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NEOVANC Report Summary

Project ID: 602041
Funded under: FP7-HEALTH
Country: Italy

Periodic Report Summary 2 - NEOVANC (Treatment of late onset bacterial sepsis caused by vancomycin susceptible bacteria in neonates and infants aged under three months)

Project Context and Objectives:
Vancomycin is the critically important antibiotic to treat neonatal Late Onset Sepsis (LOS) due to Gram positive bacteria, including Coagulase Negative Staphylococci (CoNS) and Staphylococcus aureus. The increased incidence of LOS due to bacteria such as CoNS and multi-drug resistant Staphylococcus aureus (MRSA) in neonatal intensive care units (NICUs) has led to a marked increased use of of vancomycin, which is now the third commonest antibiotic used in European NICUs. Conventional dosing of vancomycin is usually 30 to 40 mg/kg/day in divided doses with peak and trough serum concentrations serving to guide subsequent dosage adjustments. With this regimen, therapeutic drug levels are frequently only obtained many days into therapy. Recent data have demonstrated the need for higher initial doses of vancomycin to achieve more rapid, optimal serum concentrations in paediatrics, specifically for neonates and younger infants. The optimal method of therapeutic drug monitoring to maximise efficacy and minimise potential toxicity from vancomycin therapy remains unclear. Recent changes in resistance patterns to vancomycin among Staphylococcus species and CoNS, especially global neonatal outbreaks of resistant Staphylococcus capitis, mean there is an urgent need to develop optimal dosing and monitoring regimens for neonates and infants aged less than 3 months. Consequently, vancomycin was included on the “Revised priority list for studies into off-patent paediatric medicinal products (EMA/98717/2012 Rev 2012). For vancomycin, data on an optimal dosing and monitoring regimen (e.g. pharmacokinetics/pharmacodynamics [PK/PD]and safety-based efficacy studies in preterm and term neonates and infants) together with an age-appropriate formulation for neonates with sepsis caused by staphylococci and nonpyogenic streptococci are requested. The NeoVanc Consortium of leading European experts in neonatal pharmacology, animal models, infectious diseases and clinical trials, with extensive experience in recruitment into neonatal research studies has already submitted a Paediatric Investigation Plan (PIP) for vancomycin to be developed for treatment of late onset bacterial sepsis caused by vancomycin susceptible bacteria in neonates and infants aged under three months.
The project aims to develop an optimal dosing and monitoring regimen for vancomycin use in preterm neonates and infants under 3 months of age and then to conduct a PK/PD based randomised clinical trial with PK/PD targets as the primary outcome. Specific objectives are:
1) to define the pre-clinical PK/PD relationships for vancomycin against clinically relevant Gram positive pathogens in hollow fibre infection and laboratory animal models and bridge the results to human neonates (NeoVanc 1)
2) to conduct a population PK meta-analysis of all available neonatal vancomycin data and define in collaboration with NoeVanc 1 a new optimal vancomycin dosing regimen (NeoVanc 2)
3) to compare a new improved “optimal” vancomycin dosing regimen with an accepted European standard of care regimen in a Phase II randomised clinical trial in terms of efficacy and safety, with the eventual aim of leading to a Paediatric Use Marketing Authorization (PUMA).

Project Results:
All management structures outlined in the Grant Agreement to oversee both the FP7 project and the Phase II randomized clinical trial (NeoVanc) have been successfully developed and implemented. A Project Management Office was created to monitor Scientific Coordination and Management (WP1, WP9).
18 of 20 (85%) deliverables due in the first 36 months of the Project were submitted on time and have been accepted by the Commission (EC). Two deliverables, 5.4 and 5.6, will be postponed pending ethics approval of NeoVanc in Greece and accrual of more recruitment data. One deliverable will be submitted directly after the second reporting period. In NeoVanc 1 (WP2), hollow fibre infection model studies with vancomycin against clinical strains of CoNS identified the PD index best linking total dosage with observed effect and index magnitude associated with maximal antibacterial activity. Results were validated in a rabbit model of central line infection with CoNS, Enterococcus and MRSA and with biofilm studies, and bridging studies with resulting data identified a vancomycin regimen appropriate for NeoVanc clinical trial.

In NeoVanc 2 (WP3), a systematic literature review was conducted identifying all published PK studies on vancomycin in neonates for inclusion along with un-published data in a population PK meta-analysis used to optimize dosing regimen based on the PK/PD target obtained from NeoVanc 1 and define the “optimal” dose of vancomycin for NeoVanc Clinical Trial. A vancomycin dosing calculator and software to monitor vancomycin prescription in European NICUs have been developed and validated, as well as a UPLC-MSMS method to quantify vancomycin concentration in neonates according to EMA and FDA recommendations .
In WP4 on formulation and trial development, the Development Agreement for neonatal vancomycin formulation has been signed with Reig Jofre (Barcelona, Spain)and the pharmaceutical development plan was completed and submitted to the EC. The first steps of this plan, including evaluation and characterization of vancomycin powder for solution, manufacturing process development, scale up and clinical batch manufacture and labelling for clinical trial supply, Qualified Person release and delivery of product to sites, were successfully completed. Stability studies of the stored product and reconstituted solution are underway.

NeoVanc Clinical Trial (WP5) has successfully submitted the Phase II PK/PD randomised trial protocol to the EC and regulatory bodies/ethics committees at all 19 participating sites, six site initiation visits were conducted and two patients were enrolled. Study database, eCRF and standard operating and study specific procedures for study implementation have been created, and GCP-compliant Trial Master File maintenance system was put in place.

In WP6 on microbiology, PD and biomarkers, prospective surveillance of vancomycin resistance in CoNS isolates involved in LOS in NeoVanc sites in the UK and Estonia captured 171 CoNS isolates, providing necessary data on minimum inhibitory concentrations (MIC) among neonates. Further data from NeoVanc Clinical Trial will aid in refining these MIC. Development has begun for gut colonisation, biomarker development and validation and biofilm production and resistance assessment activities.

A request for modification of the vancomycin PIP was submitted based on NeoVanc 1 and 2 results as a regulatory activity (WP7), receiving a favourable opinion from the Paediatric Committee (PDCO). Pharmacovigilance and Risk Management Plans and Environmental Risk Assessment were created, implemented and submitted to the EC.

Communication and dissemination activities (WP8) include creation of the Project Information Sheet and Communication Plan, which was successfully implemented, including set-up and launch of the project web site. NeoVanc 1 and 2 results were disseminated via publication of two peer-reviewed articles and abstracts at relevant congresses.

Potential Impact:
The key expected final result from NeoVanc is to define the single optimal dosing schedule required for vancomycin, a critically important antibiotic, in neonatal LOS. Resulting data will facilitate and expedite the development of the corresponding PUMA.

NeoVanc activities have the potential to impact all Seventh Framework programme Theme Health aims.
• The project performs multidisciplinary biomedical research, including both pre-clinical and clinical activities and secondary and primary data production and use,
• addressing global health issues, as neonatal LOS is associated with high morbidity and mortality worldwide, as well as high levels of antimicrobial resistance, and
• providing scientific validation of experimental results, conducting the phase II randomised PK/PD NeoVanc Clinical Trial to validate pre-clinical NeoVanc 1 and NeoVanc 2 experimental results, aimed to identify new therapies or methods for health promotion and prevention, in this case a new optimal neonatal dosing schedule for vancomycin, including promotion of child health, clearly addressed by the focus on neonates and infants under 3 months of age.
The potential impact of NeoVanc extends to the Health 2013 specific topic on investigator-driven clinical trials for off-patent medicines using innovative, age-appropriate formulations and/or delivery systems. The aim of the project to develop an age-appropriate optimal dosing schedule for an off-patent medicine on the EMA list of priorities for paediatric medicines, with the ultimate goal of obtaining a PUMA, completely fulfils the objectives of the call. An appropriate clinical trial will be conducted among neonates and infants under 3 months of age, and a relevant patient advocacy group, the European Foundation for the Care of Newborn Infants has been involved already in the design of the study protocol and its implementation.

The fact that current summaries of product characteristics (SmPCs) for vancomycin do not include clear dosage information for neonates and young infants, despite it being one of the most commonly used medicines in this age group, indicates a gap in knowledge that urgently needs to be addressed. Current dosage information is based on data from adults and older children, and may likely result in an inadequate antibiotic concentrations due to the relative immune deficiency of these younger age groups. By providing these missing data, the NeoVanc project will allow physicians worldwide to maximize bacterial kill among neonates and young infants with LOS, improving morbidity and mortality attributable to this common infection.

By maximizing existing data to conduct population PK meta-analysis and Monte Carlo simulations and exploiting innovative methodologies such as hollow fibre infection model and rabbit model of catheter infection, NeoVanc also provides support for the viability and utility of these approaches which maximize data collected prior to conducting clinical trials among young children in the development of paediatric formulations. Such approaches can be applied to the development of other medicines for children in an effort to limit involvement of young patients in clinical trials while facilitating and expediting the procurement of much needed information on drug safety and efficacy in these special populations.

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