Late-onset Sepsis in Term and Pre-term Neonates and Infants up to 3 Months of Age

Study Overview
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Brief Summary
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This study will evaluate the safety, pharmacokinetics and efficacy of ceftobiprole in term and pre-term newborn babies and infants up to 3 months of age with late-onset sepsis (LOS). Ceftobiprole is an antibiotic which belongs to a group of medicines called 'cephalosporin antibiotics'. It is approved for its use to treat adults and children with pneumonia in many European and non-European countries.

Detailed Description
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This is a multicenter, open-label, single-arm, multiple-dose study of intravenous (IV) ceftobiprole medocaril (prodrug of the active moiety ceftobiprole). It may be combined with ampicillin and/or an aminoglycoside based on the Investigator's judgement according to manufacturer's instructions and/or local standard of care. Following screening, ceftobiprole will be administered as a 2-hour infusion at a dose of 7.5 mg/kg every 12 hours to 15 mg/kg every 8 hours, depending on age and weight. The target treatment duration is 7-10 days, which may be either extended to 14 days if considered clinically necessary by the Investigator or may be may be stopped after 5 days at the discretion of the Investigator based on resolution of signs and symptoms of sepsis and blood inflammation markers, in accordance with local standard of care.

Official Title
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A Multicenter, Open-label, Single-arm, Multiple-dose Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Ceftobiprole Medocaril in Term and Pre-term Neonates and Infants up to 3 Months of Age With Late-onset Sepsis

Conditions
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Neonatal Sepsis

Intervention / Treatment
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* Drug: Ceftobiprole medocaril


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Informed consent from parent(s) or other legally acceptable representative (LAR) to participate in the study Male or female, with a gestational age of ≥ 24 weeks and a post-natal age ranging from ≥ 3 days to ≤ 3 months Diagnosis of documented or presumed bacterial LOS requiring administration of systemic antibiotic treatment Sufficient vascular access to receive study drug and to allow blood sampling at a site separate from the study drug infusion line Key Exclusion Criteria: Refractory septic shock not responding to 60 minutes of vasopressor treatment within 48 hours before enrollment Proven ventilator-associated pneumonia Proven central nervous system infection (e.g., meningitis, brain abscess) Proven osteomyelitis, infective endocarditis, or necrotising enterocolitis Impaired renal function or known significant renal disease, as evidenced by an estimated glomerular filtration rate (using the Schwartz formula or other applicable formula) calculated to be less than 2/3 of normal for the applicable age group, OR urinary output < 0.5 mL/kg/h (measured over at least 8 hours), OR requirement for dialysis Progressively fatal underlying disease, or life expectancy < 30 days Use of systemic antibacterial therapy for longer than 48 hours within 7 days before start of study medication Participation in another clinical study with an investigational product within 30 days of enrollment in the current study

Ages Eligible for Study
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Minimum Age: 3 Days
Maximum Age: 3 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm: Ceftobiprole<br>Ceftobiprole medocaril: 7.5 mg/kg to 15 mg/kg | Drug: Ceftobiprole medocaril<br>* Ceftobiprole medocaril: 7.5 mg/kg every 12 hours to 15 mg/kg every 8 hours, administered IV as a 2-hour infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability by incidence of adverse events (AEs) and serious adverse events (SAEs) | Descriptive statistics of AEs, SAEs, deaths, and discontinuations due to AEs during treatment with ceftobiprole | Up to 5-7 weeks | 
| Number of participants with clinically relevant findings in laboratory tests | Descriptive statistics of clinical laboratory tests (including hematology, blood chemistry, urinalysis) and the change from baseline to each post-baseline visit value will also be summarized | Up to 5-7 weeks | 
| Number of participants with clinically relevant findings in vital signs | Descriptive statistics of vital signs findings including body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressures | Up to 5-7 weeks | 
| Number of participants with clinically relevant findings in physical examination | Descriptive statistics of physical examination findings including examination of general appearance, skin, head, neck, eyes, ears, nose, throat, cardiovascular system, thorax/lungs, abdomen, lymph nodes, extremities, and nervous system | Up to 5-7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed plasma concentrations of ceftobiprole, ceftobiprole medocaril, and open-ring metabolite | Descriptive analyses of these concentrations will be summarised by timepoint for term and pre-term neonates with post-natal age up to 3 months. | At day 3 | 
| Clinical response | Clinical cure rate at the end of treatment (EOT) at day 7-14 and test of cure (TOC) at 7-14 days after last ceftobiprole dose visits in the Intent-to-Treat (ITT) and Clinically Evaluable (CE) populations | 5-7 weeks | 
| All-cause mortality | All-cause mortality (ITT population) | through Day 28 | 
| Microbiological response | Microbiological eradication or presumed eradication rate at the EOT and TOC visits (in the Microbiological Intent-to-Treat [mITT] and Microbiologically Evaluable [ME] populations) | 5-7 weeks | 
| Number of participants with improved signs and symptoms of LOS | Improved signs and symptoms of LOS (including fever, hypothermia, abnormal heart rate, signs of impaired circulation, petechial rash or sclerema neonatorum, respiratory distress, gastrointestinal distress, irritability, lethargy and/or muscular or arterial hypotonia) will be assessed at Day 3, EOT, and TOC visits (ITT and CE populations) | At the Day 3 and up to 5-7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Late-onset sepsis, Neonates, Infants