutropenic mice 
were nearly the same as their corresponding serum concentrations. Therefore, f T > MIC exposures in ELF 
were similar to what was seen in the serum and the penetration ratio for ceftaroline into mouse ELF based 
on area under the plasma concentration versus time curve (AUC) was approximately 100%. The ceftaroline 
f T > MIC values in serum associated with stasis and a 1-log10 CFU reduction in bacterial density were 16.5% 
and 41.4%, respectively. The human simulated 600 mg q12h dose regimen provided considerable decreases 
in bacterial densities for all the S. aureus isolates tested, which had ceftaroline MICs of 0.5 to 4 


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mg/L. In a rabbit model of pneumonia, dose administration was by a computer-controlled infusion pump 
to accurately simulate human PK for ceftaroline and comparator ceftriaxone (Croisier-Bertin et al, 2011). 
Three pneumococcal isolates with varying susceptibility to penicillin were evaluated, including penicillin- 
susceptible S. pneumoniae (PSSP), penicillin-intermediate S. pneumoniae (PISP), and penicillin-resistant S. 
pneumoniae (PRSP). Human simulated dosing (600 mg every q12h for ceftaroline, 1 g every 24 hours [q24h] 
for ceftriaxone) was administered for 2 days beginning 5 hours after endobronchial challenge with 5 × 109 
colony forming units (CFU). Ceftaroline and ceftriaxone were similarly effective in reducing bacterial burden 
in the lungs (approximately 7 log CFU/g, to essentially undetectable levels) for the PSSP and PISP infections, 
but only ceftaroline was bactericidal against the PRSP isolate. A second study evaluated efficacy against a 
PVL-producing isolate of USA300 MRSA in the same rabbit pneumonia model with simulated human dosing 
for ceftaroline, vancomycin, linezolid, and clindamycin (Croisier-Bertin et al, 2011). High mortality observed 
in untreated control animals was completely prevented by ceftaroline and also greatly reduced by linezolid 
and clindamycin, while animals treated with vancomycin showed only marginal improvement in survival. 
Bacterial counts in lung were lowest in the ceftaroline-treated animals (approximately 5-log reduction 
compared to control), although not statistically different from the animals receiving linezolid, lindamycin, 
or vancomycin. PVL toxin levels were monitored and treatment with clindamycin, ceftaroline, and linezolid 
were found to result in greatly reduced levels of toxin compared to vancomycin, which may partially explain 
the enhanced tissue damage observed in lungs of vancomycin- treated animals. 
 
The plasma protein binding of ceftaroline in vitro was generally low (mean ± SD of 20% ± 6.1%) and 
concentration independent in human plasma over the clinically relevant concentration range. In vitro 
oxidative metabolic studies with liver microsomes demonstrated that the metabolism of ceftaroline is not 
dependent upon cytochrome P450 enzymes (CYP). In vitro studies in human liver microsomes indicated 
that neither ceftaroline fosamil nor ceftaroline inhibits the major CYP isoenzymes. In addition, studies in 
human hepatocytes also demonstrated that ceftaroline fosamil, ceftaroline, and ceftaroline M-1 are not 
inducers of CYP activity. Therefore, ceftaroline is not expected to inhibit or induce the clearance of drugs 
that are metabolized by these metabolic pathways in a clinically relevant manner. 
 
No differences in the pharmacokinetics of ceftaroline fosamil, ceftaroline, or ceftaroline M-1 were noted 
between genders in rats and monkeys. In addition, there was no accumulation of ceftaroline fosamil or 
ceftaroline after repeated once-daily administration, and only moderate accumulation of ceftaroline M-1 
was observed in the repeat-dose toxicology studies. 
 
Safety pharmacology studies were performed in various experimental animal models and in vitro testing 
systems to examine the effects of ceftaroline fosamil on behavioral and physiological effects, respiratory 
function, and the cardiovascular system. 
 
4.2.3. Completed Pediatric Studies 
One of the 11 Phase 1 clinical pharmacology studies, Study P903-15 “Pharmacokinetics of a Single Dose of 
Ceftaroline in Subjects 12 to 17 Years of Age Receiving Antibiotic Therapy,” was conducted in adolescents. 


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Study P903-15 was a Phase 1, multicenter, open-label, noncomparative, single-dose study of ceftaroline 
fosamil in subjects 12 to 17 years of age, inclusive, who were hospitalized and receiving antibiotic therapy 
for treatment of infections of any type. Subjects received a single IV infusion of ceftaroline fosamil at a dose 
of 8 mg/kg if weighing < 75 kg (165.4 lb) or 600 mg if weighing 75 kg (165.4 lb) or more. The primary objective 
was to evaluate the single-dose pharmacokinetics of ceftaroline, the prodrug ceftaroline fosamil, and the 
inactive M-1 metabolite. The secondary objective was to evaluate the safety of ceftaroline in adolescent 
subjects. 
 
Nine subjects, 5 male and 4 female subjects with a mean age of 13.7 years (range 12 to 16 years), were 
enrolled in the study. One subject was prematurely discontinued from study drug due to infusion site 
extravasation that was moderate in severity and assessed by the Investigator as unrelated to ceftaroline. 
This subject received approximately 80% of the planned dose. 
 
The remaining 8 subjects each received a complete dose of ceftaroline fosamil. All subjects completed the 
study and were included in the Safety Population. Eight treatment-emergent adverse events (TEAEs) 
occurred in 5 subjects. All TEAEs were mild or moderate in severity. Three TEAEs (extrasystoles, vomiting, 
and “electrocardiogram [ECG] prolonged QT interval”) were considered related to ceftaroline by the 
Investigator and each occurred in a different subject. All TEAEs resolved except for “ECG prolonged QT 
interval” in 1 subject that was detected on Study Day 2 and was not assessed further. (The subject’s QTcB 
and QTcF values were < 450 msec and similar between the predose and postdose measurements.) One 
subject mentioned above prematurely discontinued study drug, but no subjects prematurely withdrew 
from the study or died. One subject with osteomyelitis had a serious adverse event (SAE) of a pathologic 
fracture of the humerus that occurred 13 days after infusion of ceftaroline fosamil. The fracture was mild 
in severity and considered by the Investigator as unrelated to ceftaroline. 
 
No clinical chemistry or urinalysis values met potentially clinically significant (PCS) criteria. One hematology 
value met PCS criteria, one subject who had received several blood replacement products for blood loss 
secondary to trauma and surgery had a high activated partial thromboplastin time. One subject met PCS 
criteria for a vital sign value, a low diastolic blood pressure. Neither PCS value was associated with a TEAE. 
No ECG parameter values met PCS criteria. Most abnormal laboratory, vital sign, and ECG findings were 
consistent with the subjects’ medical conditions. 
These results show that a single dose of ceftaroline fosamil (8 mg/kg up to a maximum dose of 600 mg, IV) 
was generally well tolerated by 9 adolescent subjects who were hospitalized and receiving antibiotic 
therapy for an infection of any type. The mean values of maximum plasma drug concentration (Cmax) and 
AUC for ceftaroline observed in adolescent subjects (12 to 17 years) who received ceftaroline fosamil at a 
dose of 8 mg/kg (600 mg for subjects weighing > 75 kg) were approximately 10% and 23%, respectively, less 
than the values observed in adult subjects following administration of a 600-mg dose of ceftaroline fosamil. 
 
Study P903-21 “Pharmacokinetics of a Single Dose of Ceftaroline fosamil in Children Ages Birth to Younger 
than 12 Years With Suspected or Confirmed Infection” was a Phase 1, multicenter, open-label, 


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sequential, single-dose, prospective study of ceftaroline fosamil. Subjects were enrolled in 5  sequential 
cohorts of descending age; enrollment of sequential cohorts could overlap, depending on results from 
intermittent PK analyses. Subjects who were hospitalized and receiving antibiotic therapy for treatment of 
suspected or confirmed infections were enrolled and each received a single dose of IV ceftaroline fosamil. 
 
Data from Study P903-21, Study P903-15, and other data were used to determine the ceftaroline fosamil 
dose in this study. 
 
4.2.4. Summary of Studies in Adults 
In single- and multiple-dose Phase 1 studies in adults, the Cmax and AUC of ceftaroline increased 
approximately in proportion to increases in dose within the dose range of 50 to 1000 mg, and no 
accumulation of ceftaroline fosamil or active ceftaroline was observed with either q12h or every 24-hour 
multiple dose regimens. Ceftaroline Cmax was generally reached near the end of the IV infusion, and the 
terminal elimination half-life (T½) of ceftaroline was typically in the range of 2.0 to 2.6 hours. Following IV 
infusion of [14C] ceftaroline fosamil, 87.5% of the dose of radioactivity was excreted in urine and 6.0% was 
excreted in feces, confirming that urinary excretion is the principal route of elimination. A significant 
percentage of the ceftaroline fosamil dose was excreted in the urine as ceftaroline (approximately 40% to 
70%). No dosage adjustment is considered necessary for subjects with mild renal impairment. Dosage 
adjustment is recommended in subjects with moderate and severe renal impairment (creatinine clearance 
[CrCl] ≤ 50 mL/min). 
 
Study CEF-PK-02 was a recently completed Phase 1, open-label, multiple-dose study in healthy adult subjects 
to assess the concentration of ceftaroline in ELF. Subjects were randomized to receive one of the following 
dosing regimens: Treatment A - 600 mg ceftaroline fosamil q12h for 3 days with a single dose on Day 4; 
Treatment B - 600 mg ceftaroline fosamil every 8 hours (q8h) for 3 days with a single dose on Day 4. Twenty-
five subjects received each dosing regimen. Plasma samples for PK analysis were collected p r e do s e  and 
over 24 hours after the final dose on Day 4. Subjects underwent bronchoscopy and BAL at a single time point 
after the last dose in order to collect ELF. Preliminary data indicate that the ratio of AUCs of free ceftaroline 
in ELF to free ceftaroline in plasma, assuming 20% protein binding in plasma and no protein binding in ELF, 
was approximately 22%. All subjects had measurable ceftaroline concentrations in ELF at 1, 2, 4, and 6 hours 
after the start of the ceftaroline fosamil infusion. Eight out of 10 subjects that underwent BAL 8 hours after 
dosing had measurable ceftaroline concentration in ELF, and none of the 5 subjects that underwent BAL at 
12 hours after dosing had measurable ceftaroline in ELF. These data demonstrate that ceftaroline is able to 
penetrate into ELF and concentrations of ceftaroline in ELF appreciably exceeded the MIC90 for ceftaroline 
against S. aureus (1 mg/L) at 1 and 2 hours after the start of the ceftaroline fosamil infusion in all subjects. 
Plasma and ELF concentrations were similar for the 2 dosing regimens, with the q8h regimen showing slightly 
(approximately 15% to 20%) higher concentrations on average. Ceftaroline appeared to be eliminated from 
plasma and ELF at a similar rate. 
 
