Theme 3: Clinical Trials

Theme 3 concentrates on clinical trials of new drugs and treatment regimens for drug-sensitive TB. The interventions studied here emerge from the work of Themes 1 and 2, alongside fresh uses of existing compounds and their combinations. This theme also runs trials of new or re-purposed anti-mycobacterial and immune-modulatory drugs and combination regimens designed to shorten treatment duration for drug-sensitive TB.

A further aim is to build a network of Asian TB research sites capable of conducting TB clinical trials to a high standard. The network will refine trial methodology and foster collaborations among 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) is SPRINT-TB's flagship clinical trial, spanning multiple Asian countries to evaluate two-month treatment strategies for drug-sensitive TB. Supported by UK MRC/Wellcome Trust/DfID and Singapore NMRC, the trial includes treatment arms combining established and new drugs that are currently in Phase 3 trials. It brings together a large team of clinicians, statisticians, microbiologists and trial management staff across Asia and the UK.

Rosuvastatin Clinical Trial

Project lead: Dr. Gail Cross

Standard TB treatment lasts six months, but patients often struggle to maintain adherence over such long courses, leading to poor outcomes and the selection of drug resistance. Shorter regimens are urgently needed for drug-sensitive TB. Statins inhibit cholesterol biosynthesis and are used clinically to treat hyperlipidaemia. Depleting host cholesterol with statins may benefit TB by disrupting MTb metabolism and the survival of persisters, raising intracellular drug levels and impeding MTb entry into host macrophages. We therefore propose to clinically test 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, notably 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 (with augmentin) plus rifampicin, 2) cefadroxil (with augmentin) plus rifampicin, or 3) rifampicin alone (controls) for 2 days prior to standard TB therapy, then a further 5 days in combination with standard TB treatment. The primary outcome is change in time to positivity (TTP) in liquid culture over time. The trial also measures outcomes using a number of novel biomarkers, through cultures of Mtb in the presence of resuscitation promoting factors and through bacterial and host transcriptomics.

WBA Studies

Clinical lead: Dr. Claire Naftalin
Laboratory lead: Dr. Rupangi Verma

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. When performed alongside PK measurements, the method can evaluate drug effects throughout the dosing cycle. WBA studies under Theme 3 aim to corroborate the sterilisation efficacy of various drugs and 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 for biomarkers that give an early indication of drug or regimen activity against TB, and PET-based imaging methods hold promise for this. The study aims to assess whether PET/MRI is as good as PET/CT in measuring the extent and activity of pulmonary TB, and to evaluate the relationship between PET/MRI imaging features and clinical, microbiological and immunological markers of TB disease during chemotherapy. The study also compares PET/MRI and PET/CT findings in patients with (non-TB) bacterial pneumonia to assess whether these differ quantitatively and qualitatively from those seen 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 Collaborators

Department of Microbiology, National University of Singapore, Singapore — Sabai Phyu
Department of Medicine, National University of Singapore, Singapore — Lawrence Lee
National University Hospital, Singapore — Roland Jureen
Duke-NUS, Singapore — Yin Bun Cheung
Singapore Clinical Research Institute, Singapore — Damien Hong
Clinical Imaging Research Centre, National University of Singapore, Singapore — David Townsend, John Totman
Genome Institute of Singapore, A*STAR, Singapore — Paola de Sessions
Alexandra Hospital, Singapore — Gerald Chua
Changi Hospital, Singapore — Augustine Tee
Khoo Teck Puat Hospital, Singapore — Fai Lam Sin
Tan Tock Seng Hospital, Singapore — Roland Boey
Institute of Respiratory Medicine, Malaysia — Dato' Abdul Razak
University of Malaya Medical Centre, Malaysia — Yong-Kek Peng
Fakulti Medicine Universitas Indonesia, Indonesia — Erlina Burhan
Hasanuddin University, Indonesia — Irawan Yusoff, Nasrum Massi
National Hospital of TB and Respiratory Diseases, Vietnam — Nguyen Huu Thuong
Quezon Institute, Philippines — Elizabeth Cardena
Lung Centre of Philippines, Philippines — Vincent Balanag
National Institute for Research in Tuberculosis, India — Soumya Sawminathan
Beijing Chest Hospital, China — Li Liang
University of Leicester, UK — Mike Barer
UCL, UK — Patrick Philips, Andrew Nunn, Timothy McHugh
GlaxoSmithKline

Site Links

Home About Research News Events Journal Club Annual Symposium Giving Contact Contact Us Careers Terms & Conditions Facebook Twitter

Theme 3: Clinical Trials