Rapid Evaluation of Biomarkers in Tuberculosis

Lead Research Organisation: University of St Andrews
Department Name: Sch of Medicine

Abstract

Tuberculosis is a growing threat to human health throughout the world. If we are to reverse the increasing number of new cases and the rise of cases unable to be treated with the standard drugs we need new drugs and vaccines. The clinical studies in which drugs are tested are time consuming to perform because the treatment of tuberculosis takes a long time and patients may relapse for at least a year after they have finished their drugs. In addition large numbers of patients are required to provide a convincing result.

In the past few years a number of new potential drugs for tuberculosis have been discovered and in order for these to be developed into medicines that can be used in the clinic soon it will be necessary to find new and quicker ways of testing them safely. A biomarker is a measure of a response to treatment which permits a reliable result to be predicted and this reduces the time taken to perform studies and the number of patients required in clinical trials. In this study we will use an international clinical study of tuberculosis treatment that we are performing to test potential biomarkers. These are different ways of measuring the burden of bacteria in the patient?s body and the patient?s immune response to the invading bacteria. Thus, we expect that this study will result in better ways to measure the response to treatment that will be used in all future clinical trials and will prove useful to health care workers treating tuberculosis across the world.

Technical Summary

With the proliferation of potential new agents to be evaluated there is a pressing need to develop biomarkers that can shorten the time taken to trial new drugs and regimens. To date, the only accepted end point for tuberculosis clinical trials is bacteriological cure and absence of relapse at one year. This proposal explores clinically relevant and biologically significant biomarkers that predict the ability to render sputum culture negative and prevent relapse.

The international consortium making this proposal is responsible for a pivotal clinical trial evaluating the efficacy of moxifloxacin in tuberculosis treatment (REMoxTB - Rapid Evaluation of Moxifloxacin in Tuberculosis). This study, to be performed to international Good Clinical Practice and monitored by the Federal Drugs Administration will recruit up to 1500 patients and will follow them through treatment and for one year afterwards. Serial measures will be taken to evaluate the efficacy of two experimental regimens and the standard regimen. Thus, REMoxTB will provide an outstanding collection of well characterised clinical samples from a trial setting that will permit the comparison between the conventional measures of efficacy, bacteriological cure and relapse rate as well as several new approaches. We will collect sequential data on the bacterial load as measured by conventional bacteriological means. The delays associated with conventional culture methods will be addressed by using molecular methods; quantitative measurement of mRNA and transrenal DNA will be compared with the conventional measures of efficacy and modelling of bacterial load. We will also collect serial measures of the immune response to M. tuberculosis infection using ELISpot before during and after treatment. The REMoxTB study provides the ideal setting for the qualification of this promising, but yet not fully validated, T cell biomarker. An adaptation of our earlier non-linear model of bacteriological load measurement using a bi-exponential appraoch and the later application of non-linear mixed effects models recently proposed by Davies will be applied to analyse serial sputum culture colony counts. These methods are advantageous as they account for serial correlation and model the two phases of drug action separately.

This proposal evaluates the utility of several biomarkers in a clinical trials setting, providing the opportunity to inform the trials of the novel anti-tuberculous drugs entering the development pipeline.

Publications


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Honeyborne I (2015) Effective anti-tuberculosis therapy correlates with plasma small RNA. in The European respiratory journal


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Perrin FM (2010) Radiological cavitation, sputum mycobacterial load and treatment response in pulmonary tuberculosis. in The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease



 
Description All Party Parliamentary Group for Tuberculosis Call for evidence
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
 
Description Clinical trials call 2016
Amount € 16,500,000 (EUR)
Organisation European Developing Countries Clinical Trials Platform (EDCTP) 
Sector Public
Country Netherlands, Kingdom of the
Start 03/2017 
End 02/2022
 
Description EU Innovative Medicines Initiative
Amount £5,902,837 (GBP)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 03/2012 
End 02/2017
 
Description European Association of National Metrology Institutes (EURAMET)
Amount £176,400 (GBP)
Organisation European Association of National Metrology Institutes (EURAMET) 
Sector Charity/Non Profit
Country European Union (EU)
Start 08/2012 
End 06/2014
 
Description PreDiCT-TB
Amount £1,000,000 (GBP)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 03/2012 
End 03/2017
 
Title Analysis of trans-renal DNA 
Description Stability and detection of DNA in urine samples was assessed. This was found to be variable and the results suggest that this would not represent a reliable biomarker for following response to tuberculosis treatment 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact These results were published as a paper in 2009 
 
Title Rapid culture-free enumeration of tuberculosis bacilli in sputum 
Description A molecular assay based on rRNA was developed to detect the number of bacteria in sputum. The method is related to a standard curve and inhibition and variable loss of RNA during sample processing detected by using a newly developed internal control based on a gene from potato. The method has been validated for 43 tuberculosis patients followed longitudinally. Currently the methods available require culture of organisms. Since tuberculosis bacteria are slow growing this requires substantial time delays. Techniques are also hampered by contamination of cultures with other organisms and loss of organisms due to decontamination procedures used to kill contaminants in order to prevent this. Additionally our new technique is sensitive enough to detect 100 bacteria in 1mL sputum which is an improvement compared to smear microscopy. The method is specific for tuberculosis complex bacteria and does not detect other mycobacteria. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact N/A 
 
Description Analysis of tuberculosis RNA in sputum 
Organisation University of Stellenbosch
Country South Africa, Republic of 
Sector Academic/University 
PI Contribution We applied our newly developed molecular based culture-free method to enumerate the number of tuberculosis bacilli in sputum samples provided by our collaborators.
Collaborator Contribution provided longitudinal sputum samples from tuberculosis infected individuals
Impact Use of the samples collected and stored at the University of Stellenbosch has allowed us to validate our newly developed enumeration assay. The data generated is currently being put together as a manuscript for publication
Start Year 2009
 
Description Clinical Trials Unit 
Organisation Medical Research Council (MRC)
Department MRC Clinical Trials Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution We are providing the biological data for this analysis
Collaborator Contribution Statistical analysis for modeling of drug clearance of tuberculosis bacilli
Impact Since the data is coming from a clinical trial for this part it hasn't yet been released
Start Year 2008
 
Description Developing mathematical modelling 
Organisation University of St Andrews
Department School of Mathematics and Statistics St Andrews
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Providing data to test mathematical models developed jointly
Impact Multidisciplinary collaboration. We have developed a new model that is being exploited in the main core of our research
Start Year 2010
 
Description Diagnosis of tuberculosis bacteria in paediatric stool 
Organisation University of Cape Town
Department Institute of Infectious Disease and Molecular Medicine (IIDMM)
Country South Africa, Republic of 
Sector Academic/University 
PI Contribution We developed the assay which we will now modify and then test on the stool samples
Collaborator Contribution UCR is collecting stool samples to test our recently published respiratory assay on.
Impact ongoing work - no direct outputs yet
Start Year 2011
 
Description Evaluation of methodology i 
Organisation University of KwaZulu-Natal
Country South Africa, Republic of 
Sector Academic/University 
PI Contribution This work had trialled methodology developed in this project in the field and to be a source of collection of immunological samples.
Collaborator Contribution Access to samples and access to specialist techniqes
Impact Data from these studies have been presented informally and are being prepared for publication in international journals
Start Year 2010
 
Description British Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited lecture at the tuberculosis day of the British Science Festival Birmingham

None yet
Year(s) Of Engagement Activity 2010
 
Description Website entry 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact UCL website world TB day March 2009 http://www.ucl.ac.uk/news/news-articles/0903/09032402

N/A
Year(s) Of Engagement Activity 2009