PROJECT PERIODIC REPORT

Transcription

1 PROJECT PERIODIC REPORT Grant Agreement number: Project acronym: NEOVANC Project title: Treatment of late onset bacterial sepsis caused by vancomycin susceptible bacteria in neonates and infants aged under three months Funding Scheme: Collaborative Project - FP7 Date of latest version of Annex I against which the assessment will be made: 10/09/2013 Periodic report: 1 st þ 2 nd 3 rd 4 th Period covered: from 01/02/2014 to 31/07/2015 Name, title and organisation of the scientific representative of the project's coordinator 1 : Prof. Carlo Giaquinto, Fondazione PENTA Onlus Tel: Fax: carlog@pediatria.unipd.it Project website 2 address: 1 Usually the contact person of the coordinator as specified in Art of the Grant Agreement. 2 The home page of the website should contain the generic European flag and the FP7 logo which are available in electronic format at the Europa website (logo of the European flag: logo of the 7th FP: The area of activity of the project should also be mentioned.

2 Declaration by the scientific representative of the project coordinator I, as scientific representative of the coordinator of this project and in line with the obligations as stated in Article II.2.3 of the Grant Agreement declare that: The attached periodic report represents an accurate description of the work carried out in this project for this reporting period; The project (tick as appropriate) 3 : has fully achieved its objectives and technical goals for the period; þ has achieved most of its objectives and technical goals for the period with relatively minor deviations. has failed to achieve critical objectives and/or is not at all on schedule. The public website, if applicable þ is up to date is not up to date To my best knowledge, the financial statements which are being submitted as part of this report are in line with the actual work carried out and are consistent with the report on the resources used for the project (section 3.4) and if applicable with the certificate on financial statement. All beneficiaries, in particular non-profit public bodies, secondary and higher education establishments, research organisations and SMEs, have declared to have verified their legal status. Any changes have been reported under section (Project Management) in accordance with Article II.3.f of the Grant Agreement. Name of scientific representative of the Coordinator: Prof. Carlo Giaquinto Date: 30/09/2015 For most of the projects, the signature of this declaration could be done directly via the IT reporting tool through an adapted IT mechanism and in that case, no signed paper form needs to be sent 3 If either of these boxes below is ticked, the report should reflect these and any remedial actions taken. 2

3 1 - PUBLISHABLE SUMMARY A SUMMARY DESCRIPTION OF PROJECT CONTEXT AND OBJECTIVES A DESCRIPTION OF THE WORK PERFORMED SINCE THE BEGINNING OF THE PROJECT AND THE MAIN RESULTS ACHIEVED SO FAR EXPECTED FINAL RESULTS, POTENTIAL IMPACT AND USE (INCLUDING SOCIO- ECONOMIC IMPACT AND THE WIDER SOCIETAL IMPLICATIONS OF THE PROJECT SO FAR) CORE OF THE REPORT FOR THE PERIOD: PROJECT OBJECTIVES, WORK PROGRESS AND ACHIEVEMENTS, PROJECT MANAGEMENT PROJECT OBJECTIVES FOR THE PERIOD WORK PROGRESS AND ACHIEVEMENTS DURING THE PERIOD... 9 WP1 SCIENTIFIC COORDINATION WP2 ANIMAL AND LABORATORY PK- PD STUDIES - NEOVANC WP3 PHARMACOKINETIC MODELLING - NEOVANC WP4 - FORMULATION AND TRIAL DEVELOPMENT WP5 - CLINICAL TRIAL IMPLEMENTATION - NEOVANC WP6 MICROBIOLOGY, PHARMACODYNAMICS AND BIOMARKERS WP 7 REGULATORY ACTIVITIES WP 8 DISSEMINATION & NETWORKING PROJECT MANAGEMENT DURING THE PERIOD COSTS

