14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and
moxifloxacin combinations: a randomised trial.
Author(s): Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR,
van Niekerk C, Everitt D, Winter H, Becker P, Mendel CM, Spigelman MK.
Affiliation(s): Division of Physiology, Department of Medical Biochemistry, Faculty of Medicine
and Health Sciences, Stellenbosch University, Cape Town, South Africa.
ahd@sun.ac.za
Publication date & source: 2012, Lancet. , 380(9846):986-93
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withdrawn because of corrected QT interval changes exceeding criteria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).
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