Ceftaroline fosamil at a dose of 600 mg (or 400 mg if the subject had renal impairment) q12h was well 
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monotherapy with ceftaroline fosamil at a dose of 600 mg administered as a 1-hour IV infusion q12h for 5 
to 7 days is effective for the treatment of CABP caused by susceptible isolates of the following gram- positive 
and gram-negative microorganisms: S. pneumoniae (including cases with concurrent bacteremia), MSSA, 
H. influenzae, K. pneumoniae, K. oxytoca, and E. coli. 
 
Therapy with ceftaroline fosamil was shown to be noninferior to ceftriaxone (with or without 
clarithromycin) in the clinical cure rate at TOC in the 2 coprimary populations (Modified Intent-to-Treat 
Efficacy and Clinically Evaluable [CE]). Noninferiority was also demonstrated in the clinical response at 
End-of-Therapy (EOT) in the 2 coprimary populations. Finally, efficacy results consistently demonstrated 
similar cure rates between ceftaroline and ceftriaxone in important subgroups and key secondary 
analyses. Clinical response rates at Study Day 4 in these two studies were 69.6% and 69.0% for ceftaroline 
versus 58.3% and 61.4% for ceftriaxone. 
 
4.3. Rationale for Present Study 
 
Ceftaroline has excellent in vitro activity against S.aureus including MRSA, Group A streptococcus, 
Streptococuccus pneumoniae and Kingella kingae which are the most common causes of acute 
hematogenous osteomyelitis in children. Ceftaroline is now approved by the FDA for treating children with 
community-acccquired pneumonia and skin and soft tissue infections, conditions which are generally 
caused by the same bacteria that cause hematogenous osteomyelitis. Currently CA-MRSA is a major 
problem throughout the United States and the use of vancomycin or clindamycin has increased dramatically 
in children as a result. 
 
Dosing of vancomycin is problematic and vancomycin has common side effects such as red man syndrome 
and renal dysfunction. Clindamycin is not recommended if there are concerns for concomitant 
bacteremia because it is a bacteristatic agent. Daptomycin may be useful but is just being studied in 
pediatric patients for osteomyelitis and should not be used if there is evidence of concomitant pneumonia. 
Thus, the addition of another parenteral antibiotic for treatment of acute hematogenous osteomyelitis 
in children is desirable. 
 
There is no safety data available for administering ceftaroline to adults every 8 hours.  The safety data 
for administering ceftaroline every 8 hours to children has been determined in three pediatric trials. 
(Cannavino et al.  A Randomized, Prospective Study of Pediatric Patients with Community-acquired 
Pneumonia Treated with Ceftaroline Versus Ceftriaxone. Pediatr Infect Dis J 2016; 35:752-9; Blumer et 
al. A Multicenter, Randomized, Observer-blinded, Active-Controlled Study Evaluating the Safety and 
Effectiveness of Ceftaroline Compared with Ceftriaxone Plus Vancomycin in Pediatric Patients with 
Complicated Community-acquired Bacterial Pneumonia. Pediatr Infect Dis J 2016; 35:760-6; Korczowski 
et al. A Multicenter, Randomized, Observer-blinded, Active-controlled Study to Evaluate the Safety and 
Efficacy of Ceftaroline Versus Comparator in Pediatric Patients with Acute Bacterial Skin and Skin 
Structure Infection. Pediatr Infect Dis J 20; 35:e239-47. The most common adverse events for patients 
receiving ceftaroline were diarrhea and vomiting.  Eosinophilia developed in about 5% of patients. The 
proportions of patients developing adverse events were similar for the  
 


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ceftaroline and comparator groups in each of these studies.  We are using the same dose and interval 
for ceftaroline that was used for the pediatric trial of ceftaroline for complicated pneumonia (clinical 
trials identifier number NCT01669980). 
 
4.4. Rationale for Ceftaroline Fosamil Dosage Regimen 
 
The selected ceftaroline dose regimens (15 mg/kg [600 mg if > 40 kg] as a 2-hour infusion q8h) are 
expected to achieve PK/PD targets associated with 1-log kill of S. aureus in the murine pneumonia model 
for organisms with MIC values up to 1 mg/L in > 90% of patients 2 months to < 18 years. The median 
Cmax value in children 1 year to < 18 years with normal renal function dosed with 15 mg/kg q8h as a 2-
hour infusion predicted to be less than the median Cmax value in adults dosed with 600 mg q8h as a 1-
hour infusion. The median AUC0-24h in children 1 year to < 18 years dosed with the above regimen is 
predicted to be up to 15% greater than in adults dosed with 600 mg q8h. The median f T > MIC for an 
MIC of 1 mg/L is predicted to be 84-93% for the recommended pediatric dose regimens compared to 
100% in adults dosed with 600 mg q8h. 
 
Initially, the sponsor believed that a dose of15 mg/kg q8h to match the dose of 600 mg q8h in adults 
was appropriate for children from 6 months to <18 years. However, based on findings in the pediatric 
ABSSSI and CABP studies, a lower dose of 10 mg/kg q8h is more appropriate for children from 6 months 
to          < 2 years in order to avoid higher AUC values. The 10 mg/kg q8h dose in this age range is expected 
to result in a median fT (unbound drug time over MIC)>MIC of 78-88% for an MIC of 1 mg/L and 58-66% 
for an MIC of 2 mg/L. This would give nearly 100% target attainment for a target of 50% at an MIC of 1 
mg/L. The higher dose of 15 mg/kg q8h would still be appropriate for children 2 and older. 
 
4.5. Outpatient Parenteral Antimicrobial Therapy 
 
If a subject is going to require continued parenteral therapy with an antibiotic to complete therapy at home, 
they will be dropped from the study protocol because of the difficulty in providing parenteral antibiotics in 
a study using a home health company. Patient will continue therapy with another agent at home. The 
subjects will be followed and assessed for outcome at the time of discharge as well as for  safety 
assessments at the completion of ceftaroline administration. The home therapy will be determined as 
clinically indicated for such subjects. 
 
4.6. Oral Drugs 
 
A switch to one of the following open-label PO drugs (as per accepted clinical care processes) is expected / 
allowed on or after EOIV assessments are completed and if criteria in Section 9.2 are met: 
• 
PO clindamycin 13 mg/kg/dose q8h in subjects with proven MRSA infection due to clindamycin 
susceptible MRSA or if no pathogen has been isolated. 
OR 
 
• 
PO cephalexin 25 to 33 mg/kg/dose q 8 hours in subjects with proven MSSA infection. 
 
OR 
• 
PO linezolid 600 mg q12h (Children > 12 years old) or 10 mg/kg q8h (children < 12 years old) in 


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subjects with clindamycin-resistant MRSA pathogens or for subjects with MRSA isolates who are 
unable to tolerate clindamycin. 
 
5. STUDY OBJECTIVES 
5.1. Primary Objectives 
 
• 
Evaluate the safety of ceftaroline in pediatric subjects 1 to 17 years of age (inclusive) with acute 
hematogenous osteomyelitis at the end of intravenous therapy. 
 
5.2. Secondary Objectives 
 
• 
Evaluate efficacy of ceftaroline in pediatric subjects with acute hematogenous osteomyelitis at the 
end of IV therapy, at the end of total therapy (anticipated to be at 4 to 6 weeks after enrollment), 
and at one year after enrollment. 
• 
Evaluate clearance of S. aureus bacteremia if blood cultures initially positive. 
• 
Assess proportion of patients with plasma levels of ceftaroline that exceed 1 µg/mL for over 60% of 
a dosing interval. 
 
6. STUDY DESIGN 
 
This is a Phase 1/2, open-label, single-center study to determine safety and tolerability of ceftaroline in 
pediatric subjects 1 to 17 years of age (inclusive) with signs and symptoms of acute hematogenous 
osteomyelitis at the end of intravenous therapy. After informed consent/assent is obtained, ceftaroline 
will be administered intravenously. After the subject has been afebrile for at least 48 hours, has negative 
blood cultures, is clearly improving in general, is able to eat and drink, and is able to use or move the 
involved extremity, the subject may be switched to oral antibiotic administration as outlined in section 
5.4.2. The expenses will be covered by the study. 
 
6.1. Outcome Measures 
Primary: Safety evaluations will be conducted in the children who have started treatment with 
ceftaroline. Assessments will include: 
 
• AEs, SAEs, deaths, and discontinuations due to SAEs. 
 
• Vital signs and laboratory parameters. 
 
Secondary: 
• 
Clinical response (the subject has been afebrile for at least 48 hours, has negative blood cultures, is 
clearly improving in general, is able to eat and drink, and is able to use or move the involved 
extremity) at the end of parenteral therapy (approximately days 5 to 14) by subject and by baseline 
pathogens although S.aureus is expected to be the predominant pathogen. 
 
• 
Clinical outcome (site of infection has complete resolution of pain, swelling and warmth and the 
patient is able to use the affected extremity normally and is back to normal activities) at the EOT and 
at the one year follow up visit. 


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• 
Clinical relapse within a year of enrollment in the study or the development of a pathologic fracture. 
PK: 
• 
Concentrations of ceftaroline fosamil, ceftaroline, and ceftaroline M-1 in plasma. 
 
• 
If available, concentrations of ceftaroline fosamil, ceftaroline, and ceftaroline M-1 in purulent material 
such as bone or subperiosteal abscess or synovial fluid. 
 
6.2. Number of Subjects 
 
18 Children 1 to 17 years of age, inclusive. Each subject will receive ceftaroline.  2 subjects above 5 years 
old will be enrolled before the younger subjects are enrolled. 
 
Based on A’Hern’s single-stage design for Phase II clinical trials 18 subjects would be required to reject 
H_0:π≤0.50 and conclude H_1:π≥0.80 with 80% power assuming a Type 1 error rate of 0.05.  
 
6.3. Expected Duration of Subject Participation 
 
The duration of subject participation from signing the informed consent form will be up to 14 months 
(includes screening period (1 Day), study IV drug administration (approximately 5-14 Days), Standard of 
Care Oral Drug Administration (4-5 weeks) (the total maximum treatment period is typically 6 weeks), 
and a follow-up visit 12 months after the last dose of study drug).  Baseline assessments for study eligibility 
will occur within 24 hours before the first dose of study drug. A minimum of 2 days (48 hours) of study 
drug administration is required. 
 
6.4. Data Review Committee 
 
A Data and Safety Review Committee (DRC) will be established to review safety data on a regular basis to 
ensure safety of all subjects enrolled.  
A DRC meeting is to be held at regular intervals to evaluate the safety of this study and other ongoing 
pediatric studies of ceftaroline fosamil. The role of the DRC members is to evaluate the safety of the pediatric 
studies 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 enrollment. 
 
A detailed DRC charter will be prepared by the Investigator and agreed to by all DRC members before 
initiation of enrollment in this study. This charter will document the timing, membership, analysis content, 
and review procedures for each DRC meeting. Safety information will be prepared in advance of each DRC 
meeting. Safety analyses will include, at a minimum, summaries of study disposition and all SAEs, deaths, 
and discontinuations due to AEs, PCS laboratory results, and individual subject listings of selected safety 
data. 
 
7. SELECTION, DISCONTINUATION AND WITHDRAWAL OF STUDY SUBJECTS 
 
7.1. Inclusion Criteria 
 
Subjects are required to meet the following inclusion criteria: 


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1. Informed consent in writing from parent(s) or other legally acceptable representative(s) and assent 
from subject (if appropriate according to local requirements). 
2. Male or female 1 to 17 years of age, inclusive. 
3. Suspected hematogenous SA osteomyelitis in a large bone (upper or lower extremities, pelvis) based 
on clinical findings and radiology results. 
4. One to three sites of osteomyelitis with expectation that transition to oral antibiotics will be likely  prior 
to discharge to complete IV therapy (The second or third site might be contiguous like a proximal tibia 
and distal femur but could also be at sites unrelated such as a distal femur and pelvic bone). 
5. Female subjects who have reached menarche must have a negative urine pregnancy test. 
6. Female subjects who have reached menarche and are sexually active must be willing to practice sexual 
abstinence or dual methods of birth control (eg, condom or diaphragm with spermicidal foam or gel) 
during treatment and for at least 28 days after the last dose of any study drug. 
7. Sufficient IV access to receive medication. 
 
7.2. Exclusion Criteria 
 
Subjects must NOT meet any of the following exclusion criteria. Septic arthritis contiguous to 
the site of osteomyelitis is not an exclusion criterion. 
1. Received more than 24 hours of IV antibiotics prior to enrollment. 
2. More than three bones infected. 
3. Disseminated infection or is admitted to the pediatric intensive care unit. 
4. Underlying condition (excludes mild eczema or reactive airways disease). 
5. Suspected venous thrombosis or concern for endocarditis. 
6. Requirement for other reasons for another antibiotic potentially active against organisms 
commonly causing osteomyelitis in children. 
7. Creatinine clearance < 50 mL/min/1.73m2 (calculated by the Schwartz formula) 
8. AST or ALT > 3 times the upper limit of normal. 
9. Neutropenia (<500 neutrophils/mm3) 
10. Thrombocytopenia (<50,000 platelets/mm3) 
11. Females who are currently pregnant or breast feeding. 
12. Hypersensitivity reaction to any Beta-lactam antibiotic 
13. Has had an allergic reaction to ceftaroline in the past. 
 
7.3. Prior and Concomitant Treatment and Medications 
 
All antimicrobials, painmedications, andantipyreticsthatweretakenorreceivedwithin 14 daysbeforethefirstdoseof 
studydrugandthosetakenduringthestudy will be recorded. Pain medications such as acetaminophen-codeine, 
ketorolac, and morphine, will be recorded unless they were used during administration of anesthesia. 
Medications related to adverse events will be recorded. In addition, each subject’s history of pneumococcal 
vaccinations will be documented, if possible. 
 
 
7.4. Permitted Treatment and Medications 
 
Concomitant use of the following is permitted: 1) antipyretics as standard of care for fever or symptoms, 
provided temperature is measured before administration of the antipyretics; 2) Topical antibiotics; and 3) 
all other concomitant medications and nutrients necessary for the health and well- being of the subject. 
 


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7.5. Prohibited Medications and Therapies 
 
Concomitant use of the following is not permitted: 1) potentially effective systemic antibacterial therapy; 2) 
any drug known to exhibit a contraindicated drug-drug interaction with the study drug; or labeled 
contraindication to use of oral drug(s); and 3) other cephalosporins/aminoglycosides or other nephrotoxic 
agents. 
 
7.6. Screening Failures 
 
Subjects who sign and date the ICF but who fail to meet the inclusion and exclusion criteria are defined as 
screen failures. A screening log will be maintained for all screen failures. 
 
7.7. Subject Discontinuation or Withdrawal 
 
Subjects should be encouraged to complete all study outcome assessments. However, a subject may be 
discontinued from study drug or may withdraw assent/consent to participate in this study at any time 
without penalty or loss of benefits to which the subject is otherwise entitled. Subjects will be assessed for 
safety of ceftaroline at the time points outlined in the schedule of evaluations, if possible. 
 
7.7.1. Off Study Criteria: 
• 
Subjects who require continued home parenteral antibiotics will be discontinued from the study. 
• 
Subjects that require IV treatment after switching to Oral drug. 
• 
If a subject’s estimated CrCl decreases to < 50 mL/min during the treatment period, the subject will be 
discontinued from the study. 
• 
Diarrhea (the occurrence of > 4 loose stools /day) with blood or mucus 
• 
Moderate to severe maculopapular rash that does not resolve following administration of 
diphenhydramine (Benadryl®) or any urticarial rash. 
• 
Absolute neutrophil count < 500 WBC/mm3 (Grade 4) 
• 
Hemolytic anemia Grade 2 (evidence of > 2 g decrease in hemoglobin but does not require blood 
transfusion) or above. 
• 
Thrombocytopenia-Platelet count < 100,000/mm3 (Grade 1) 
• 
AST/ALT > 3 X ULN (grade 3) 
 
7.8. Premature Discontinuation From Study Drug Administration 
7.8.1. Discontinuations Due to Safety 
 
Assessments and Procedures: A subject who is prematurely discontinued from study drug administration (ie, 
before the anticipated full course of study drug required for effective treatment of hematogenous SA 
osteomyelitis for safety reasons) should have EOIV or EOT (if on PO drug) assessments conducted per Section 
9, and undergo subsequent assessments at FU, if possible. The same procedures will be followed if the 
subject needs to continue home IV therapy to complete treatment because the subject is intolerant of an 
appropriate oral antibiotic or there is no oral agent that is active against the organism isolated. 
 
Clinical Outcome Assessment: 
 
If a subject prematurely discontinues the study drug due to an SAE and requires alternative non-study 
antimicrobials for hematogenous SA osteomyelitis, the subject should be assessed indeterminate. 
 
Reasons: Reason(s) for premature discontinuation from study drug administration due to safety may 
include, but are not limited to, the following: 


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• 
Occurrence of an SAE that, in the opinion of the Investigator, warrants the subject’s permanent 
discontinuation from the study drug or oral drug administration. 
 
• 
Known pregnancy or breastfeeding during the drug administration period. A female subject whose 
pregnancy test is positive at the end of total treatment must be followed through the immediate 
postnatal period or until termination of the pregnancy. Every pregnancy will be reported as soon as 
possible (within 24 hours of learning of the pregnancy), as described in Section 11.1.4. 
 
7.8.2. Discontinuations Due to Insufficient Therapeutic Effect 
 
Assessments and Procedures: A subject who is prematurely discontinued from study drug administration 
due to insufficient therapeutic effect should have EOIV (if on IV study drug) or EOT (if on PO drug) assessments 
conducted per Section 9, and undergo subsequent safety assessments at the 4 to 6 week follow up visit. If a 
subject is discontinued from IV study drug administration due to insufficient therapeutic effect and is 
switched to an alternative IV antibiotic, the alternative therapy should be recorded. 
 
Clinical Outcome Assessment: A subject who is prematurely discontinued from study drug administration 
due to insufficient therapeutic effect should be assessed as a clinical failure on the day of discontinuation. 
Such a subject will be automatically assigned an outcome of clinical failure at all subsequent evaluation time 
points. 
Reasons: Reason(s) for discontinuation from study drug administration due to insufficient therapeutic 
effect may include, but are not limited to, the following: 
 
• 
Clinical Worsening: A subject who shows signs of clinical worsening may be prematurely discontinued 
from study drug administration at any time. If the Investigator deems the benefit-to-risk ratio of 
continuing study drug acceptable, study drug administration for at least 48 hours is encouraged before 
discontinuation.   If the subject is improving clinically but the blood cultures are persistently positive for 
S. aureus for up to 5 days, ceftaroline can be continued at the discretion of the investigator. 
 
• 
Lack of Clinical Progress: For a subject who is stable, yet does not show signs of improvement, the 
Investigator is encouraged to continue study drug administration at least 48 hours before such a 
subject is assessed as a clinical failure and the subject is prematurely discontinued from study drug. 
 
7.8.3. Withdrawal 
 
Assessments and Procedures: A subject may withdraw from the study, or be withdrawn at the request of 
their parent(s) or legally acceptable representative(s), the Investigator, or Sponsor. A subject who is 
withdrawn completely from this study during study treatment should be encouraged to undergo, if possible, 
EOIV (if on IV study drug) or EOT (if not on IV study drug) assessments per Section 10, respectively, on the 
day of withdrawal. 
Clinical Outcome Assessment: A subject withdrawn from the study who is not assessed as a clinical failure 
should be assessed as indeterminate at all subsequent outcome evaluation time points. 
 
