Giuseppe
Emeritus
[Source: The Lancet Infect Dis., full text: (LINK). Abstract, edited.]
The Lancet, Early Online Publication, 23 July 2012
doi:10.1016/S0140-6736(12)61080-0
14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial
Original Text
Prof Andreas H Diacon MD, Rodney Dawson MD, Florian von Groote-Bidlingmaier MD, Gregory Symons MBChB, Amour Venter NatDipTech, Prof Peter R Donald MD, Christo van Niekerk MD, Daniel Everitt MD, Helen Winter PhD, Piet Becker PhD, Carl M Mendel MD, Melvin K Spigelman MD
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 first 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-moxifloxacin-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 fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851.
Findings
The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0?233 [SD 0?128]) was significantly 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 One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.
Interpretation
PA-824-moxifloxacin-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).
- ------doi:10.1016/S0140-6736(12)61080-0
14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial
Original Text
Prof Andreas H Diacon MD, Rodney Dawson MD, Florian von Groote-Bidlingmaier MD, Gregory Symons MBChB, Amour Venter NatDipTech, Prof Peter R Donald MD, Christo van Niekerk MD, Daniel Everitt MD, Helen Winter PhD, Piet Becker PhD, Carl M Mendel MD, Melvin K Spigelman MD
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 first 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-moxifloxacin-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 fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851.
Findings
The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0?233 [SD 0?128]) was significantly 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-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.
Interpretation
PA-824-moxifloxacin-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).