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
概览
- 阶段
- 2 期
- 干预措施
- Vancomycin
- 疾病 / 适应症
- Late Onset Neonatal Sepsis
- 发起方
- PENTA Foundation
- 入组人数
- 242
- 试验地点
- 18
- 主要终点
- Successful outcome at Test of Cure visit
- 状态
- 终止
- 最后更新
- 5年前
概览
简要总结
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
详细描述
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
研究者
入排标准
入选标准
- •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,
排除标准
- •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
研究组 & 干预措施
Vancomycin - Optimised Regimen
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
干预措施: Vancomycin
Vancomycin - Standard Regimen
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
干预措施: Vancomycin
结局指标
主要结局
Successful outcome at Test of Cure visit
时间窗: 10±1 days after End of Actual Vancomycin Therapy
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.
次要结局
- 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)
- Pharmacokinetic parameters of vancomycin using population PK modelling by allocation group(Up to 2 years (final data collection date for outcome measure))
- Probability of target attainment (PTA) with different study regimens(Up to 2 years (final data collection date for outcome measure))
- Abnormal hearing screening test(By Day 90 post-initiation of vancomycin therapy)
- Abnormal renal function tests at the Short-term Follow-Up Visit(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(Day 3 and Day 5±1, Day 10±1 (standard arm only))
- 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)
- 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)
- 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)