Reasons: Reason(s) for withdrawal from the study may include, but are not limited to, the following: 
 
• 
Withdrawal of assent or consent 
• 
Lost to follow up 
• 
Significant subject noncompliance, defined as refusal or inability to adhere to the prescribed dosing or 


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follow-up regimen 
• 
Investigator determination that it is in the best interest of the subject to withdraw from the study, due 
to reasons other than an SAE. 
 
7.9. Replacement of Subjects 
 
Subjects who are withdrawn from study before receiving any amount of study drug will be replaced in order 
to enroll a total of 18 treated subjects for safety evaluations. Subject numbers will not be reused. 
 
7.10. Stopping Rules 
 
The incidence or severity of AEs indicates a potential health hazard to subjects. The study will be stopped 
if treatment failures occur in two patients or severe adverse events that are due to ceftaroline in the opinion 
of the PI occur in two patients. 
 
8. STUDY DRUGS 
8.1. Ceftaroline Fosamil Intravenous Study Drug 
 
 
Ceftaroline fosamil for injection, 400 or 600 mg per vial, is supplied as a sterile pale yellowish-white to light 
yellow crystalline powder in a single-dose, clear glass 20-mL vial. The excipient L-arginine is added as an 
alkalizing agent to maintain the pH of the constituted solution between 4.8 and 6.5. 
 
Ceftaroline fosamil is approved in the United States for use in adults with ABSSSI or CABP. Ceftaroline fosamil 
is limited in pediatric subjects to investigational use only. Refer to the current ceftaroline fosamil IB 
(Ceftaroline fosamil, 2011) for additional information. 
 
Dosing Information: IV ceftaroline fosamil 15 mg/kg (or 600 mg if > 40 kg) infused over 120 (± 10) minutes 
q8h (± 1 hour) for children 2 years of age – 17 years of age (inclusive). 
 
IV ceftaroline fosamil 10 mg/kg infused over 120 (± 10) minutes q 8h (± 1 hour) for children from 1 year of 
age to < 2 years (inclusive). 
 
8.2. Directions for Use 
 
Vials of ceftaroline fosamil are constituted with 20.0 mL of Sterile Water for Injection; the amount of solution 
containing the appropriate dose is further diluted in sterile normal saline before infusion. 
 
8.3. Storage 
 
Vials containing unconstituted ceftaroline fosamil are stored according to labeled requirements. 
 
8.4. Criteria for Switching to Oral Drug 
 
A switch to PO drug (see Section 9.2.2) is allowed on or after EOIV assessments are completed and if all of 
the following criteria are met: 
 
• 
Received at least 48 hours of IV study drug. 
 


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• 
Clinical signs and symptoms have been assessed. 
 
• 
Ability to maintain oral intake. 
 
• 
Afebrile (temperature ≤ 38.0°C) for at least 48 hours. 
 
• Blood cultures are negative for 48 hours. 
 
• CRP decreased compared with baseline value. 
 
• 
Absence of new or improvement in at least 1 of the following signs and symptoms and worsening of 
none: 
 
o Extremity movement or pain. 
 
o Able to ambulate either unaided or with a walker or crutches. 
 
Subjects that require IV treatment after switching to Oral drug will be discontinued from the study. 
 
8.4.1. Oral Drug Options 
 
The appropriate PO drug may depend on the pathogen, the options include the following: 
 
• 
Preferred oral switch for subjects with infections due to methicillin-susceptible S. aureus, Group A 
streptococcus or K. kingae-cephalexin 75-100 mg/kg/day in three divided doses. 
 
• 
Alternative PO option for subjects with proven MRSA infections due to clindamycin-susceptible is 
clindamycin 13 mg/kg/dose q8h. Clindamycin is also the oral agent typically selected to complete 
treatment when no organism is isolated. 
 
• 
Linezolid is an option for completing therapy for a clindamycin resistant MRSA isolate or for patients 
who cannot tolerate clindamycin. Linezolid dosing is 10 mg/kg/dose q 8 hours for children < 12 year 
old and 600 mg q 12 hours for children > 12 years old. 
 
Dosing adjustments are discussed in Section 9.3. Consult the package inserts, labels, and local dosing 
guidelines regarding preparation, storage, administration, maximum doses, contraindications, warnings, 
precautions, and AEs reported with the use of the PO study drugs. 
 
8.5. Dose Adjustments 
 
Subjects with moderately (CrCl 30 mL/min to ≤ 50 mL/min) or severely (CrCl < 30 mL/min) impaired renal 
function (calculated using the appropriate updated Schwartz “bedside” formula; Schwartz et al, 2009) will 
not be enrolled in this study; thus no ceftaroline fosamil dose adjustments are expected to be required for 
renal impairment. However, if the subject’s estimated CrCl decreases to < 50 mL/min during the treatment 
period, the patient will be discontinued from the study. 
 
8.6. Adjunctive Surgical Procedures 
 
Details of adjunctive surgical procedure(s) related to hematogenous SA osteomyelitis that are performed 
for any subject in this study will be collected and documented. 


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8.7. Treatment Compliance 
 
Treatment compliance will be documented in the eCRF by recording the date, time, and whether or not 
each IV dose study drug was completely infused and, if applicable, whether or not each intended dose of 
PO drug was taken. 
 
8.8. Accountability Procedures 
 
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. 
 
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. 
 
All study drugs provided by Allergan should be retained at the site until otherwise instructed in writing by 
Allegan. Upon completion of the study all used (vials), unused, and partially used IV study drugs will be 
shipped to a site designated by Allergan. Refer to the Pharmacy instructions or package insert for additional 
information. 
 
9. STUDY ASSESSMENTS AND PROCEDURES 
 
The Schedule of Assessments and Procedures is located in Table 2.1. Unless otherwise noted, the 
assessments and procedures should be conducted in person by the Investigator or designee. 
 
Any protocol-required evaluations (eg, laboratory tests and) already done locally on the corresponding 
study day, including baseline, as part of the subject’s regular medical care can be recorded on the eCRFs 
and do not have to be repeated for purposes of this study. 
 
9.1. Baseline 
 
Baseline procedures must be completed within 24 hours before the start of the first dose of IV study drug. 
Potential subjects who do not meet entrance criteria may, as appropriate, repeat baseline evaluations at a 
later time for possible enrollment into the study. 
 
• 
Obtain informed consent in writing from parent(s) or legally acceptable representative(s) and assent 
from subject (as applicable) before initiating any study assessment or procedure. 
 
• 
Collect demographic information including age, gender, race and ethnicity. 
 
• 
Clinical Assessments (assessments will be performed for research unless they are already being performed 
per standard of care; exceptions are indicated): 
 
o 
Obtain a complete medical and surgical history, including history of surgical procedures for 
complications of hematogenous SA osteomyelitis (eg, drainage of the bone) and all active conditions 
and all conditions diagnosed within the previous 5 years (from the following categories: allergic; 
cardiovascular; dermatological; gastrointestinal; genital and reproductive; head, eyes, ears, nose, 
and throat; hematology; hepatic; immunological; metabolic and endocrine; musculoskeletal; 


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neurologic; psychiatric; renal; and respiratory). 
 
o 
Record prior medications (Section 8.3) taken or received within 14 days before the first dose of 
study drug. For children who are being breast fed, record all medications taken by the lactating 
mother during the 3 days before the first dose of IV study drug. In addition, record history of 
pneumococcal vaccinations. 
 
o 
Record standard of care radiology results.  
o 
Record the findings of a complete physical examination including physical findings of hematogenous 
SA osteomyelitis (eg, warmth, tenderness, swelling, erythema, and movement of the infected 
extremity). Involved extremity will be assessed as at enrollment, if possible. Most of the subjects 
are expected to have surgical incision and drainage procedures and thus assessing the extremity for 
swelling, erythema, warmth and tenderness may not be possible because of drains in place and 
large surgical dressings that cannot be removed. 
o 
Record height and weight. 
 
o 
Record vital signs: resting pulse, blood pressure, and respiratory rate; and highest daily 
temperature (Tmax) measured. 
 
o 
Identify, assess, and record any AEs and SAEs starting from the time that informed consent is 
obtained. 
 
o 
Record adjunctive therapeutic procedures (eg, surgeries). 
 
Laboratory Assessments (assessments will be performed for research unless they are already being 
performed per standard of care; exceptions are indicated) 
 
o 
Any protocol-required eligibility laboratory evaluations already done locally as part of the subject’s 
regular medical care within 24 hours before the start of the first dose of IV study drug do not have 
to be repeated for purposes of this study. 
 
o 
Collect complete blood count (CBC) with differential and CRP, ESR, BUN, and Creatinine lab results. 
 
o 
Blood cultures per standard of care. 
 
o 
Obtain blood samples for Alkaline Phosphatase, Bilirubin, AST and ALT. 
 
o 
Obtain blood sample for Direct Coombs test. 
 
o 
Obtain urine sample for pregnancy test (for a female who has reached menarche); ensure that the 
test is negative before enrollment. 
o 
Estimate CrCl using the updated Schwartz “bedside” formula (Schwartz et al, 2009): 
CrCl (mL/min/1.73m2) = 0.413 x height (length) (cm) 
serum creatinine (mg/dL) 
o 
Collect purulent material from bone only if a procedure is performed for standard of care. 
 
• 
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should be no medically inappropriate delay in enrollment and subsequent administration of IV study 
drug. 
 
9.2. Study Day 1 
 
• 
Study Drug Administration: 
 
IV ceftaroline fosamil 15 mg/kg (or 600 mg if > 40 kg) infused over 120 (± 10) minutes q8h (± 1 hour) for 
children 2 years of age – 17 years of age (inclusive). 
 
IV ceftaroline fosamil 10 mg/kg infused over 120 (± 10) minutes q 8h (± 1 hour) for children from 
1 year of age to < 2 years (inclusive). 
 
