Safety, Tolerability and Efficacy of Ceftaroline in Paediatrics With Late-Onset Sepsis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and tolerability of ceftaroline for the treatment of Late Onset Sepsis in neonates and young infants aged 7 to <60 days

Detailed Description
-----------------
This is a multicentre, multinational, open-label, single treatment arm study of intravenous (IV) ceftaroline fosamil and ampicillin, plus an optional aminoglycoside of choice, in hospitalized neonates and young infants aged 7 to < 60 days with late-onset sepsis (LOS). Baseline assessments for study eligibility will occur within 36 hours before administration of the first dose of study therapy. Study Day 1 is defined as the 24-hour period starting at the onset of the first administration of study therapy. Thereafter, subsequent Study Days are to follow the same pattern. Safety assessments will occur throughout the study. Clinical outcome evaluations will occur at End-of-Therapy (EOT; within 24 hours after completion of last infusion) and Test-of-Cure (TOC; 8 to 15 days after the last dose of study therapy).

Official Title
-----------------
Open-label, Multicentre Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Efficacy Of Ceftaroline In Neonates And Young Infants With Late-onset Sepsis

Conditions
-----------------
Late-onset Sepsis

Intervention / Treatment
-----------------
* Drug: Ceftaroline Fosamil
* Drug: Ampicillin
* Drug: Aminoglycoside


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed consent in writing from parent(s) or other legally-acceptable representative(s); Male or female, gestational age ≥34 weeks, and chronological age 7 to <60 days at the time of screening; Diagnosis of sepsis within 36 hours before enrolment, defined as the presence of at least 2 clinical criteria and at least 1 laboratory criterion in the presence of or as a result of suspected or proven bacterial infection that requires IV antibiotic therapy; Patients must meet at least 2 of the following clinical criteria :Hypothermia (<36°C) OR fever (>38.5°C); Bradycardia OR tachycardia OR rhythm instability; Urine output 0.5 to 1 mL/kg/h OR hypotension OR mottled skin OR impaired peripheral perfusion; Petechial rash OR sclerema neonatorum; New onset or worsening of apnoea episodes OR tachypnoea episodes OR increased oxygen requirements OR requirement for ventilation support; Feeding intolerance OR poor sucking OR abdominal distension; Irritability; Lethargy; Hypotonia: Patients must meet at least 1 of the following laboratory criteria: White blood cell count ≤4,000 × 109/L OR ≥20,000 × 109/L; Immature to total neutrophil ratio >0.2; Platelet count ≤100,000 × 109/L; C-reactive protein (CRP) >15 mg/L OR procalcitonin ≥2 ng/mL; Hyperglycaemia OR Hypoglycaemia; Metabolic acidosis. Exclusion Criteria: Documented history of any hypersensitivity or allergic reaction to any β-lactam antibiotic or aminoglycoside; At study entry, has confirmed infection with a pathogen known to be resistant to the combination of ceftaroline fosamil, ampicillin, and the optional aminoglycoside of choice OR confirmed viral, fungal, or parasitic pathogen as the sole cause of infection; Refractory septic shock within 24 hours before enrolment that does not resolve after 60 minutes of vasopressor therapy; Moderate or severe renal impairment defined as serum creatinine ≥2 times the upper limit of normal (× ULN) for age OR urine output <0.5 mL/kg/h (measured over at least 8 hours) OR requirement for dialysis; Evidence of progressively fatal underlying disease, or life expectancy of ≤60 days; Documented history of seizure; Requiring or currently taking antiretroviral therapy for human immunodeficiency virus (HIV) or a child from an HIV positive mother; Proven or suspected central nervous system (CNS) infection (eg, meningitis, brain abscess, subdural abscess), osteomyelitis, endocarditis, or necrotizing enterocolitis (NEC); Any condition (eg, cystic fibrosis, urea cycle disorders), antepartum/peripartum factors, or procedures that would, in the opinion of the investigator, make the patient unsuitable for the study, place a patient at risk, or compromise the quality of data; Patient's parent(s) or legally-acceptable representative(s) involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Concurrent participation in another clinical study with an investigational product (IP), previous enrolment/participation in this study, or participation in another study of ceftaroline fosamil within 14 days before the intended start of the first dose of study therapy.

Ages Eligible for Study
-----------------
Minimum Age: 7 Days
Maximum Age: 59 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ceftaroline Fosamil<br>Ceftaroline Fosamil | Drug: Ceftaroline Fosamil<br>* Ceftaroline fosamil will be given at a dose of 6 mg/kg IV over 60 (± 10) minutes every 8 hours (q8h) (± 1 hour).<br>* Other names: Zinforo, Teflaro;Drug: Ampicillin<br>* Ampicillin IV is required for the first 48 hours if the presence of an organism that requires treatment with ampicillin cannot be excluded. Will be given as per local standard of care.<br>Drug: Aminoglycoside<br>* Optional, will be given as per local standard of care.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to study follow-up (SFU) visit (28 to 35 days after last dose of study treatment) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. | Baseline up to SFU visit (up to a maximum study duration of 49 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration of Ceftaroline Fosamil | Data was not summarized and provided for individual participants only and reported in this end point for only those participants who had concentrations above limit of quantification (LOQ). LOQ was 50 nanogram per milliliter (ng/mL). | At the end of infusion (EOI) | 
| Plasma Concentration of Ceftaroline | Ceftaroline fosamil was the prodrug of ceftaroline. Data was not summarized and provided for individual participants only and reported in this end point for only those participants who had concentrations above LOQ at any specific time-point. LOQ was 50 ng/mL | At EOI, 15 minutes to 2 hours, 3 to 4 hours and 5 to 7 hours after EOI | 
| Plasma Concentration of Ceftaroline M-1 | Ceftaroline M-1 was the inactive metabolite of ceftaroline. Data was not summarized and provided for individual participants only and reported in this end point for only those participants who had concentrations above LOQ at any specific time-point. LOQ was 50 ng/mL | At EOI, 15 minutes to 2 hours, 3 to 4 hours and 5 to 7 hours after EOI | 
| Percentage of Participants With Favorable Clinical Response | Clinical response was assessed by the investigator as Cure, Failure or Indeterminate at End of treatment (EOT) and Test of Cure (TOC). Favorable clinical response was defined as clinical response of Cure (defined as resolution of all acute signs and symptoms of Late-onset sepsis [LOS] or improvement to such an extent that no further antibacterial therapy is required). EOT visit occurred within 24 hours after the end of last infusion. TOC visit occurred within 8 to 15 days after the last dose of study therapy. | EOT visit (up to Day 15), TOC visit (up to Day 29) | 
| Percentage of Participants With Favorable Microbiological Response | Microbiological response was determining programmatically and assessed at the participants level at EOT and TOC. Microbiological response was defined as Favorable (Eradication or Presumed Eradication), Unfavorable (Persistence or Presumed Persistence) or Indeterminate (participant's clinical response is Indeterminate and no microbiological culture data is available). Eradication defined as absence of the original baseline pathogen from the source specimen; presumed eradication was defined when source specimen was not available to culture and the participant was assessed as a clinical cure (resolution of all acute signs and symptoms of LOS or improvement to such an extent that no further antibacterial therapy was required). EOT visit occurred within 24 hours after the end of last infusion. TOC visit occurred within 8 to 15 days after last dose of study drug. | EOT visit (up to Day 15), TOC visit (up to Day 29) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Late-onset Sepsis