Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis.
Author(s): Gillespie SH(1), Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, Pappas
F, Phillips PP, Nunn AJ; REMoxTB Consortium.
Collaborators: Diacon A, Hanekom M, Venter A, Dawson R, Narunsky K, Mtafya B,
Ntinginya N, Rachow A, Amukoye E, Miheso B, Njoroje M, Sam N, Damas D, Liyoyo A,
Mahayiddin A, Chuchottaworn C, Boonyasopun J, Saipan B, Lakhi S, Chanda D, Mcyeze
J, Pym A, Ngcobo N, Louw C, Veldsman H, Amaya-Tapia G, Aguirre T, Chauhan D, Garg
R, Jain NK, Aggarwal A, Mishra M, Teotia S, Charalambous S, Hattidge N,
Pretorious L, Padayachi N, Mohapi L, Gao M, Li X, Zhang L, Zhang Q, Aggarwal S,
Belizaire K, Benhayoun M, Everitt D, Ginsberg A, Laurenzi M, Rawls B, Ridali C,
Spigelman M, Uys A, van Niekerk C, Bateson A, Betteridge M, Birkby S, Bongard E,
Brown M, Ciesielczuk H, Cook C, Cunningham E, Huggett J, Hunt R, Ling C, Lipman
M, Mee P, Murphy M, Murthy S, Perrin F, Shorten R, Singh K, Smith K,
Yorke-Edwards V, Zumla A, Magee J, O'Brien R, Ormerod P, Fielding K, Mwinga A,
Peto T.
Affiliation(s): Author information:
(1)From the University of St. Andrews Medical School, St. Andrews (S.H.G.), and the
Medical Research Council Clinical Trials Unit at University College London
(A.M.C., S.K.M., P.P.J.P., A.J.N.) and the Division of Infection and Immunity,
University College London (T.D.M.), London - both in the United Kingdom; and the
TB Alliance, New York (C.M.M., S.R.M., F.P.).
Publication date & source: 2014, N Engl J Med. , 371(17):1577-87
BACKGROUND: Early-phase and preclinical studies suggest that
moxifloxacin-containing regimens could allow for effective 4-month treatment of
uncomplicated, smear-positive pulmonary tuberculosis.
METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3
trial to test the noninferiority of two moxifloxacin-containing regimens as
compared with a control regimen. One group of patients received isoniazid,
rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of
isoniazid and rifampin (control group). In the second group, we replaced
ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo
(isoniazid group), and in the third group, we replaced isoniazid with
moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The
primary end point was treatment failure or relapse within 18 months after
randomization.
RESULTS: Of the 1931 patients who underwent randomization, in the per-protocol
analysis, a favorable outcome was reported in fewer patients in the isoniazid
group (85%) and the ethambutol group (80%) than in the control group (92%), for a
difference favoring the control group of 6.1 percentage points (97.5% confidence
interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points
(97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in
the modified intention-to-treat analysis and all sensitivity analyses. The hazard
ratios for the time to culture negativity in both solid and liquid mediums for
the isoniazid and ethambutol groups, as compared with the control group, ranged
from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the
95% confidence intervals exceeding 1.00 in all cases. There was no significant
difference in the incidence of grade 3 or 4 adverse events, with events reported
in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group,
and 123 (19%) in the control group.
CONCLUSIONS: The two moxifloxacin-containing regimens produced a more rapid
initial decline in bacterial load, as compared with the control group. However,
noninferiority for these regimens was not shown, which indicates that shortening
treatment to 4 months was not effective in this setting. (Funded by the Global
Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number,
NCT00864383.).
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