The following Clinical and Laboratory Assessments for Study Day 1 do not need to be repeated if dosing of 
study medicine is done on the same day as the baseline visit: 
 
• Clinical Assessments - after at least 1 dose of IV study drug (assessments will be performed for research 
unless they are already being performed per standard of care; exceptions are indicated): 
 
o 
Record concomitant medications (Section 8.3). For subjects who are being breast fed, record all 
medications taken by the lactating mother. 
 
o 
Record resting vital signs (pulse, blood pressure, and respiratory rate), and highest postdose 
temperature measured. 
 
o 
Record adjunctive therapeutic procedures (eg, surgeries). 
 
o 
Record standard of care radiology results. 
 
o 
Evaluate and record physical findings of hematogenous SA osteomyelitis (eg, warmth, tenderness, 
swelling, erythema, and movement of the infected extremity). Most of the subjects are expected to 
have surgical incision and drainage procedures and thus assessing the extremity for swelling, 
erythema, warmth and tenderness may not be possible because of drains in place and large surgical 
dressings that cannot be removed. The degree of the subject’s ability to ambulate will be assessed 
if the osteomyelitis is in the lower extremity-i.e. walks unaided, able to bear weight, can walk aid 
using a walker, etc. The use of upper and lower extremities will be assessed in terms of movement 
and range of motion. 
 
o 
Identify, assess, and record any new or ongoing AEs or SAEs 
 
• Laboratory Assessments - after at least 1 dose of IV study drug (assessments will be performed for research 
unless they are already being performed per standard of care; exceptions are indicated) 
 
o 
If clinically indicated, calculate CrCl using the updated Schwartz “bedside” formula (Schwartz et 
al, 2009). 
 
o 
Collect results of blood cultures only if conducted per standard of care.  
 
o 
Collect purulent material from bone only if a procedure is performed for standard of 
care. 
 


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9.3. Study Days 2-14 
 
The total duration of IV ceftaroline is dependent on the subject's response to therapy but 5-14 days is 
anticipated in most subjects. If the subject is able to switch to oral drug before Day 15, the procedures 
outlined for Day 15 (EOIV) should be performed. The rest of the visit schedule will be followed as described 
in Table 2.1. 
• 
Study Drug Administration: 
 
IV ceftaroline fosamil 15 mg/kg (or 600 mg if > 40 kg) infused over 120 (± 10) minutes q8h (± 1 hour) for 
children 2 years of age – 17 years of age (inclusive). 
 
IV ceftaroline fosamil 10 mg/kg infused over 120 (± 10) minutes q 8h (± 1 hour) for children from 
1 year of age to < 2 years (inclusive) until the subject transitions to oral therapy. 
 
• Clinical Assessments – any time during study day (assessments will be performed for research unless they 
are already being performed per standard of care; exceptions are indicated): 
o 
Record concomitant medications (Section 8.3). For subjects who are being breast fed, 
record all medications taken by the lactating mother. 
 
o 
Record resting vital signs (pulse, blood pressure, and respiratory rate), and highest 
postdose temperature measured. 
 
o 
Record adjunctive therapeutic procedures (eg, surgeries). 
 
o 
Record standard of care radiology results. 
 
o 
Evaluate and record physical findings of hematogenous SA osteomyelitis (eg, warmth, 
tenderness, swelling, erythema, and movement of the infected extremity). Most of the 
subjects are expected to have surgical incision and drainage procedures and thus assessing 
the extremity for swelling, erythema, warmth and tenderness may not be possible 
because of drains in place and large surgical dressings that cannot be removed. The degree 
of the subject’s ability to ambulate will be assessed if the osteomyelitis is in the lower 
extremity-ie. walks unaided, able to bear weight, can walk aid using a walker, etc. The use 
of upper and lower extremities will be assessed in terms of movement and range of 
motion. 
 
o 
Identify, assess, and record any new or ongoing AEs or SAEs 
 
• Laboratory Assessments – any time during the study period if clinically indicated (assessments will be 
performed for research unless they are already being performed per standard of care; exceptions are 
indicated): 
○ 
Collect CRP and ESR lab results, if clinically indicated.  
 
o 
Collect CBC with differential, BUN, and Creatinine, lab results, if clinically indicated.  
 
o 
Obtain blood sample for Alkaline Phosphatase, Bilirubin, AST and ALT, if clinically indicated.  
 
○ 
If clinically indicated, estimate CrCl using the updated Schwartz “bedside” formula (Schwartz et al, 
2009). 
 
○ 
Collect results of blood cultures only if conducted per standard of care. 


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○ 
Collect purulent material from bone only if a procedure is performed for standard of care when 
possible. 
 
• 
PK Procedures: 
 
o 
Efforts will be made to obtain 1 PK blood sample (approximately 0.6 mL) at steady state from all 
subjects who received ceftaroline fosamil on Days 2 to 5 of treatment (only one PK sample 
collected on days 2-5) 4 hours (+/- 30 minutes) after the end of the infusion (before the start of 
the next infusion). PK samples may be collected after any infusion of ceftaroline fosamil on those 
days and before oral switch. 
 
o 
If purulent material is being obtained from bone or subperiosteal abscesses at surgery or via 
drainage by interventional radiology, we will attempt to obtain specimens for measurement of 
ceftaroline concentrations. 
 
9.4. Study Day 15 (End of IV Treatment-EOIV) 
 
The total duration of IV ceftaroline is dependent on the subject’s response to therapy but 5-14 days is 
anticipated in most subjects. If the subject is able to switch to oral drug before Day 15, these procedures 
may be performed before Day 15. Conduct EOIV assessments within 24 hours after administration of the 
last dose of IV study drug (subjects will likely remain in the hospital for less than 24 hours once they are 
transitioned to oral therapy as per standard of care) or at time of premature discontinuation of study drug 
or early withdrawal from study (if on IV study drug). Conduct the EOIV assessments in place of the regular 
study visit assessments that would have been performed the day of that visit. A subject may be eligible to 
switch to PO drug on or after Study Day 3 (Section 9.2). EOIV assessments must occur before starting PO 
drug.  The rest of the visit schedule should be followed as described in Table 2.1. 
 
If applicable, as IV study drug may or may not be given on the same calendar day as EOIV assessments, 
administer IV study drug IV ceftaroline fosamil 15 mg/kg (or 600 mg if > 40 kg) infused over 120 (± 10) minutes 
q8h (± 1 hour) for children 2 years of age – 17 years of age (inclusive). 
 
IV ceftaroline fosamil 10 mg/kg infused over 120 (± 10) minutes q 8h (± 1 hour) for children from 
1 year of age to < 2 years (inclusive) until the subject transitions to oral therapy. 
 
• 
Clinical Assessments - any time during study day, but before starting PO study drug, if applicable 
(assessments will be performed for research unless they are already being performed per standard of 
care; exceptions are indicated): 
 
o 
Record concomitant medications (Section 8.3). For subjects who are being breast fed, record all 
medications taken by the lactating mother. 
 
o 
Record vital signs: resting pulse, blood pressure, and respiratory rate; and highest daily 
temperature measured. 
 
o 
Record adjunctive therapeutic procedures (eg, surgeries). 
o 
Record standard of care radiology results. 
o 
Evaluate and record physical findings of hematogenous SA osteomyelitis (eg, warmth, tenderness, 
swelling, erythema, and movement of the infected extremity). Most of the subjects are expected 


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to have surgical incision and drainage procedures and thus assessing the extremity for swelling, 
erythema, warmth and tenderness may not be possible because of drains in place and large 
surgical dressings that cannot be removed. The degree of the subject’s ability to ambulate will be 
assessed if the osteomyelitis is in the lower extremity-ie.  Walks unaided, able to bear weight, can 
walk aid using a walker, etc. The use of upper and lower extremities will be assessed in terms of 
movement and range of motion. 
 
o 
Assess clinical outcome (site of infection has complete resolution of pain, swelling and warmth 
and the patient is able to use the affected extremity normally and is back to normal activities). 
 
o 
Identify, assess, and record any new or ongoing AEs or SAEs. Subjects will likely remain in the 
hospital for less than 24 hours once they are transitioned to oral therapy as per standard of care. 
 
• 
Laboratory Assessments- any time during study day, but before starting PO drug, if applicable. If these 
assessments are performed within 48 hours of latest results, do not repeat these assessments 
(assessments will be performed for research unless they are already being performed per standard of 
care; exceptions are indicated): 
 
o 
Collect CRP and ESR lab results.   
 
o 
Collect CBC with differential, BUN, and Creatinine. 
 
o 
Obtain blood sample for AST, ALT, Alkaline Phosphatase, Bilirubin and Direct Coombs. 
 
o 
If clinically indicated, estimate CrCl using the updated Schwartz “bedside” formula (Schwartz et al, 
2009). 
 
o 
Collect results of blood cultures for S. aureus only if conducted per standard of care. 
 
o 
Collect purulent material from bone only if a procedure is performed for standard of care 
when possible. 
 
9.5. Week 2, Week 4, and Week 6 After Discharge 
 
• 
PO drug administration: 
 
o PO clindamycin 13 mg/kg/dose q8h in subjects with proven MRSA infection due to clindamycin 
susceptible MRSA or when no pathogen is isolated. 
OR 
o PO cephalexin 25 to 33 mg/kg/dose q 8 hours in subjects with proven MSSA infection. 
OR 
o PO linezolid 600 mg q12h (Children > 12 years old) or 10 mg/kg q8h (children < 12 years old) in 
subjects with clindamycin-resistant MRSA pathogens. 
 
Clinical Assessments - any time during study day (assessments will be performed for research unless they are 
already being performed per standard of care; exceptions are indicated): 
 
o 
Obtain an interval medical and surgical history focusing on the involved extremity, including history 


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of surgical procedures for complications of hematogenous SA osteomyelitis (eg, drainage of the 
bone) and all active conditions from the following categories.  
 
o 
Record concomitant medications (Section 8.3). For subjects who are being breast fed, record all 
medications taken by the lactating mother. 
 
o 
Record vital signs: resting pulse, blood pressure, and respiratory rate. 
 
o 
Record adjunctive therapeutic procedures (eg, surgeries). 
 
o 
Record standard of care radiology results. 
 
o 
Evaluate and record physical findings of hematogenous SA osteomyelitis (eg, warmth, tenderness, 
swelling, erythema, and movement of the infected extremity). Most of the subjects are expected to 
have surgical incision and drainage procedures and thus assessing the extremity for swelling, 
erythema, warmth and tenderness may not be possible because of drains in place and large surgical 
dressings that cannot be removed. The degree of the subject’s ability to ambulate will be assessed 
if the osteomyelitis is in the lower extremity-ie. walks unaided, able to bear weight, can walk aid 
using a walker, etc. The use of upper and lower extremities will be assessed in terms of movement 
and range of motion. 
 
o 
Assess clinical outcome (site of infection has complete resolution of pain, swelling and warmth 
and the patient is able to use the affected extremity normally and is back to normal activities). 
 
o 
Identify, assess, and record any new or ongoing AEs or SAEs. 
 
