Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial

PLoS One. 2018 Jul 19;13(7):e0200539. doi: 10.1371/journal.pone.0200539. eCollection 2018.

Abstract

The emergence of multidrug resistant-tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis strains with in vitro resistance to at least isoniazid and rifampicin, has necessitated evaluation and validation of appropriate surrogate endpoints for treatment response in drug trials for MDR-TB. The trial that has demonstrated efficacy of bedaquiline, a diarylquinoline that inhibits mycobacterial ATP synthase, possesses the requisite features to conduct this evaluation. Approval of bedaquiline for use in MDR-TB was based primarily on the results of the controlled C208 Stage II study (ClinicalTrials.gov number, NCT00449644) including 160 patients randomized 1:1 to receive bedaquiline or placebo for 24 weeks when added to an 18-24-month preferred five-drug background regimen. Since randomization in C208 Stage II was preserved until study end, the trial results allow for the investigation of the complex relationship between sustained durable outcome with either Week 8 or Week 24 culture conversion as putative surrogate endpoints. The relationship between Week 120 outcome with Week 8 or Week 24 culture conversion was investigated using a descriptive analysis and with a recently developed statistical methodology for surrogate endpoint evaluation using methods of causal inference. The results demonstrate that sputum culture conversion at 24 weeks is more reliable than sputum culture conversion at 8 weeks when assessing the outcome of adding one new drug to a MDR-TB regimen.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antitubercular Agents / therapeutic use*
  • Bacteriological Techniques / methods
  • Biomarkers / analysis*
  • Diarylquinolines / therapeutic use
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / physiology
  • Outcome Assessment, Health Care
  • Sputum / microbiology*
  • Time Factors
  • Tuberculosis, Multidrug-Resistant / diagnosis
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / microbiology
  • Young Adult

Substances

  • Antitubercular Agents
  • Biomarkers
  • Diarylquinolines
  • bedaquiline

Associated data

  • ClinicalTrials.gov/NCT00449644

Grants and funding

Janssen funded the C208 Stage II trial and was involved in its design and conduct and in the collection and analysis of the data. All the authors who worked for Janssen at the time of the analysis and manuscript preparation (Paul Meyvisch, Chrispin Kambili, Koen Andries, Myriam Theeuwes, Brian Dannemann, An Vandebosch, Wim Van der Elst) played a role in the decision to publish and preparation of the manuscript.