Neonatal Vancomycin Trial

Study Overview
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Brief Summary
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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 Description
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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

Official Title
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Multi-centre, Randomised, Open Label, Phase IIb Study 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

Conditions
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Late Onset Neonatal Sepsis

Intervention / Treatment
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* Drug: Vancomycin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 72 Hours
Maximum Age: 90 Days

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vancomycin - Optimised Regimen<br>A single loading dose of 25 mg/kg followed by a maintenance dose of: Postmenstrual age ≤ 35 weeks - 15 mg/kg 12 hourly; Postmenstrual age > 35 weeks - 15 mg/kg 8 hourly | Drug: Vancomycin<br>* Vancomycin is an antibiotic used to treat a number of bacterial infections.It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant S. aureus.<br>|
| Active Comparator: Vancomycin - Standard Regimen<br>Postmenstrual age < 29 weeks - 15 mg/kg given 24 hourly; Postmenstrual age 29 - 35 weeks - 15 mg/kg 12 hourly; Postmenstrual age > 35 weeks - 15 mg/kg 8 hourly | Drug: Vancomycin<br>* Vancomycin is an antibiotic used to treat a number of bacterial infections.It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant S. aureus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful outcome at Test of Cure visit | Patient is alive AND has a successful outcome at the end of actual vancomycin therapy AND the patient has not had a clinically or microbiologically significant relapse or new infection. | 10±1 days after End of Actual Vancomycin Therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically or microbiologically significant relapse or new infection requiring treatment with any other antibiotic for more than 24 hours |  | 10±1 days after the End of Actual Vancomycin Treatment | 
| Successful outcome at Visit 4 or End of Actual Vancomycin Therapy including total duration of vancomycin therapy |  | Day 5±1 or Day 10±2 | 
| Abnormal renal function tests at the Short-term Follow-Up Visit |  | 30±5 days post-initiation of vancomycin therapy | 
| Abnormal hearing screening test |  | By Day 90 post-initiation of vancomycin therapy | 
| Comparative safety of vancomycin (relating to the number of treatment-related adverse events other than those associated with renal function and hearing) at Short Term Follow-Up Visit |  | 30±5 days post-initiation of vancomycin therapy | 
| Pharmacokinetic parameters of vancomycin using population PK modelling by allocation group | Area under the plasma concentration time curve - AUC (mg*hour/L) | Up to 2 years (final data collection date for outcome measure) | 
| Probability of target attainment (PTA) with different study regimens | Different bacteriological targets will be tested, based on the MIC of different bacteria of interest with level of sensitivity. Simulations based on the vancomycin popPK model will be conducted to define the number of patients in the different allocation groups reaching the predefined targets when modifying the dose. | Up to 2 years (final data collection date for outcome measure) | 
| Relationship between CoNS species and duration of treatment and CRP response |  | Day 5±1 or Day 10±1 | 
| Gut colonisation by vancomycin resistant organisms at baseline, Test of Cure Visit and Short-term Follow-Up Visit |  | Baseline, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of vancomycin therapy | 
| Skin colonisation and resistance patterns before and after vancomycin treatment |  | Baseline, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of vancomycin therapy | 
| Assessment of changes in host biomarker panel profiles from baseline to End of Actual Vancomycin Therapy and the relationship between host biomarker and duration of treatment | Functional molecular units based on a multimarker panel - a set of 52 biomarkers will be performed as a classifier with high accuracy and specificity in predicting bacterial infection | Day 3 and Day 5±1, Day 10±1 (standard arm only) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, neonate, vancomycin