Laboratory Assessments - any time during study day, but before starting PO study drug, if applicable 
(assessments will be performed for research unless they are already being performed per standard of care; 
exceptions are indicated): 
 
o 
Collect CRP and ESR lab results, if clinically indicated for standard of care. 
 
o 
If clinically indicated, estimate CrCl using the updated Schwartz “bedside” formula (Schwartz et al, 
2009). 
 
9.6. End of Antibiotic Therapy (EOT)/Week 4/ OR Week 6 
 
Note that EOT visit and assessments may occur at the Week 4 visit or the Week 6 visit.   If the EOT visit occurs 
on the same day as the Week 4 or Week 6 visit, only the EOT visit will be recorded in CTMS. 
 
• 
If applicable, as PO drug may or may not be given on the same calendar day as EOT assessments, 
administer PO drug as described in Section 9.2. 
 
• 
Clinical Assessments - any time during visit (assessments will be performed for research unless they are 
already being performed per standard of care; exceptions are indicated): 
 


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o 
Record concomitant medications (Section 8.3). For subjects who are being breast fed, record all 
medications taken by the lactating mother.  
o 
Record height and weight. 
 
o 
Record vital signs: resting pulse, blood pressure, respiratory rate and temperature. 
 
o 
Record adjunctive therapeutic procedures (eg, surgeries), if performed. 
 
o 
Record standard of care radiology results. 
o 
Evaluate and record physical findings of hematogenous SA osteomyelitis (eg, warmth, tenderness, 
swelling, erythema, and movement of the infected extremity). The degree of the subject’s ability to 
ambulate will be assessed if the osteomyelitis is in the lower extremity-ie. walks unaided, able to 
bear weight, can walk aid using a walker, etc. The use of upper and lower extremities will be 
assessed in terms of movement and range of motion. 
 
o 
Assess clinical outcome (site of infection has complete resolution of pain, swelling and warmth and 
the patient is able to use the affected extremity normally and is back to normal activities). 
 
o 
Identify, assess, and record any new or ongoing AEs or SAEs 
 
• 
Laboratory Assessments (Local Laboratory) - any time during visit, Collect CRP and ESR lab results, if 
clinically indicated for standard of care. 
 
o 
Obtain urine sample for urine pregnancy (for a female who has reached menarche). 
 
o 
If clinically indicated, estimate CrCl using the updated Schwartz “bedside” formula (Schwartz et al, 
2009). 
 
9.7. Follow Up 
 
Conduct FU assessments 12 months after administration of the last dose of the drug (IV or PO whichever is 
the latest). 
 
• Clinical Assessments - any time during visit (assessments will be performed for research unless they are 
already being performed per standard of care; exceptions are indicated):  
 
o 
Record concomitant medications (Section 8.3). For subjects who are being breast fed, record all 
medications taken by the lactating mother. 
 
o 
Record vital signs: resting pulse, blood pressure, respiratory rate and temperature. 
 
o 
Record adjunctive therapeutic procedures (eg, surgeries). 
 
o 
Record standard of care radiology results. 
 
o 
Assess clinical outcome (site of infection has complete resolution of pain, swelling and warmth 
and the patient is able to use the affected extremity normally and is back to normal activities). 
 
o 
Identify, assess, and record event such as pathologic fractures and growth disturbances.  
o 
Laboratory Assessments - any time during visit: 


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o 
If clinically indicated, estimate CrCl using the updated Schwartz “bedside” formula (Schwartz et al, 
2009). 
 
9.8. Safety Lab Tests 
9.8.1. Study Required Lab Tests 
 
Alkaline Phosphatase, Bilirubin, AST, ALT and Direct Coombs (DATscreen) will be obtained within 24 hours 
prior to enrollment; and at the completion of ceftaroline treatment (EOIV visit). 
 
Isolate susceptibilities: The ceftaroline MIC of S. aureus isolates or other isolates such as Group A 
streptococcus, Streptococcus pneumoniae or Kingella kingae that are obtained from the patients with acute 
hematogenous osteomyelitis will be determined using Clinical and Laboratory Standards Institute (CLSI) 
methods. These will be performed in the CAP certified Infectious Disease Research Laboratory. CLSI 
interpretive breakpoints will be used to determine if the isolate is susceptible, intermediate or resistant to 
ceftaroline. The samples will be obtained from pathology (from already collected samples) to conduct the 
Isolate susceptibility studies. 
 
9.8.2. Standard of Care Labs 
 
Record the following local safety labs if performed per standard of care: hemoglobin, hematocrit, WBC, 
platelet count, BUN, serum creatinine, CRP and ESR.  If multiple laboratory tests are obtained on the same 
day, record test results closest to administration of study drug. 
 
9.8.3. PK Assessments 
 
The pharmacokinetic (PK) outcome measures will include concentrations of ceftaroline, ceftaroline fosamil 
(prodrug), and ceftaroline M-1 (inactive metabolite) in plasma in subjects on days 2 to 5 of treatment (only 
one PK sample collected on days 2-5) 4 hours (+/- 30 minutes) after the end of the infusion (before the start 
of the next infusion). Efforts will be made to obtain 1 PK blood sample (approximately 0.6 mL) at steady 
state from all subjects who receive ceftaroline fosamil. PK samples may be collected after any infusion of 
ceftaroline fosamil on those days and before oral switch. 
 
If purulent material is being obtained from bone or sub periosteal abscesses at surgery or via drainage by 
interventional radiology, we will attempt to obtain specimens for measurement of ceftaroline 
concentrations. 
 
All samples will be sent to Keystone Bioanalytical, Inc. for analysis. 
 
9.9. Diagnostic Imaging and Non-Pharmacological Assessments 
 
All diagnostic imaging procedures including x-ray or MRIs, in accordance with routine standard of care, will 
be recorded on the study eCRF. Non-pharmacologic treatments/procedures (such as surgeries) performed 
in accordance with routine standard of care will be recorded on the study eCRF. 


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10. SAFETY ASSESSMENTS 
 
Subjects must be seen by a physician or an appropriately trained healthcare professional at every study 
visit, and the evaluation must be documented. The procedures discussed below will be completed at the 
designated visits as outlined in Section 10.0. 
 
10.1. Adverse Events 
 
An AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
 
Examples of AEs are as follows: 
 
• 
Changes in the general condition of the subject. 
 
• 
Subjective symptoms offered by or elicited from the subject. 
 
• 
Objective signs observed by the Investigator or other study personnel. 
 
• 
All diseases that occur after the start of the study, including any change in severity or frequency of 
preexisting disease. 
 
• 
All clinically relevant abnormalities in laboratory values or clinically relevant physical findings that occur 
during the study. 
 
10.2. Causality and Severity Assessments 
 
The causality assessment must be recorded on the appropriate AE CRF. Causal relationship must be assessed 
by answering the following question: 
 
Is there a reasonable possibility the study drug caused the event? 
 
Yes: 
There is evidence to suggest a causal relationship between the study drug and AE, ie,: 
 
o There is a reasonable temporal relationship between the study drug and the event, and 
 
o The event is unlikely to be attributed to underlying/concurrent disease, other drugs, or other 
factors, and/or 
 
o Positive de-challenge and/or re-challenge exist 
 
No: 
There is no evidence to suggest a causal relationship between the study drug and AE, ie,: 
 
o There is no reasonable temporal relationship between the study drug and the event, or 
 
o The subject did not take the study drug, or 


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o The event is likely to be attributed to underlying/concurrent disease, other drugs, or other 
factors, or 
 
o The event is commonly occurring in the (study) population independent of drug exposure 
The Investigator must provide an assessment of the severity of each AE by recording a severity rating on the 
appropriate AE screen(s) of the subject’s eCRF. Severity, which is a description of the intensity of 
manifestation of the AE, is distinct from seriousness, which implies a subject outcome or AE-required 
treatment measure associated with a threat to life or functionality (Section 11.1.2). Severity will be assessed 
according to the following scale. 
 
Mild: 
Minor awareness of signs or symptoms that are easily tolerated without specific 
medical intervention. 
Moderate: 
Discomfort that interferes with usual activities and may require minimal intervention. 
Severe: 
Significant signs or symptoms that are incapacitating with an inability to work or 
perform routine activities and/or that require medical intervention. 
 
10.3. Serious Adverse Events/Suspected Adverse Reaction 
 
 An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 
 
• 
Results in death 
 
• 
Results in a life threatening adverse event 
 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
• 
Is a congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based on appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or the development 
of drug dependency or drug abuse. 
 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of IND safety reporting, "reasonable possibility" means 
there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug. 
 
Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or suspected 
adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational plan or elsewhere in the 


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current application, as amended. For example, under this definition, hepatic necrosis would be unexpected 
(by virtue of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure listed only cerebral vascular accidents. "Unexpected," as 
used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
 
Emergency room visits that do not result in hospitalization (ie, an overnight stay) should be evaluated for 
one of the other serious outcomes to determine if they qualify as SAEs. 
 
Preplanned hospitalizations (eg, elective procedures for preexisting conditions that did not worsen) are 
excluded from SAE reporting. 
 
Study endpoints (eg, mortality or major morbidity) must be reported to FDA by the Sponsor as described in 
the protocol and ordinarily would not be reported under paragraph (c) of the CFR § 312.32. However, if a 
serious and unexpected AE occurs for which there is evidence suggesting a causal relationship between the 
drug and the event (eg, death from anaphylaxis), the event must be reported under CFR § 312.32(c)(1)(i) as a 
serious and unexpected suspected adverse reaction even if it is a component of the study endpoint (eg, all-
cause mortality). 
 
The new regulations require that “study endpoints (eg, mortality or major morbidity) must be reported 
according to the protocol instead of as IND safety reports except when there is evidence suggesting a 
causal relationship between the drug and the event.” 
 
