Paediatric Infectious Diseases Research Group, Institute for Infection & Immunity, St George's, University of London, London, UK.
UCL Great Ormond Street Institute of Child Health, London, UK.
Trials. 2020 Apr 15;21(1):329. doi: 10.1186/s13063-020-4184-8.
Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late-onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin's continued efficacy.
NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excluding Staphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation. The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA. The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h. Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy.
Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS.
ClinicalTrials.gov, NCT02790996. Registered on 7 April 2016. EudraCT, 2015-000203-89. Entered on 18 July 2016.
万古霉素在临床实践中已使用超过 50 年；然而，缺乏针对新生儿不同剂量方案与临床结局相关的经验证的药代动力学（PK）数据。凝固酶阴性葡萄球菌（CoNS）是新生儿晚发性败血症（LOS）中最常分离的病原体。为了确保万古霉素的持续疗效，优化使用以最大程度提高疗效，同时最小化毒性和耐药性选择至关重要。
NeoVanc 是一项欧洲、开放标签、IIb 期、随机、对照、非劣效性试验，比较了优化万古霉素方案与标准万古霉素方案治疗 LOS 的疗效，LOS 已知/疑似由革兰氏阳性菌（不包括金黄色葡萄球菌）引起，婴儿年龄≤90 天。将招募 300 名婴儿，并以 1:1 的比例进行随机分组。如果婴儿在随机分组前 24 小时内有培养证实（来自正常无菌部位的阳性培养物和至少一项临床/实验室标准）或临床败血症（存在任何≥3 项临床/实验室标准），则可以招募。优化方案包括万古霉素负荷剂量（25mg/kg），随后根据胎龄（PMA）进行 5±1 天的 15mg/kg q12h 或 q8h。标准方案是万古霉素疗程为 10±2 天，剂量为 15mg/kg q24h、q12h 或 q8h，也取决于 PMA。主要终点是在治愈试验访视（万古霉素治疗结束后 10±1 天）时获得成功的结果。成功的结果包括患者存活、成功完成研究万古霉素治疗且无临床/微生物学复发/新感染，需要万古霉素或其他抗葡萄球菌抗生素治疗>24 小时。次要终点包括短期随访访视时的临床/微生物学复发/新感染（开始万古霉素治疗后 30±5 天）、安全性评估（肾脏/听力）、万古霉素 PK 以及在万古霉素治疗过程中评估宿主生物标志物谱。
基于之前的临床前数据和一项针对新生儿 PK/药效动力学的大型荟萃分析，NeoVanc 的设立旨在提供证据，证明负荷剂量后短疗程的万古霉素在疗效方面是否不劣于标准的、较长疗程。如果证明非劣效性，这将支持采用优化方案，作为一种安全降低治疗新生儿革兰氏阳性 LOS 时万古霉素暴露的方法。
ClinicalTrials.gov，NCT02790996。于 2016 年 4 月 7 日注册。EudraCT，2015-000203-89。于 2016 年 7 月 18 日输入。
