First CFMATTERS results
Work performed since the beginning of the project and the main results achieved so far
During the first 18 months 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 have all been established. In addition the Scientific Advisory Board has also been appointed. The CFMATTERS study protocol has been approved and a Trial master file and manual of operations prepared. The treatment algorithm of the study has also been developed.
WP02 (Data management) A web based management system eCRF platform and the associated tools have been delivered. A comprehensive data management plan is also in place.
WP03 (Conduction of clinical trial) To date, the CFMATTERS study has enrolled 57 patients across 4 centres and has treated 5 eligible pulmonary exacerbations. Equally 8 non-eligible exacerbations have been recorded. Serial microbiome sputum samples have been analysed and therapies recommended by the consensus treatment panel uploaded to the eCRF every two weeks. 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 6 of the 7 study sites. The trial monitoring plan is currently underway.
WP05 (Microbial activities and functions) The Optimisation of viral and bacterial DNA extraction from CF sputum samples has been completed with identification of genes upregulated during CF patient exacerbation during antibiotic therapy failure by microbial metatranscriptomics and metabolic evaluation.
WP06 (Human host defence response) Effective innate antimicrobial peptides as bactericidal agents have been demonstrated using radial diffusion assays against a range of bacterial isolates.
WP07 (Lung Microbiome) a stock bank of bacterial isolates to be used by all partners has been prepared and in vivo co-infection models of disease using CF specific bacterial isolates successfully created.
WP08 (Gastrointestinal microbiota) A protocol for the optimum storage of faecal samples for subsequent characterisation has been developed. Additionally, a bacterial bio-bank for the development of potential probiotics has been collected from stool samples.
WP09 (Project management) Two General Assembly Meetings and two Steering Committee Meetings for the CFMATTERS consortium have been completed. The creation of a communication structure including weekly phone conferences with all partners, mailings lists as well as internal sections of the website used to circulate documents is in existence.
WP10 (Dissemination, outreach and training) Design and launch of CFMATTERS study logo, website, phone app, project flyer and circulation of detailed dissemination guide for the study is complete. Currently, outreach and education programmes are on-going.
The expected final results and their potential impact and use
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.