Any worsening of hematogenous SA osteomyelitis under study because of lack of therapeutic effect of any 
study drug (reported within study endpoints reporting time frame) is captured as an efficacy endpoint and 
is, therefore, excluded from SAE reporting, unless the event is considered related to the drug. 
 
10.4. Follow Up of Serious Adverse Events 
 
When additional relevant information becomes available, the investigator will record follow-up 
information according to the same process used for reporting the initial event as described above. The 
investigator will follow all SAEs until resolution, stabilization, or the event is otherwise explained. DRC will 
follow all SAEs until resolution, stabilization, until otherwise explained, or until the last patient completes 
the final follow-up, whichever occurs first. 
 
10.5. Collecting and Reporting Adverse Events and Serious Adverse Events 
 
Research related AEs and SAEs are collected from the signing of the informed consent form (ICF) (and assent 
form, if applicable) until EOT. At Month 12 follow up problems such as pathologic fractures and growth 
disturbances will be evaluated. The investigational site personnel are to follow unresolved AEs and SAEs at 
EOT until resolution or stabilization. 
 
At each visit, subjects and/or their parent(s) (or other legally acceptable representative[s]) are to be 
queried regarding any new or ongoing AEs/SAEs that have occurred since the previous visit. Each, as 
appropriate, will be asked to volunteer information with a non-leading question such as, for the subjects, 
“How have you felt since your last visit?” Study center personnel will then record all pertinent information 
on the appropriate screens of the subject’s eCRF. 
 


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All research related AEs/SAEs reported by the subject or subject’s parent(s) (or legally acceptable 
representative[s]) or observed or otherwise identified by the Investigator (or other study site personnel) at 
a defined study visit or during any communication with the subject (or subject’s representative[s]) 
occurring outside a defined study visit must be documented. 
 
All research related AEs must be recorded on the appropriate CRF, whether or not they are considered 
causally related to the study drug. 
 
For every AE, the Investigator must: 
 
• 
Provide an assessment of the severity, causal relationship to the study drug), and seriousness of the event 
(ie, SAE). 
 
• 
Document all actions taken with regard to the study drug. 
 
• 
Detail any other treatment measures taken for the AE. 
 
Within 24 business hours of learning of any AE that meets one of the criteria for an SAE, the study center 
personnel must report the event to Allergan on an SAE/AESI form (Global Patient Safety & Epidemiology 
Form) and to the FDA and IRB per regulation/local IRB policy. 
 
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an SAE, that AE 
should be recorded as a new SAE. 
 
The PI will transmit the SAE/AESI Form to the email and fax number indicated on the most current version 
of the form. Even if an initial report is made by telephone, an SAE/AESI form completed with all available 
details must still be emailed/faxed within 24 business hours of knowledge of the event at the study center. 
 
Supplemental information shall be submitted as soon as available and may include laboratory results, 
radiology reports, progress notes, hospital admission and emergency room notes, holding and observation 
notes, discharge summaries, autopsy reports, and death certificates. 
 
The Investigator is expected to take all therapeutic measures necessary for resolution of the SAE/AE. Any 
medications or procedures necessary for treatment of the SAE/AE must be recorded on the appropriate 
screen(s) of the subject’s CRF. All SAEs/AEs are to be followed until resolution or until the SAE/AE is deemed 
stable. The Sponsor may contact the study center to solicit additional information or follow up on the event. 
 
10.6. Other Reportable Events – Pregnancy 
 
Study center personnel must report every pregnancy on a Clinical Trial Pregnancy Form as soon as possible 
(within 24 business hours of learning of the pregnancy) to the email/fax number as indicated on the form, 
even if no AE has occurred. Pregnancies in female partners of male subjects must also be reported. The 
pregnancy must be followed to term and the outcome reported by completing the Clinical Trial Pregnancy 
Form. If, however, the pregnancy is associated with an SAE (eg, if the mother is hospitalized for 
hemorrhage), in addition to the Clinical Trial Pregnancy Form, a separate SAE/AESI Form for Clinical Trials 
must be filed as described in Section 11.1.3 with the appropriate serious criterion (eg, hospitalization) 
indicated on the SAE/AESI Form. 
 
10.7. IND Safety Reports 
 
For serious adverse events that require expedited regulatory reporting under 21 CFR 312.32(c)(1), the PI 
will notify the FDA in a written Investigational New Drug (IND) safety report and report to the IRB per local 


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policy. 
 
10.8. Other Clinical Assessments 
 
Safety parameters will be monitored according to standard medical practice and guidelines for IV 
administration of study drug. Vital sign assessments (pulse, blood pressure, respiratory rate, and 
temperature) will be conducted at the specified time points outlined in the Schedule of Assessments and 
Procedures (Table 2-1) and Section 10.0. 
 
Medical and surgical history, prior and concomitant medications, height (length), weight, physical 
examination findings, and hematogenous SA osteomyelitis sign and symptom assessments will be 
recordedat baseline and if applicable, during study according to the Schedule of Assessments and 
Procedures (Table 2–1) and Section 10.0. 
 
10.9. Laboratory Assessments 
 
Blood samples for clinical laboratory tests and urine samples for pregnancy tests (females who have reached 
menarche only) will be collected at baseline and throughout the study according to the Schedule  of 
Assessments and Procedures (Table 2–1) and Section 10.0. If a subject’s estimated CrCl (as calculated using 
the updated Schwartz “bedside” formula; Schwartz et al, 2009) decreases to < 50 mL/min during the 
treatment period, the DRC should be contacted. If a subject’s hemoglobin or hematocrit decreases 
significantly (Investigator’s judgment) during IV study drug therapy, an evaluation for hemolytic anemia will 
be conducted per standard of care. 
 
11. DATA MANAGEMENT 
 
An institutional Electronic Data Capture (EDC) system, the Clinical Trials Management System (CTMS), will 
be used for this trial. Study specific electronic case report forms (eCRFs) designed to provide reliable and 
secure data entry for clinical research purposes will be utilized. The web based software tools in the CTMS 
employ 2048-bit Secure Socket Layer (SSL) encryption; all transactions are encrypted in both directions. 
The CTMS meets the regulatory requirements of HIPAA and 21 CFR Part 11 compliance. In addition, the 
system has an offsite, fully mirrored disaster recovery backup. 
 
Data entered into the CTMS will include a subject study identification number; names will not be linked 
with subject data in the database. Study staff will maintain records linking the subject name with the 
identification number assigned for the study in a secure area. 
 
All data changes in the CTMS are written to an audit trail that identifies the user, date and time, as well as 
the old value and new value. Both patient-related data as well as trial configuration data are written to the 
audit trail. Data are saved at regular intervals during data entry to prevent loss of information in the event 
of a disruption of the Internet connection. 
 
The eCRFs include standard logical checks and range checks, as well as support for multiple languages in 
the user interface.  There is emphasis on tracking deadlines and milestones with automated notifications 
and reports of study progress. The module includes a data locking mechanism to ensure that data 
accuracy and integrity are maintained to facilitate data analyses promptly after study completion. 
Several levels of security are employed to ensure privacy and integrity of the study data, including the 
following: 
 
• 
Study access requires use of assigned unique user names and passwords that are modified at specified 
time intervals 


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• 
Individual roles and access levels are assigned 
• 
Passwords are changed regularly 
• 
Data are not stored on laptop computers 
The study coordinator will be responsible for data entry and maintaining appropriate source 
documentation. Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. 
The study coordinator will enter data within 7 days of the screening visit and within 14 days of each 
subsequent visit. 
 
12. STATISTICAL ASSUMPTIONS 
12.1. Statistical Methods and Planned Analysis 
 
• 
Descriptive statistical methods will be used to summarize the demographic characteristics of the 
subjects as well as selected clinical features such as duration of fever or positive blood cultures, time 
until normalization of ESR and CRP. 
• 
The proportion of children with plasma concentrations of ceftaroline that exceed 1µg/mL at 5-6 hours 
following a 2 hour infusion of ceftaroline dose will be determined. 
• 
Safety analyses will be conducted on all subjects who received at least one dose of ceftaroline. 
 
12.2. Primary End Points 
 
• 
Assessment of safety of ceftaroline in children during initial treatment of acute hematogenous 
osteomyelitis at the end of intravenous therapy. 
 
12.3. Secondary Endpoints 
 
1. Successful treatment of acute hematogenous osteomyelitis at one year after completion of a 4 to 6 
week total antibiotic treatment and at one year after enrollment. 
2. Clearance of S. aureus bacteremia if blood cultures initially positive. 
 
3. The proportion of children with plasma concentrations of ceftaroline that exceed 1µg/mL for over 60% 
of a dosing interval. 
 
12.4. Safety Analysis 
 
Adverse event and serious adverse event monitoring, vital signs and laboratory tests (CBC,BUN, Creatinine, 
Bilirubin, Alkaline Phosphatase,  AST and ALT will be obtained within 24 hours prior to enrollment and 
weekly during ceftaroline treatment and at the completion of ceftaroline treatment). The 
Alkaline 
Phosphatase, Bilirubin, AST/ALT results may not be available prior to enrollment of the patient. 
We do not anticipate that the AST/ALT concentrations will be > 3 UNL but if they were to be this elevated, 
the patient subject will be dropped from the study immediately. 
 
Safety parameters include AEs, SAEs, deaths, clinical laboratory parameters (eg, hematology parameters, 
chemistry parameters), and vital signs. For each safety parameter, the last assessment made before the 
first dose of IV study drug will be used as the baseline for all analyses. 
 
The incidences of TEAEs, 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 
the study drug, and by severity.  


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Descriptive statistics of observed results and the change from baseline will be presented for clinical 
laboratory results, and vital signs. The incidence of PCS laboratory results will be summarized. 
 
12.5. Efficacy Analysis 
 
• 
Clinical response by subject and by baseline pathogen at the conclusion of IV ceftaroline. 
• 
Clinical outcome at the completion of total therapy (IV plus oral) 
• 
Clinical outcome at one year after enrollment into study long-term follow-up. 
 
