MOAB0202 - Oral Abstract
Randomized trial of the bactericidal activity of 8-weeks treatment with moxifloxacin, Pa-824, and pyrazinamide in drug sensitive and multi-drug resistant tuberculosis
Presented by Daniel Everitt (United States).
D. Everitt1, R. Dawson2, A. Diacon3, D. Burger4, R. Schall5, C. Van Niekerk6, A. Conradie6, C. Mendel1
1Global Alliance for TB Drug Development, R&D, New York, United States, 2University of Cape Town, Division of Pulmonology, Department of Medicine, Cape Town, South Africa, 3Stellenbosch University and Task Applied Sciences, Department of Medical Biochemistry, Cape Town, South Africa, 4University of Free State, and Quintiles, Bloemfontein, South Africa, 5University of Free State, Department of Biostatistics, Bloemfontein, South Africa, 6Global Alliance for TB Drug Development, R&D, Pretoria, South Africa
Background: New regimens that are shorter, less costly, better tolerated, oral and compatible with anti-retroviral therapy are urgently needed to treat TB, especially multi-drug resistant (MDR) TB. Moxifloxacin (M), with the nitroimidazole Pa-824 (PA), and pyrazinamide (Z) had excellent bactericidal activity in patients with DS-TB over 14 days in a previous study.
Methods: This was an 8 center open‐label clinical trial. We randomized smear positive patients with DS-TB in equal proportions to daily M 400 mg plus PA 100 mg plus Z 1500 mg (M-PA100-Z), to M 400 mg plus PA 200 mg plus Z 1500 mg (M-PA200-Z) or to weight-adjusted isoniazid (H), rifampicin (R), Z, and ethambutol (E) for 8 weeks of treatment. Patients with MDR‐TB received M-PA200-Z. The primary endpoint was the rate of change in colony forming units (CFU) from sputum on solid culture over 8 weeks. Five secondary endpoints included the change in the time to sputum positivity in liquid culture and median time to conversion to negative growth and % negative growth in solid and liquid culture at 8 weeks.
Results: We included 181 DS-TB and 26 MDR-TB subjects in the study. Nine MDR-TB subjects were included in the statistical analysis of the 8 week data, as many others were late exclusions for Z resistance; median age was 28 years, 35% were female, and 19.5% were HIV-infected. All 3 experimental treatment arms had greater average reductions in CFU counts than HRZE over 8 weeks, which was statistically significant for the M-PA200-Z arm (p< 0.05): Log CFU daily decreases of M-PA200-Z = 0.155 CI [0.133; 0.178], M-PA100-Z = 0.133 CI [0.109; 0.155], M-PA200-Z MDR = 0.117 CI [0.070; 0.174], and H-R-Z-E = 0.112 CI [0.093; 0.131]. M-PA200-Z was statistically significantly better than HRZE in 3 of 5 secondary outcome measures. The rate of decline in CFU over days 7-14 correlated highly with that over days 7-56, with correlation coefficients ranging from 0.90-0.98.
Conclusions: The M-Pa-Z regimen has active bactericidal activity against both DS-TB and MDR-TB that extends from 2 weeks through 2 months and is significantly greater than that of HRZE therapy in patients with DS TB.
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