Articles www.thelancet.com Published online July 23, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61080-0 1 Published Online July 23, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61080-0 See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(12)61183-0 Division of Physiology, Department of Medical Biochemistry (Prof A H Diacon MD), MRC Centre for Molecular and Cellular Biology (A Venter NatDipTech), Department of Paediatrics and Child Health (Prof P R Donald MD), Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Task Applied Science, Karl Bremer Hospital, Bellville, Cape Town, South Africa (A H Diacon, F von Groote-Bidlingmaier MD); Division of Pulmonology, Department of Medicine, Groote Schuur Hospital and University of Cape Town Lung Institute, Cape Town, South Africa (R Dawson MD, G Symons MBChB); Global Alliance for TB Drug Development, New York, NY, USA (D Everitt MD, C M Mendel MD, M K Spigelman MD); Global Alliance for TB Drug Development, Pretoria, South Africa (C van Niekerk MD); School of Pharmacy, University of Otago, Dunedin, New Zealand (H Winter PhD); and Medical Research Council, Pretoria, South Africa (P Becker PhD) Correspondence to: Prof Andreas H Diacon, Division of Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, 7505 Tygerberg, South Africa ahd@sun.ac.za 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial Andreas H Diacon, Rodney Dawson, Florian von Groote-Bidlingmaier, Gregory Symons, Amour Venter, Peter R Donald, Christo van Niekerk, Daniel Everitt, Helen Winter, Piet Becker, Carl M Mendel, Melvin K Spigelman Summary Background New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the frst 14 days of treatment to assess their suitability for future development. Methods In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifoxacin- pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were ftted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staf were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. Findings The mean 14-day EBA of PA-824-moxifoxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was signifcantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifoxacin- pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecifed in the protocol. Interpretation PA-824-moxifoxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug- resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. Funding The Global Alliance for TB Drug Development (TB Alliance). Introduction Tuberculosis remains a major global health problem; although recently the global incidence has fallen slightly, the number of cases remains daunting and has over- whelmed the capabilities of many health systems, espe- cially in countries with a concomitant HIV epidemic. 1 Antituberculosis therapy relies on combinations of bactericidal and sterilising drugs that protect from development of resistance. 2 Crucial to containing and defeating the tuberculosis epidemic are new, shorter, and safe treatment regimens, which are afordable and practical for use in low-resource settings. Ideally, such regimens would contain new drugs able to combat tuberculosis resistant to currently available drugs, especially multidrug-resistant (MDR) tuberculosis re- sistant to at least isoniazid and rifampicin, and free of interactions with antiretroviral regimens. Since 2004 several new antituberculosis drugs have entered clinical assessment; among these drugs are bedaquiline, a diarylquinoline previously known as TMC207, and PA-824, a nitroimidazo-oxazine, which have completed initial dose-ranging monotherapy studies and have shown dose-related early bactericidal activity (EBA). 3–5 Murine studies have provided evidence of the signifcant sterilising activity of both compounds. 6,7 Bedaquiline has also been studied in the frst 6 months of MDR-TB treatment with promising early results. 8,9 In mouse experiments there is synergism between the frst- line agent pyrazinamide and bedaquiline and between pyrazinamide and PA-824. 10,11 Moxifoxacin and other fuoroquinolones have shown bactericidal activity ap- proaching that of isoniazid in EBA studies 12–14 and murine studies have shown a powerful sterilising efect for moxifoxacin alone 15–17 and when combined with PA-824 and pyrazinamide. 18 Although formal interaction studies have not been completed, preclinical data suggest a low likelihood of clinically signifcant interactions of PA-824, moxifoxacin, and pyrazinamide with antiretroviral drugs. EBA studies assess the fall in colony forming units (CFU) of Mycobacterium tuberculosis in sputum of patients with smear-microscopy-positive pulmonary tuberculosis in response to treatment. These studies are most often