12.6. Interim Analysis 
 
An interim analysis of pharmacokinetics parameters may be performed using data from the first 5 evaluable 
patients to complete the study. The results of this interim analysis may be used to confirm the planned 
Ceftaroline dose, or support an appropriate dose adjustment. Enrollment will not be held during the 
interim PK analysis. 
 
12.7. PK Analysis 
 
The mean and median concentrations of ceftaroline in plasma at the end of infusion will be determined. 
The proportion of children with plasma ceftaroline concentrations > 1 µg/mL at 4 hours after infusion will 
be determined. 
 
The plasma levels of ceftaroline obtained at 4 hours after the end of a 2 hour infusion will be compared to 
the ceftaroline MIC for the S. aureus isolate recovered causing the osteomyelitis. Ideally, the plasma level 
should exceed the MIC at this time point which would be for at least 75% of a dosing interval. Assuming 
the patients do well clinically, there will be no adjustment of the dose even if the target concentration is 
not achieved at the 6 hour time point following the start of ceftaroline infusion. However, if two subjects 
do not improve as anticipated, the study will be halted and plasma levels compared to the MICs of the 
causative S. aureus isolates.  If plasma levels exceed the MIC and yet the subjects are considered treatment 
failures in that they are not responded as expected, the investigator would conclude that ceftaroline may 
not be particularly effective in treating S. aureus osteomyelitis in children. If the plasma levels at this time 
point are below the MIC, a dose modification may be considered but the investigator may decide that 
studying ceftaroline for this indication is no longer necessary. 
 
12.8. Handling of Dropouts and Missing Data 
 
Every effort will be made to collect all data at specified times. All subjects and data will be assessed up to the 
time that the subject is dropped. Missing data will be noted in the CRFs. 
 
13. ADMINISTRATIVE ASPECTS 
13.1. Compliance with Regulatory Requirements 
 
This study will be conducted in compliance with the current ICH E6 GCP, the ethical principles of the 
Declaration of Helsinki, current FDA GCP guidelines, and any additional national or IRB -required 
procedures, whichever represents the greater protection for the individual. 
 


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13.2. Institutional Review Board 
 
The IRB must approve the protocol or amended protocol (if applicable) and the corresponding ICF (and 
assent form, if applicable) before the study may be initiated and/or amendments are instituted (unless 
required for subject safety); and any recruiting materials before use. 
 
The Investigator is responsible for informing the IRB of any changes made to the protocol, and to advise the 
IRB, at least once a year, about the progress of the study. The Investigator is also responsible for notifying 
the IRB of any significant AEs that occur during the study according to local IRB requirements. 
 
13.3. Informed Consent 
 
This study will be conducted in compliance with current ICH E6 GCP pertaining to informed consent, the 
current CFR (Title 21, Parts 50 Subparts B and D, 56 and 312). For a child to participate in the study, the 
child’s parent(s) or legally authorized representative(s) will sign and date the ICF at the first visit, after 
having been informed about the nature and purpose of the study, participation and termination conditions, 
risks, and benefits, before initiation of any study-related procedures. A pediatric subject who is                   old 
enough to provide assent, will be asked for such assent, according to institution-specific guidelines. A copy 
of the signed ICF (and assent form, if applicable), must be provided to the subject’s parent(s) or legally 
acceptable representative(s). If applicable, the ICF (and assent form, if applicable) will be provided in 
certified translation for non-English-speaking subjects and parents or other legally acceptable 
representatives. Signed ICFs (and assent form, if applicable) will remain in the subjects’ study files and be 
available for verification at any time. 
 
13.4. Confidentiality 
 
Personal study patient data collected and processed for the purposes of this study will be managed by the 
investigator and his/her staff with adequate precautions to ensure the confidentiality of those data, and in 
accordance with applicable national and/or local laws and regulations on personal data protection.  
 
Monitors, auditors and other authorized agents of Cempra Pharmaceuticals, the IRB approving this 
research, and the FDA, as well as any other applicable regulatory authorities, will be granted direct access 
to the study subjects’ original medical records for verification of clinical trial procedures and/or data, 
without violating the confidentiality of the patients, to the extent permitted by the law and regulations. In 
any presentation of the results of this study at meetings or in publications, the patient identities will remain 
confidential. 
 
13.5. Compensation, Insurance, and Indemnity 
 
Information regarding compensation, insurance, and indemnity is presented in the clinical trial research 
agreement. 
 
13.6. Protocol Amendments 
 
If a protocol has been filed with regulatory agencies or submitted to an IRB and requires changes, a 
protocol amendment will be written. Any changes to the protocol will be made by the Investigator. 
Changes to the protocol will be submitted to regulatory agencies when required. 
 
13.7. Case Report Forms 
 
An institutional Electronic Data Capture (EDC) system, the Clinical Trials Management System (CTMS), will 


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be used for this trial. Study specific electronic case report forms (eCRFs) designed to provide reliable and 
secure data entry for clinical research purposes will be utilized. The web based software tools in the CTMS 
employ 2048-bit Secure Socket Layer (SSL) encryption; all transactions are encrypted in both directions. 
The CTMS meets the regulatory requirements of HIPAA and 21 CFR Part 11 compliance. In addition, the 
system has an offsite, fully mirrored disaster recovery backup. 
 
Data entered into the CTMS will include a subject identifiers and study identification number; the subject 
identifiers other that the study identification will not be included in the database reports when required. 
All data changes in the CTMS are written to an audit trail that identifies the user, date and time, as well as 
the old value and new value. Both patient-related data as well as trial configuration data are written to the 
audit trail. Data are saved at regular intervals during data entry to prevent loss of information in the event 
of a disruption of the Internet connection. 
 
The eCRFs include standard logical checks and range checks, as well as support for multiple languages in 
the user interface.  There is emphasis on tracking deadlines and milestones with automated notifications 
and reports of study progress. The module includes a data locking mechanism to ensure that data 
accuracy and integrity are maintained to facilitate data analyses promptly after study completion. 
Several levels of security are employed to ensure privacy and integrity of the study data, including the 
following: 
• 
Study access requires use of assigned unique user names and passwords that are modified at specified 
time intervals 
• 
Individual roles and access levels are assigned 
• 
Passwords are changed regularly 
• 
Data are not stored on laptop computers 
 
The study coordinator will be responsible for data entry and maintaining appropriate source 
documentation. Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. 
The study coordinator will enter data within 7 days of the screening visit and within 14 days of each 
subsequent visit. 
 
13.8. Source Document Maintenance 
 
Source documents may include, but are not limited to, study progress notes, study- or subject-specific e- 
mail correspondence, computer printouts, laboratory data, and recorded data from automated instruments. 
The original signed ICF (and assent form, if applicable) for each participating subject shall be filed with 
records kept by the Investigator. All documents produced in this study will be maintained by the Investigator 
and made available for inspections. 
 
13.9. Study Monitoring/Quality Assurance 
 
The study data will be reviewed by the Investigator and the QA Analyst as per the internal institutional SOPs. 
 
The Investigator will allow the applicable regulatory authorities to inspect facilities and records relevant to 
this study. 
 
13.10. Study File Management 
 
The study file will contain all required documents as per the regulations, IRB requirements and the 
internal SOPs including, but not be limited to: 
 


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• 
Final study protocol. 
• 
Protocol amendments (if applicable). 
• 
Study manual (if applicable). 
• 
ICF and assent (blank). 
• 
Revised ICFs and/or all addenda (blank). 
• 
Copy of signed form(s) Form FDA 1572. 
• 
Curricula vitae of investigator and sub investigators. 
• 
Documentation of IRB approval of protocol, consent form, any protocol amendments, and any 
consent form revisions. 
• 
Annual IRB updates and approvals. 
• 
All correspondence between the investigator, IRB, Allergan and FDA. 
• 
Copies of all IND safety reports submitted to the FDA and IRB correspondence documenting their 
submission (if applicable). 
• 
Laboratory certifications/normal laboratory value ranges. 
• 
Screening log. 
• 
Study drug accountability records and invoices for receipt/return of study drug. 
• 
Protocol signature page. 
• 
Laboratory director’s curriculum vitae and medical/professional license, if available.  
 
13.11. Study Completion 
 
The following data and materials will be on file before a study can be considered completed or 
terminated: 
 
• 
Laboratory findings, clinical data, and all special test results from screening through the end of the 
study follow-up period. 
• 
eCRFs properly completed by appropriate study personnel and electronically signed and dated by the 
investigator. 
• 
Complete drug accountability records (drug inventory log and an inventory of returned or destroyed 
clinical material). 
• 
Copies of protocol amendments and IRB approval/notification, if appropriate. 
• 
A summary of the study prepared by the principal investigator (an IRB summary letter is acceptable). 
 
13.12. Audits 
 
During the course of the study, or after completion of the study, FDA and/or other regulatory authorities 
may audit the study. Every attempt will be made to notify Allergan in writing in advance of the audit. 
 
13.13. Retention of Records 
 
It is the responsibility of the Investigator to ensure that the essential documents are available in the 
Investigator’s files or at the institutional center. Any or all of these documents should be available for 
monitoring and inspection by the regulatory authorities as defined in the monitoring plan. 
 
Records and documents pertaining to the conduct of this study in all formats (including, but not limited to, 
written, electronic, magnetic, and x-rays) must be retained by the Investigator for at least 15 years after 
study completion unless local regulations or institutional policies require a longer retention period. These 
records include eCRFs, source documents, ICFs (and assent form, if applicable), regulatory documents, 
clinical reports and laboratory results (including, but not limited to, all local and central laboratory results), 


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and medication inventory records. 
 
After the required retention period, long-term storage arrangements will be made for such study records if 
possible. 
 
If the Investigator for the study retires, relocates, or for other reasons withdraws from the responsibility of 
keeping study records, custody must be transferred to a suitable alternate custodian employee of the 
institution or to a suitably qualified and responsible third party. 
 
At the request of a subject’s parent(s) (or other legally authorized representative[s]), medical information 
may be given to the subject’s personal physician or other appropriate medical personnel responsible for 
the subject’s welfare. 
 
13.14. Publication Policy 
 
The data generated in this clinical study are the exclusive property of the Investigator and are confidential. 
The Investigator will make all reasonable efforts to publish the results of the study in an appropriate peer- 
reviewed journal. 


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14. REFERENCES 
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