Planned interim analysis yielded different event rate affecting sample size and ability to recruit sufficient numbers within remaining trial time frame

The study aims to compare the efficacy, safety and pharmacokinetics (PK) of an optimised dosing to a standard dosing regimen of vancomycin in neonates and infants aged ≤ 90 days with late onset bacterial sepsis known or suspected to be caused by Gram-positive microorganisms

Detailed objectives of the study are:

• To compare the efficacy of an optimised vancomycin dosing regimen to a standard vancomycin dosing regimen in patients with late onset, bacterial sepsis, known or suspected to be caused by Gram-positive microorganisms.
• To compare the safety of vancomycin (including renal and hearing safety) by allocation group in the intention to treat (ITT) population
• To describe the PK parameters according to vancomycin dosing regimen and outcome using population PK modelling in the ITT population
• To describe PK/PD in terms of the probability of target attainment (PTA) with different vancomycin dosing regimens in the ITT and per protocol (PP) populations
• To describe outcomes and duration of therapy at the end of vancomycin treatment and at the short term follow-up visit by allocation group in the ITT and PP populations
• To compare the clinical outcome to the antibacterial susceptibility of infecting organisms
• To compare colonisation by resistant microorganisms (e.g. vancomycin-resistant enterococci (VRE)) and Candida spp. by allocation group at baseline, TOC and short-term follow-up
• To validate across multiple centres a host biomarker panel to allow improved diagnosis of bacterial sepsis and monitor response to antibacterial therapy

Inclusion Criteria:

• Postnatal age ≤ 90 days AND
• Postnatal age ≥ 72 hours at onset of sepsis AND
• Clinical sepsis as defined by presence of any three clinical or laboratory criteria from the list below OR
• Confirmed, significant bacterial sepsis as defined by positive culture with a Gram-positive bacterium from a normally sterile site and at least one clinical or one laboratory criterion from the list below, in the 24 hours before randomisation

Clinical criteria

• hyper- or hypothermia,
• hypotension or impaired peripheral perfusion or mottled skin,
• apnoea or increased oxygen requirement or increased requirement for ventilatory support,
• bradycardic episodes or tachycardia,
• worsening feeding intolerance or abdominal distension,
• lethargy or hypotonia or irritability

Laboratory criteria:

• white blood cell (WBC) count < 4 or > 20 x 109 cells/L
• immature to total neutrophil ratio (I/T) > 0.2
• platelet count < 100 x 109/L
• C-reactive protein (CRP) > 10 mg/L
• glucose intolerance as defined by a blood glucose value > 180 mg/dL (> 10 mmol/L) when receiving normal glucose amounts (8 - 15 g/kg/day)
• metabolic acidosis as defined by a base excess (BE) < -10 mmol/L (-10 mEq/L) or a blood lactate value > 2 mmol/L

Exclusion Criteria:

• Administration of any systemic antibiotic regimen for more than 24 hours prior to randomisation, unless the change is driven by the apparent lack of efficacy of the original regimen
• Treatment with vancomycin for ≥ 24 hours at any time within 7 days of enrolment
• Known toxicity, hypersensitivity or intolerance to vancomycin
• Known renal impairment with urinary output < 0.7 ml/kg/hour for 24 hours or a creatinine value ≥ 100 µmol/L (1.13 mg/dL)
• Patient receiving (or planned to receive) haemofiltration, haemodialysis, peritoneal dialysis, extracorporeal membrane oxygenation (ECMO) or cardiopulmonary bypass
• Severe congenital malformations where the infant is not expected to survive for more than 3 months
• Patient known to have S. aureus (MSSA or MRSA) bacteraemia
• Patient with osteomyelitis, septic arthritis, urinary tract infection (UTI) or meningitis
• Patient with high suspicion of/confirmed sepsis caused by Gram-negative organisms or fungi
• Other situations where the treating physician considers a different empiric antibiotic regimen necessary
• Current participation in any other clinical study of an investigational medicinal product (IMP)

Post-randomisation exclusions

• Any participant found to have Gram-negative or fungal sepsis, osteomyelitis, septic arthritis, UTI, meningitis or S. aureus (MSSA or MRSA) bacteraemia after randomisation will be excluded from analysis. Participants who have received at least one dose of study vancomycin will be followed up for safety