4 1 - Publishable summary A summary description of project context and objectives Vancomycin was introduced into clinical medicine in 1956 and is the critical antibiotic used globally for the management of severe Gram- positive infections. It is a high molecular weight complex glycopeptide, which inhibits the cell wall synthesis of Gram- positive bacteria by the formation of stable complex murein pentapeptides, thus causing inhibition of further peptidoglycan formation. Vancomycin is used for moderate to severe infections that are caused by vancomycin susceptible bacteria and also widely used to treat nosocomial infections due to staphylococci and enterococci in neonates. The increased incidence of late onset sepsis (LOS) in neonates due to Coagulase Negative Staphylococci (CoNS) and MRSA has led to an increased use of vancomycin. 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 aureus 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. Vancomycin was included on the Revised priority list for studies into off- patent paediatric medicinal products (EMA/98717/2012 Rev 2012). According to the list, data on an optimal dosing and monitoring regimen (e.g. pharmacokinetics/pharmacodynamics 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. A paediatric formulation could be eligible for a PUMA (Paediatric Use Marketing Authorisation). The aims of this project include developing an age- appropriate formulation (new strength: 125 mg vial) suitable for vancomycin in neonates and infants aged less than 3 months without a dilutional step, an optimised dosing regimen and recommendations for therapeutic drug monitoring in this age group, evaluating the efficacy and safety of this optimised dose compared to current, standard treatment and subsequently to obtain a new PUMA for vancomycin for this age and indication. Fondazione PENTA 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 PIP has provisionally received a favourable 120 day opinion and this application includes the detailed scientific aspects of the PIP. The applicants have formed a well- balanced consortium of leading European experts in neonatal pharmacology, animal models, infectious diseases and clinical trials, with extensive experience in recruitment into neonatal research studies. This application includes an experienced SME, with the aim to produce a PUMA for vancomycin and to determine the optimal dosing regimen to treat Coagulase Negative Staphylococci (CoNS), methicillin- resistant Staphylococcus aureus (MRSA) and other beta- lactam- resistant Gram- positive infections, which have major cost and clinical implications for neonatal practice. The key objective of this strategically designed paediatric clinical development programme is: 4

5 - 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. In addition, the efficacy and safety of different dosing regimens will be described. An age- appropriate formulation (a new 125 mg vial) will be investigated in the clinical trial as recommended by the PDCO in the provisional PIP 120- day feedback. Gender and age subgroups will be accounted for in the PK models used to define the optimal dosage regimen and in the design and analysis of the clinical trial. The clinical study is based on an innovative PK/PD bridging strategy in which two different dosing regimens of vancomycin will be directly compared to each other. The most appropriate PD endpoint (most likely AUC/MIC) for CoNS will be evaluated and defined in the experimental preclinical animal studies, combined with a detailed population PK meta- analysis. The preclinical studies defining the optimal PK/PD target will be taken forward to the randomised clinical trial. The specific objectives will be: i) to define the preclinical 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) ii) 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) iii) to compare a new improved Optimal vancomycin dosing regimen with an accepted European standard of care regimen in a Phase II RCT in terms of efficacy and safety (NeoVanc 3) NeoVanc is built on the previously FP7 funded NeoMero and TiNN projects, including highly experienced neonatal networks. The consortium will include a wide range of international experts in PK analysis, laboratory animal model studies, neonatology, infectious diseases, regulatory affairs, clinical trials and project management. The consortium as a whole will be submitted as a PENTA- ID Project, bringing together very considerable experience in managing paediatric infectious disease clinical trials in Europe. PENTA- ID is recognised as the Level 1 Paediatric Research Network by the European Medicines Agency (EMA) to conduct antimicrobial clinical trials in children and is the paediatric partner in the IMI AMR COMBACTE network. The NeoVanc study will also act to further the development of this experienced European neonatal infection research network, facilitating the development of future clinical trials in novel antimicrobials as they progress through the EMA regulatory processes. The SME in the consortium, Therakind, is the SME that was pivotal in the only successfully obtained PUMA in Europe to date. PENTA Foundation, the project coordinator is the PIP holder and sponsor of the trial A description of the work performed since the beginning of the project and the main results achieved so far PENTA (Coordinator) set up, in collaboration with all Partners, the management and steering boards forecasted by DoW to provide the Project with an armoured ground for the development of the 3 NeoVanc trial- related activities (WP2, WP3 and WP5). A PMO, which meets twice a month (TCons or F2F), composed by Management Partner (SYNAPSE) and representatives of the Coordinator and the Scientific Coordinator, has been created. Its functioning has already been successfully tested (e.g. all deliverables for the first 9 months were achieved on time, showing a high level of synchrony in the Consortium). Most of the deliverables due during the first 12 months of the Project have been submitted on time. The Commission accepted all of them with no rejection. 5

