Theme 3: Clinical TrialsTheme 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. Nick Paton
Department of Medicine, National University of Singapore (NUS), Singapore |
Projects
TRUNCATE-TB Clinical Trial
Project lead: Dr. Christopher Cousins 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. Rosuvastatin Clinical Trial
Project lead: Dr. Gail Cross Standard TB treatment lasts 6 months but patients struggle to maintain adherence throughout such long courses, resulting in poor outcomes and selection of drug resistance. Shorter treatment regimens are urgently needed for drug-sensitive TB. Statins inhibit cholesterol biosynthesis and are used clinically for the treatment of hyperlipidaemia. Statins depletion of host cholesterol may be of benefit in TB by disrupting MTb metabolism and survival of persisters, enhancing intracellular drug levels, and impeding entry of MTb into host macrophages. As such, we propose to clinically test the use of rosuvastatin as an adjunct to standard combination treatment for drug-sensitive TB. Faropenem Clinical Trial
Project lead: Dr. Claire Naftalin In vitro studies and animal model data indicate that the Beta Lactam class of drugs has activity against TB, in particular showing synergy with rifampicin, but this has not been tested in rigorous clinical trials. Faropenem, the only oral penem, and cefadroxil, a first generation cephalosporin, are tested in this randomized controlled trial. Treatment naïve patients receive either: 1) faropenem (in combination with augmentin) plus rifampicin, 2) cefadroxil (in combination with augmentin) plus rifampicin, or 3) rifampicin alone (controls) for 2 days (prior to standard TB therapy) then with a further 5 days in combination with standard TB treatment. The primary outcome parameter is change in time to positivity (TTP) in liquid culture 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. WBA Studies
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. Select publications: Activity of faropenem with and without rifampicin against Mycobacterium tuberculosis: evaluation in a whole-blood bactericidal activity trial. Journal of Antimicrobial Chemotherapy. 2017 Mar 18. 72(7):2012-2019. Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model. Antimicrob Agents Chemother. 2017 Sep 22. 61:e00482-17. Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model. Sci Rep. 2018 Sep 10;8(1):13491. Imaging Study
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. Select publications: A comparison of 18F-FDG PET/MR with PET/CT in pulmonary tuberculosis. Nucl Med Commun. 2017 Nov. 38:971-978. Sub-clinical abnormalities detected by PET/MRI in household tuberculosis contacts. BMC Infect Dis. 2019 Jan 24;19(1):83. |
Theme 3 CollaboratorsDepartment of Microbiology, National University of Singapore, Singapore
Department of Medicine, National University of Singapore, Singapore
National University Hospital, Singapore
Duke-NUS, 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
UCL, UK
GlaxoSmithKline |
