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CFMATTERS Report Summary

Project ID: 603038
Funded under: FP7-HEALTH
Country: Ireland

Periodic Report Summary 2 - CFMATTERS (Cystic Fibrosis Microbiome-determined Antibiotic Therapy Trial in Exacerbations: Results Stratified.)

Project Context and Objectives:
Cystic Fibrosis Microbiome-determined Antimicrobial Therapy Trial in Exacerbations: Results Stratified (CFMATTERS) will provide a randomized multi-centre controlled trial of microbiome-derived antimicrobial treatments versus current empirical therapy for Cystic Fibrosis Patients. Simultaneously parallel human host-pathogen interaction studies in sputa, human gut faecal analysis and evaluation of in vivo co-infection exacerbation models will be performed. Antimicrobial resistance is arguably the most significant challenge facing the EU health care system. The unnecessary use of antibiotics is a key driver in the development of antibiotic resistance. Cystic Fibrosis (CF) represents a unique disease model to study bacterial resistance and to explore therapeutic strategies for the same, as chronic lung infection overlaps with acute lung exacerbations caused by a multitude of organisms that traditionally evolve various mechanisms of resistance. With time, chronic polymicrobial infection develops, in the lung with the most dominant infecting organism being Pseudomonas aeruginosa, which is also important in other infections including wounds, burns and patients with medical devices, making it an important clinical target for the EU. In CF infections, empiric intravenous antibiotics are usually given for two weeks. Recurrent infections and treatments result in increasing antimicrobial resistance, and alterations in pathogen host interactions in the lung and gut flora. Next-generation DNA sequencing technology now offers DNA-based personalised diagnostics and treatment strategies. Based on bacterial molecular profiling of sputum, the use of stratified targeted antibacterial therapy can be compared with standard empirical antibacterial therapy currently used. We believe this will reduce antibiotic usage, and optimize dosage and duration strategies, as the therapy will be tailored to the actual individual patient needs and consequently, decrease adverse effects as well as emergence of drug resistance. The throughput and quality of next-generation DNA sequencing technology now brings DNA-based personalised diagnostics within immediate reach for routine application in medical diagnostics and treatment strategies.
CFMATTERS will undertake 4 key objectives:
1. Provide randomized, controlled clinical data regarding the treatment effectiveness of microbiome-derived, tailored antimicrobial treatments versus current empirical therapy.
2. Enhance the understanding of human host-pathogen interaction via molecular profiling of antimicrobial peptide synthesis and innate immune responses in responders to treatment versus non-responders.
3. Use in vivo models to determine the impact of the lung microbiome on host response to infection by:
• investigating the role of host-pathogen interaction and pathogen-pathogen interaction in the development of acute and chronic infection
• characterising the treatment effectiveness of tailored microbiome-derived antimicrobial therapy via measurement of the emergence of antibiotic resistance mechanisms
4. Examine the consequences of antimicrobial treatment of CF lung exacerbations on the gut microflora, its influence on disease progression, and determine the potential role of the GI tract as a reservoir for resistant bacteria.

Project Results:
During Period 2 of the study the CFMATTERS consortium have made significant progress towards achieving our 4 key objectives;
WP01 (Clinical Trial management and analysis) The Trial Coordinating Centre, Trial Monitoring Committee, Trial Steering Committee continue to meet as outlined in period 1. The DSMB have also met and have approved continued enrolment in the trial. The Trial MC has also overseen the successful enrollment to date of 172 patients to date (as of October 17, 2016) at 8 clinical trial sites. A number of onsite monitoring visit have been carried out as per monitoring plan in order to ensure patient safety and data quality.
WP02 (Data management) The web based management system eCRF platform continues to function well. Data management activities continue to be carried out as outlined in the data management plan.
WP03 (Conduction of clinical trial) To date, the CFMATTERS study has enrolled 172 patients across 8 centres. 15 expert consensus panels have been carried out. To date 97 patients have had eligible exacerbations. Serial microbiome sputum samples have been analysed and therapies recommended by the consensus treatment panel uploaded to the eCRF regularly. To date 18 analysis runs have taken palce. All aspects of the eCRF, TCC, and clinical trial interfacing to date have functioned successfully.
WP04 (Ethical, data and safety monitoring) The CFMATTERS Ethics, Data and Safety Review group have been established. Ethical approval for the CFMATTERS study is in place in 9 of the 9 study sites. The trial monitoring plan is currently underway. Site initiation and training has been carried out for all 9 sites. Onsite monitoring has also taken place. Central data monitoring continues in real time as outlined in the monitoring plan.
WP05 (Microbial activities and functions) The Work Package is currently suspended please refer to alert in WP05.
WP06 (Human host defence response). To date, a target list of 10 HFP proteins have been analysed for individual protein levels or activity. A total of 300 sputum samples have been analysed for 8 out of 10 of these activities
WP07 (Lung Microbiome). Unique in vivo models have been developed to allow us to examine the role of the lung microbiome in chronic P. aeruginosa infection. We have shown that the lung microbiome does have the potential to modulate P. aeruginosa infection. This modulation is however, bacterial species and isolate specific. Whilst Streptococcal spp. coinfection does not alter the course of P. aeruginosa infection, S. aureus and H. influenzae infections are able to modulate bacterial burden and host immune responses.
WP08 (Gastrointestinal microbiota) We have used cutting edge whole genome sequencing to identify the impact of an altered gut microbiota on gut microbiota functionality and shown the CF gut to have increased ability to metabolise xenobiotics, lipids and carbohydrates. We have shown the alterations that occur in the gut microbiota during exacerbation and we are correlating the lung and gut microbiota. We have a biobank of over 600 isolates of Lactobacillus and Bifidobacterium from CF samples and from this have identified a potential probiotic for use in CF patients. There are currently several publications emanating from this work package in preparation for submission to peer reviewed journals.
WP09 (Project management) 1 General Assembly Meeting and two Steering Committee Meetings for the CFMATTERS consortium have been completed in this period. Weekly trial teleconference meetings are held for all members of the CFMATTERS group. TCC meetings are carried out weekly. Consensus panel teleconference meetings are carried out every two weeks. We also successfully submitted the first CFMATTERS amendment.
WP10 (Dissemination, outreach and training) Design and launch of CFMATTERS phone app and virtual reality lung and cystic fibrosis visualizer. Currently, outreach and education programmes are on-going.

