title: Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis.
abstract: 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.).
authors.affiliation: 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.).
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gillespie
authors.forename: Angela M
authors.initials: AM
authors.lastname: Crook
authors.forename: Timothy D
authors.initials: TD
authors.lastname: McHugh
authors.forename: Carl M
authors.initials: CM
authors.lastname: Mendel
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Meredith
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Murray
authors.forename: Frances
authors.initials: F
authors.lastname: Pappas
authors.forename: Patrick P J
authors.initials: PP
authors.lastname: Phillips
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nunn
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000627:therapeutic use; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects / Q000627:therapeutic use*; D006679:HIV Seropositivity / Q000150:complications; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification*; D011718:Pyrazinamide / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D011718:Pyrazinamide; D004977:Ethambutol; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin