High-dose rifapentine with moxifloxacin for pulmonary tuberculosis

N Engl J Med. 2014 Oct 23;371(17):1599-608. doi: 10.1056/NEJMoa1314210.

Abstract

Background: Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed.

Methods: We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.

Results: We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).

Conclusions: The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / therapeutic use*
  • Coinfection
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Ethambutol / therapeutic use
  • Female
  • Fluoroquinolones / administration & dosage*
  • Fluoroquinolones / adverse effects
  • HIV Seropositivity / complications
  • Humans
  • Isoniazid / therapeutic use
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Moxifloxacin
  • Mycobacterium tuberculosis / isolation & purification
  • Pyrazinamide / therapeutic use
  • Rifampin / administration & dosage
  • Rifampin / adverse effects
  • Rifampin / analogs & derivatives*
  • Rifampin / therapeutic use
  • Tuberculosis, Pulmonary / complications
  • Tuberculosis, Pulmonary / drug therapy*
  • Young Adult

Substances

  • Antitubercular Agents
  • Fluoroquinolones
  • Pyrazinamide
  • Ethambutol
  • Moxifloxacin
  • Isoniazid
  • Rifampin
  • rifapentine

Associated data

  • ISRCTN/ISRCTN44153044