6 Furthermore, also Internal Deliverables have been regularly submitted to the Coordinator by Partners on time. The hollow fibre infection model studies with vancomycin against clinical strains of coagulase negative Staphylococcus infection have been completed. The rabbit models of coagulase negative Staphylococcus infection have been completed. The mathematical modelling for the in vitro work and the rabbit work has been completed. The results have been bridged to human neonates. A systematic literature review has been conducted to identify all published pharmacokinetic studies on vancomycin in neonates. The data also showed the absence of consensus on optimal dose. This review of all available vancomycin PK data demonstrated the need for population pharmacokinetic meta- analysis to understand difference between published studies, determine conditions of pharmacokinetic evaluation and establish an optimal dose. A questionnaire to identify participating centres has been developed by the Therakind. A population PK model has been developed. Monte- Carlo simulations were performed in order to compare different dosage schedules with and without a loading dose. The target concentration was fixed at 20 mg/l and percentage of patients reaching the target in different neonatal age groups were compared. This allowed the selection of the dosage regimen to be evaluated in the clinical trial. The Development Agreement with the chosen manufacturer, Reig Jofre (Barcelona, Spain) has been signed and the pharmaceutical development plan has been completed and submitted to the EC. Therakind is currently reviewing Neonatal units with the aim of identifying suitable neonatal units for the NEOVANC trial. A questionnaire has been sent out to 23 potential sites as part of the site selection process. All the data resulting from the completed questionnaires has been collated and used to inform decisions on feasibility of sites for the study. Available data on the previous experience of sites has been reviewed. One site has been visited in order to familiarise the clinical project team with the potential compliance issues specific to trials in a NICU. Seven sites have been visited in three countries in accordance with our procedures for pre- selection activities. Administrative files have been set up in order to comply with GCP requirements for maintenance of Trial Master Files. An inventory of study specific procedures and documents has been set up and is being populated as documents and standard operating procedures are being generated. OPBG has contributed with identification of the Italian neonatal units potentially participating; facilitating contacts and pre- screening assessment of potential units in Italy; helping in screening out Sites not complying with feasibility schemes; and tailoring eligibility criteria for Sites to participate. SERMAS has been monitoring nosocomial infections in the neonatal unit in order to know the number of patients that may be included in the trial. SGUL has implemented and led the protocol writing committee with members of the consortium in order to develop the protocol for the clinical trial. The nearly final version of the NeoVanc3 protocol has now been circulated to the wider consortium for the final revision. In the first reporting period, a call for tender was carried out to select NeoVanc- 3 ecrf provider. The tender was issued in June Ten different companies were invited to participate in the tender and 8 submitted their quotations. In June 2015, the decision to select ClinInfo as ecrf provided was agreed upon between CVBF, PENTA and Therakind and confirmed by the Consortium. A number of 67 coagulase negative staphylococci isolates from the UK and 104 from Estonia were collected and characterised from babies with invasive infection. The MIC distribution from these data was in keeping with current EUCAST breakpoints based on data from adults, suggesting that the proposed MIC of 2 µg/ml used for PK/PD target calculation is appropriate in most clinical circumstances. 6

7 Another 60 isolates have been collected from a range of participating European countries and will be tested in the latter part of 2015, bringing this to a total of 231 isolates. Laboratory and clinical protocols have been developed involving considerable scaling down of the total blood volume required. Clinical and laboratory standard operating procedures (SOPs) have been created for 50µl draw (two drops of blood). This involves a significant advance in requiring a much reduced sample volume from the outline proposal of a 200 µl sample volume. The activities performed in the first 18 months of the project have been mainly addressed to the regulatory aspects of the PIP implementation (falling within task 7.1 Coordination and management of all PIP process aspects) and to the definition of the pharmacovigilance aspects (falling within task 7.2 Preparation and implementation of the pharmacovigilance plan). Activities were devoted to provide regulatory advice on aspects related to the preparation of the NeoVanc- 3 protocol, the supply of the IMP. A pharmacovigilance plan, describing the procedures for the collection and reporting of safety information, setting out the responsibilities of the involved parties has been prepared in accordance with Directive 2011/20/EC and the guidance elaborated by the Commission in order to provide precise indication on the reporting activities. The results of the NeoVanc 1 (WP2) and the NeoVanc 2 (WP3) studies were unexpected and have required a revision of NeoVanc clinical strategy. This needed a submission of a request for modification (RfM) of the vancomycin PIP. The planned submission date for the RfM (September 21st, 2015), as agreed during the NGC teleconference in August, was met. At this early stage of the Project, no results have been published and several dissemination activities have been performed. A Project website is now online and it works for both general public - with provision of general project and Consortium information - and a reserved area for all Project's Partners, a moodle platform where they are able to share, exchange documents, discuss issues and organise meetings and TCons in a unique environment. The website was designed based on the relevant best practices of the Project NeoMero, to which NeoVanc Consortium is collaborating with Expected final results, potential impact and use (including socioeconomic impact and the wider societal implications of the project so far) Theme Health within the Seventh Framework programme aims to stimulate and sustain multidisciplinary biomedical research while addressing global health issues, providing scientific validation of experimental results aimed to identify new therapies or methods for health promotion and prevention including promotion of child health. The focus of these activities are on research into age- appropriate use of medicines, drug safety research and methodologies for clinical trials in small populations in view of supporting regulatory decisions related to orphan drugs and personalised medicine. The NeoVanc proposal addresses very well the aims of the programme and is completely aligned with the goals of the call on the following aspects: Vancomycin has been off- patent for many years and largely used off label for the treatment of neonatal sepsis without sufficient data on pharmacokinetics, safety and efficacy Vancomycin was included in the Revised priority list for studies into off- patent paediatric medicinal products. 7

8 The aim of NeoVanc is to finally define the single optimal dosing schedule required for this critically important antibiotic and at the end to file a PUMA application. The actual proposal is based on the PDCO feedback and will be eventually modified if major changes are suggested by the reviewers. NeoVanc includes the development of an age- appropriate formulation (125 mg - suitable for neonates and young infants), which will no longer require a double dilution to prepare the vancomycin for administration in neonates; improving patient safety. The optimal dosage regimen will be used in a randomised (1:1), parallel- group, controlled PK/PD trial to compare the proportion of patients reaching the PD target (as defined in NeoVanc 1 and NeoVanc 2) when treated with standard vs optimised vancomycin regimens (NeoVanc 3). One of the key expected impacts of NeoVanc is the development of a template for efficient clinical trial design in vulnerable patients. Large Phase 3 trials are very expensive, difficult to conduct and may not always be ethically and clinically appropriate in vulnerable populations. This study design therefore acts as a template for rapid structured clinical trials in other vulnerable populations in Europe where similar issues of complex pharmacokinetics, and difficult to measure clinical outcomes are relevant, including the immunosuppressed and the elderly. Improvement of neonatal health is expected by the project. This study aims to be the definitive study to determine the optimal dosing regimen of this critically important antimicrobial, improving clinical outcomes, minimising toxicity and the development of antimicrobial resistance. The study therefore has global significance. NeoVanc also acts as an innovative bridging project in other key ways. From a microbiological perspective, classical MIC methods will also be compared with direct speciation through MALDI- TOF technology, but also molecular sequencing of key isolates as well. This is part of a deliberate introduction of bacterial sequencing data into PK/PD studies. 8