Theme 3: Clinical Trials
Theme 3 focuses on clinical trials of new drugs and treatment regimens of drug-sensitive TB. The new interventions arise from the research in Themes 1-2, as well as novel applications of existing compounds and their combinations.
The theme also conducts clinical trials of new or re-purposed anti-mycobacterial or immune-modulatory drugs and combination regimens to shorten treatment duration for drug-sensitive TB.
Theme 3 also aims to establish a network of Asian TB research sites that can conduct, to a high standard, TB clinical trials. The network will work on improving trial methodology and establishing collaborations between Singapore, regional and international research centres.
Theme 3 Lead: Prof. Nicholas Paton
Department of Medicine, National University of Singapore (NUS), Singapore
TRUNCATE-TB Clinical Trial
Project lead: Dr. Padmasayee Papineni
TRUNCATE-TB (Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for drug-sensitive Tuberculosis (TB)) is SPRINT-TB’s flagship clinical trial across multiple Asian countries evaluating the effectiveness of two-month treatment strategies for drug-sensitive TB. Funded by UK MRC/Wellcome Trust /DfID and Singapore NMRC, the trial includes treatment arms with novel combinations of established and new drugs that are currently in Phase 3 trials. The trial brings together a large team of clinicians, statisticians, microbiologists, and trial management staff across Asia and UK.
Anti-IL-4 Clinical Trial
Project lead: Dr. Meera Gurumurthy
Interleukin-4 (IL-4) is a key cytokine in the immune response to TB that may impair the clearance of dormant mycobacteria. This proof-of-concept trial aims to evaluate the safety and efficacy of pascolizumab, an anti-IL-4 monoclonal antibody. Patients enrolled in this trial receive pascolizumab or placebo in addition to normal treatment. Preliminary evidence of efficacy is sought on a range of parameters including bacterial clearance in sputum, changes in bacterial and host transcriptome patterns, host immune response and lung imaging by PET/MRI. The trial has the potential to identify a new approach to TB therapy that might merit subsequent evaluation in large-scale clinical trials and that might ultimately improve clinical outcomes.
Faropenem Clinical Trial
Project lead: Dr. Meera Gurumurthy
In vitro studies, animal model data and clinical case reports indicate that the carbapenem class of drugs has activity against TB but this has not been tested in rigorous clinical trials. Faropenem, the only oral agent in the carbapenem class, is tested in this randomized controlled trial. Patients receive faropenem plus augmentin, isoniazid or pyrazinamide (controls) prior to standard TB therapy. The primary outcome parameter is change in colony forming units in sputum over time. The trial also measures outcomes on a number of novel biomarkers by methods of cultures of Mtb in the presence of resuscitation promoting factors, bacterial and host transcriptomics, and PET/MRI.
Clinical lead: Dr. Claire Naftalin
Laboratory lead: Dr. Rupangi Verma
The whole blood bactericidal activity (WBA) is an ex vivo model for measuring the combined effects of administered drugs, host factors and strain factors on mycobacterial sterilisation. If performed in parallel with PK measurements, the method can be used to evaluate the effect of drugs throughout the dosing cycle. WBA studies run under Theme 3 aim to corroborate the sterilization efficacy of various drugs and drug regimens (e.g. high dose rifampicin, faropenem, celecoxib, and others) in an ex vivo WBA model with healthy volunteers and/or TB patients.
Bortezomib WBA Study
Project lead: Dr. Gail Cross
Theme 1 researchers identified bortezomib as a novel whole-cell active mycobacterial caseinolytic protease (Clp) inhibitor. Clp was found to be potently inhibited by bortezomib and its derivatives, followed by mycobacterial growth inhibition. Bortezomib evaluation is now ongoing in a WBA assay (above) under Theme 3.
Sputum Transcriptomics Study
Project lead: Dr. Wenwei Lin
Studies have shown that sputum samples are dominated by a population of Mtb cells that can be cultured only by addition of resuscitation promotion factors (RPFs). It appears that an RPF-dependent population present at the time of initiating chemotherapy is eliminated more slowly than the colony-forming population, or RPF-dependent cells are induced by chemotherapy. The existence of this Mtb population offers important opportunities for the development of biomarkers and enhanced diagnostic methods.
The aims of this study are to describe early changes in the bacterial transcriptome following TB treatment initiation, determine whether there are differences in the transcriptome following TB treatment initiation between Mtb strain types, and evaluate the time to detection on liquid cultures in the presence of RPFs.
Project lead: Dr. James Molton
There is a pressing need to develop biomarkers that can provide an early indication of activity of drugs or combination regimens against TB, and PET-based imaging methods hold promise for this indication. The study aims to assess whether PET/MRI is as good as PET/CT in measuring the extent and activity of pulmonary TB and evaluate the relationship between PET/MRI imaging features and clinical, microbiological and immunological markers of TB disease during chemotherapy.The study also compares the PET/MRI and PET/CT findings in patients with (non-TB) bacterial pneumonia to assess whether these differ quantitatively and qualitatively from those observed in TB.
Project lead: Dr. James Molton
In order reduce the global burden of TB, it is critical to identify and treat patients at risk of developing pulmonary TB before they become infectious. It is likely that within the population traditionally defined as “latent” TB there is a spectrum of subclinical disease, and it is crucial to develop a test that can differentiate between patients with completely quiescent TB, and those with subclinical disease. The study aims to determine the prevalence and spectrum of PET-MRI imaging abnormalities in a cohort of contacts heavily exposed to TB, and relate the imaging findings to clinical symptoms, standard TB evaluation test results, and comprehensive immunological profiles.
Theme 3 Collaborators
Department of Microbiology, National University of Singapore, Singapore
Department of Medicine, National University of Singapore, Singapore
National University Hospital, Singapore
Singapore Clinical Research Institute, Singapore
Clinical Imaging Research Centre, National University of Singapore, Singapore
Genome Institute of Singapore, A*STAR, Singapore
Alexandra Hospital, Singapore
Changi Hospital, Singapore
Koo Teck Phuat Hospital, Singapore
Tan Tock Seng Hospital , Singapore
Institute of Respiratory Medicine, Malaysia
University of Malaya Medical Centre, Malaysia
Fakulti Medicine Universitas Indonesia, Indonesia
Hasanuddin University, Indonesia
National Hospital of TB and Respiratory Diseases, Vietnam
Quezon Institute, Philippines
Lung Centre of Philippines, Philippines
National Institute for Research in Tuberculosis, India
Beijing Chest Hospital, China
University of Leicester, UK