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Treatment of late onset bacterial sepsis caused by vancomycin susceptible bacteria in neonates and infants aged under three months

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

Executive Summary:
Vancomycin is a cornerstone antibiotic in the management of severe Gram-positive sepsis. The EMA included vancomycin in the “Revised priority list for studies into off-patent paediatric medicinal products” (Doc. Ref. EMA/98717/2012 Rev 2012), as data on optimal dosing, pharmacokinetics/pharmacodynamics and safety based efficacy studies in preterm and term neonates are lacking. The NeoVanc project was a direct response to this call.

The NeoVanc clinical trial primary objective is to compare the efficacy of an optimised vancomycin dosing regimen (including a loading dose; 5±1 day course) to a standard regimen (10±2 day course) in neonates with LOS caused or suspected to be caused by Gram-positive microorganisms. The optimised dosing regimen was determined through several pre-clinical studies: a hollow-fibre infection model, a rabbit model and a neonatal, vancomycin population pharmacokinetic meta-analysis. Secondary objectives include comparing safety (e.g. renal and hearing outcomes), pharmacokinetics and colonisation with resistant organisms between treatment arms.

Babies were recruited from 22 neonatal intensive care units in 5 European countries (Estonia, Greece, Italy, Spain and the UK).

The three pre-clinical studies were completed successfully and informed the optimised dosing regimen to be taken through to the clinical trial. The NeoVanc clinical trial recruited 242 babies, however, it was closed early as a planned interim analysis yielded a different event rate to that used to calculate the sample size; post-randomisation exclusions also occurred at a higher rate than anticipated. Following the discussion with the IDMC and hypothesising different statistical scenarios, it was concluded that it would not be possible to recruit sufficient babies, within the remaining trial time frame, and so the study was closed. However, the data collected will contribute to the secondary endpoints and exploratory analyses, covering pharmacokinetics, microbiology, biomarker and safety analyses. The pharmacokinetics data will add, particularly, to the safety data available for vancomycin in this population. The NeoVanc trial remains the largest, neonatal vancomycin efficacy trial ever conducted.
Project Context and Objectives:
Vancomycin is a 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 methicillin resistant Staphylococcus aureus (MRSA) in neonatal intensive care units (NICUs) has led to a marked increased use of vancomycin, which is now the third commonest antibiotic used in European NICUs. Conventional dosing of vancomycin in neonates is 15 mg/kg/day with 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 (loading) doses of vancomycin to achieve more rapid, optimal serum concentrations in 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, 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 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 NeoVanc 1 a new optimal vancomycin dosing regimen (NeoVanc 2)
3) to compare a new “optimal” vancomycin dosing regimen with an accepted European standard of care regimen in a Phase IIb randomised clinical trial in terms of efficacy and safety, with the possibility of leading to a Paediatric Use Marketing Authorization (PUMA).
Project Results:
All management structures outlined in the GA to oversee the FP7 project and the Phase II randomized trial are successfully in place.
All 39 deliverables related to the Project were submitted on time.
In NeoVanc 1 (WP2), a hollow fibre infection model with vancomycin against clinical strains of CoNS identified the best PD index. Results were validated in a rabbit model and resulting data identified the most appropriate vancomycin regimen for the NeoVanc clinical trial.
In NeoVanc 2 (WP3), source data were collected and, together with un-published data, were used for a population PK meta-analysis to optimize the dosing regimen from the PK/PD target obtained from NeoVanc 1 and define the “optimal” regimen of vancomycin for NeoVanc Clinical Trial. A UPLC-MSMS method to quantify vancomycin concentration in neonates according to EMA and FDA recommendations was used.
In WP4 on formulation and trial development, the Development Agreement was signed with Reig Jofre (Barcelona, Spain) and the pharmaceutical development plan was completed and submitted to the European Commission. A commercial supply of 500mg/vial would be used for the clinical trial to expedite availability of supplies. Clinical batch manufacture, labelling for clinical trial supply, Qualified Person release and delivery of product to sites, were successfully completed.
NeoVanc Clinical Trial (WP5) activated the approval process in 22 participating sites. 6 did not open to recruitment/did not recruit any participants. 16 sites have actively recruited patients into the NeoVanc trial. Constant monitoring of recruiting sites and support for any protocol queries has been offered.

