title: A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis.
abstract: The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment.
  
  
  
  Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment.
  
  
  
  121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm).
  
  
  
  For intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin.
  
  
  
  www.ClinicalTrials.gov NCT00728507.
authors.affiliation: Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Marcus B
authors.initials: MB
authors.lastname: Conde
authors.affiliation: Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Fernanda C Q
authors.initials: FC
authors.lastname: Mello
authors.affiliation: Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Rafael Silva
authors.initials: RS
authors.lastname: Duarte
authors.affiliation: Municipal Health Secretariat, Rio de Janeiro, Brazil.|Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Solange C
authors.initials: SC
authors.lastname: Cavalcante
authors.affiliation: Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Valeria
authors.initials: V
authors.lastname: Rolla
authors.affiliation: Centro de Referência Hélio Fraga, Ministério da Saúde, Fiocruz Rio de Janeiro, Brazil.
authors.forename: Margareth
authors.initials: M
authors.lastname: Dalcolmo
authors.affiliation: Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Loredo
authors.affiliation: Municipal Health Secretariat, Rio de Janeiro, Brazil.
authors.forename: Betina
authors.initials: B
authors.lastname: Durovni
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Derek T
authors.initials: DT
authors.lastname: Armstrong
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Efron
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Grace L
authors.initials: GL
authors.lastname: Barnes
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.affiliation: University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Radojka M
authors.initials: RM
authors.lastname: Savic
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cohn
authors.affiliation: Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Moulton
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Chaisson
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Dorman
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016022:Case-Control Studies; D004359:Drug Therapy, Combination; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011718:Pyrazinamide / Q000008:administration & dosage / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D011718:Pyrazinamide; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine