14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial

Lancet. 2012 Sep 15;380(9846):986-93. doi: 10.1016/S0140-6736(12)61080-0. Epub 2012 Jul 23.

Abstract

Background: New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development.

Methods: In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851.

Findings: The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.

Interpretation: PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens.

Funding: The Global Alliance for TB Drug Development (TB Alliance).

Publication types

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

MeSH terms

  • Adult
  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / therapeutic use*
  • Aza Compounds / adverse effects
  • Aza Compounds / therapeutic use
  • Colony Count, Microbial
  • Diarylquinolines
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Fluoroquinolones
  • Humans
  • Male
  • Microbial Viability / drug effects
  • Moxifloxacin
  • Mycobacterium tuberculosis / growth & development
  • Nitroimidazoles / adverse effects
  • Nitroimidazoles / therapeutic use
  • Prospective Studies
  • Pyrazinamide / adverse effects
  • Pyrazinamide / therapeutic use
  • Quinolines / adverse effects
  • Quinolines / therapeutic use
  • Sputum / microbiology
  • Tuberculosis, Pulmonary / drug therapy*
  • Tuberculosis, Pulmonary / microbiology
  • Young Adult

Substances

  • Antitubercular Agents
  • Aza Compounds
  • Diarylquinolines
  • Fluoroquinolones
  • Nitroimidazoles
  • Quinolines
  • pretomanid
  • Pyrazinamide
  • bedaquiline
  • Moxifloxacin

Associated data

  • ClinicalTrials.gov/NCT01215851