A preliminary overview of the data collected was presented, in September 2018, to the IDMC in a face to face meeting in London. The IDMC requested further information, and an interim analysis was presented to the IDMC during a teleconference meeting in April 2019. Following this more detailed analysis, and additional clarifications, in May 2019, the President of the IDMC replied on behalf of the Committee and indicated that the event rate was different to that which had been used in the power calculation, which could impact the power of the study. The Sponsor called for an extraordinary NMG teleconference to discuss the way forward. At the time of the teleconference (30th July 2019) 242 participants had been randomised to the study.

The study originally aimed for a sample size of 300 participants (based on a 5% failure rate). The NMG confirmed that the number of post-randomisation exclusions was higher than predicted and would have meant that ~15% of the babies would potentially need to be replaced. Projected timelines indicated that 350 patients would be achieved by September 2020, which would be beyond the end of the project (July 2020). As previously mentioned, the IDMC indicated that the event rate was different to that which had been used in the power calculation. Statistical input was sought, and different scenarios were hypothesised with varying sample size predictions without reference to, or knowledge of, the observed event rate. Continuing recruitment until September 2020 was discussed, however, replacement of the post-randomisation exclusions up to 350 babies would, in most likelihood, still have been insufficient. Recruitment at all sites had already been optimised and the opening of new sites was not possible within the given timeframes. It was concluded that recruiting sufficient babies to determine the primary endpoint would not be possible within the remaining timelines and resources and so the NMG decided to close to recruitment on 31st July 2019. At the time of closure to recruitment, 242 babies had been recruited, making NeoVanc the largest neonatal vancomycin efficacy trial. The data collected were revise and cleaned and database lock was performed on 1st April 2020. The final dataset was analysed as per the statistical analysis plan by the trial statistician. A report on final results was produced and presented to the relevant stakeholders on 29th April 2020. A separate meeting to inform the IDMC too place on 12th May 2020. Data collected also contributed to the secondary endpoints and exploratory analyses, covering pharmacokinetics, pharmacodynamics, microbiology, biomarker and safety analyses. The pharmacokinetics data contributed particularly to the safety data available for vancomycin in this population.

A previously completed deliverable (6.1) a prospective surveillance of vancomycin resistance in CoNS isolates from LOS in NeoVanc sites located in the UK and Estonia, had already contributed information in relation to minimum inhibitory concentrations (MIC) of coagulase negative staphylococci. 171 CoNS isolates were analysed, providing information on the MICs of invasive organisms causing sepsis in neonates.
Activities on gut colonisation, biomarker development and validation, biofilm production and resistance assessment are ongoing.

A request for modification of the vancomycin PIP was submitted and agreed with EMA/PDCO based on NeoVanc 1 and 2 results as part of WP7 activity.
Communication and dissemination activities (WP8) were successfully implemented.
The key final result from NeoVanc is the definition of the 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.
Potential Impact:
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 the 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 is involved 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 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 concentration due to the relative immune deficiency of these younger age groups. By filling this gap, 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.

With the implementation of population PK meta-analysis, Monte Carlo simulations and 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 maximising information prior to conducting clinical trials among young children. Such approaches can be instrumental in limiting the 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 population.
List of Websites:
www.neovanc.org
Relevant contacts
• Sponsor (Penta) Project Manager: Davide Bilardi davide.bilardi@pentafodundation.org
• Sponsor (Penta) Dissemination team: communication@pentafoundation.org
• St. George’s, University of London- Clinical Research Fellow - Louise Hill lhill@sgul.ac.uk
• Therakind- NeoVanc Project coordinator- Louise Rawcliffe louise.rawcliffe@therakind.com