Potential Impact:
CFMATTERS offers a stratified next generation approach to antibacterial treatment in a disease model of chronic bacterial infection with super-imposed acute exacerbations. It is the first randomized, controlled trial comparing the use of microbiome-directed antibiotic treatment versus standard therapy. The analysis of the constituent microbiome and its genomes will pave the way for more effective therapeutic regimes and ultimately contribute to the development of personalized medicine and personalized CF treatment. CFMATTERS for the first time will offer patients a targeted treatment model personalized to the individual Microbiome.
CF is a unique disease model. In CF, acute polymicrobial bacterial infections overlap with chronic polymicrobial bacterial colonisation and thus findings from the CFMATTERS study have potential applications in other diseases involving Pseudomonas aeruginosa, and/or polymicrobial infection (both acute and chronic) such as wounds, burns, mechanical devices patients and ventilator associated pneumonias. CFMATTERS may potentially revolutionize the practice of antibiotic prescription in acute and chronic infections and limit the development of antimicrobial resistance globally by decreasing antibiotic consumption therefore decreasing the likelihood of bacterial resistance and side-effects from repeated non-personalized antibiotic courses. Not only will this potentially improve survival of the 36,000 EU patients with CF who die significantly younger from lung disease when compared to non-CF EU citizens, but will also have subsequent application of these principles to patients with other acute and chronic infections.
We believe that this approach will also have profound implications for the EU and global public policy makers. An estimated 25,000 patients die annually and approximately €0.9 billion is spent on additional health costs related to bacterial resistance. Furthermore, the consequent economic value of lost productivity at work resulting from illness and its treatment of patients is estimated to be at least €1.5 billion in Europe each year.
CFMATTERS may also lead to identification of within-host evolution of pathogens during infection, bacterial persistence mechanisms and identification of genetic resistance mechanisms. Metabolite profiling of sputum (pathogen) and/or interrogation of host defense proteins (host factors) may discover new biomarkers to supplement traditional clinical assessment of antibiotic responses of CF patients. Given the difficulties associated with assessment of response to antibiotic treatment the development of such a biomarker(s) would be a welcome advance for patients with acute and/or chronic microbial infection. The development of in-vivo models of co-infection will also offer unparalleled insight into the impact into bacterial cross talk, bacterial virulence, the efficacy of treatment regimens and interaction between the lung and GI tract in response to pathogenic bacteria in the lung.
Finally CFMATTERS is examining the consequences of antimicrobial therapy on the gut microflora. Little is known of the effect of antibiotic administration on gut microbiome composition and/or inflammatory implications. Understanding the consequence of antibiotic administration on the gut microbiome is crucial in addressing the associated clinical symptoms such as diarrhea, occurring in as many as 30% of patients receiving antibiotics. Interestingly CF patients are known to have high carrier rates for Clostridium difficile. Recent reports suggest an increase in incidence of C. difficile infection in Europe, with significant medical complications. Data has estimated C. difficile infections cost the EU €3 billion per annum. Using CF as a model to understand this problem has important potential benefits. In totality these studies will increase understanding of the gut and immunologic consequences of antibiotic treatment, which could have broad implications in many areas of medicine.

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