title: A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project.
abstract: BACKGROUND
  There have been no major advances in tuberculosis (TB) drug development since the first East African/British Medical Research Council short course chemotherapy trial 35 years ago. Since then, the landscape for conducting TB clinical trials has profoundly changed with the emergence of HIV infection, the spread of resistant TB bacilli strains, recent advances in mycobacteriological capacity, and drug discovery. As a consequence questions have arisen on the most appropriate approach to design and conduct current TB trials. To highlight key issues discussed: Is a superiority, equivalence, or non-inferiority design most appropriate? What should be the primary efficacy outcome? How to consider re-infections in the definition of the outcome? What is the optimal length of patient follow-up? Is blinding appropriate when treatment duration in test arm is shorter? What are the appropriate assumptions for sample size calculation?
  
  
  METHODS
  Various drugs are currently in the development pipeline. We are presenting in this paper the design of the most recently completed phase III TB trial, the OFLOTUB project, which is the pivotal trial of a registration portfolio for a gatifloxacin-containing TB regimen. It is a randomized, open-label, multicenter, controlled trial aiming to evaluate the efficacy and safety of a gatifloxacin-containing 4-month regimen (trial registration: ClinicalTrial.gov database: NCT00216385).
  
  
  RESULTS
  In the light of the recent scientific and regulatory discussions, we discuss some of the design issues in TB clinical trials and more specifically the reasons that guided our choices, in order to best answer the trial objectives, while at the same time satisfying regulatory authority requirements.
  
  
  CONCLUSIONS
  When shortening TB treatment, we are advocating for a non-inferiority, non-blinded design, with a composite unfavorable endpoint assessed 12 months post treatment completion, and added trial procedures specifically aiming to: (1) minimize endpoint unavailability; and (2) distinguish between relapse and re-infection.
authors.affiliation: Faculty of Epidemiology and Population Health, Tropical Epidemiological Group, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. corinne.merle@lshtm.ac.uk
authors.forename: Corinne S C
authors.initials: CS
authors.lastname: Merle
authors.forename: Charalambos
authors.initials: C
authors.lastname: Sismanidis
authors.forename: Oumou Bah
authors.initials: OB
authors.lastname: Sow
authors.forename: Martin
authors.initials: M
authors.lastname: Gninafon
authors.forename: John
authors.initials: J
authors.lastname: Horton
authors.forename: Olivier
authors.initials: O
authors.lastname: Lapujade
authors.forename: Mame Bocar
authors.initials: MB
authors.lastname: Lo
authors.forename: Denis A
authors.initials: DA
authors.lastname: Mitchinson
authors.forename: Christian
authors.initials: C
authors.lastname: Perronne
authors.forename: Francoise
authors.initials: F
authors.lastname: Portaels
authors.forename: Joseph
authors.initials: J
authors.lastname: Odhiambo
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
authors.forename: Roxana
authors.initials: R
authors.lastname: Rustomjee
authors.forename: Christian
authors.initials: C
authors.lastname: Lienhardt
authors.forename: Katherine
authors.initials: K
authors.lastname: Fielding
mesh_terms: D000349:Africa; D000995:Antitubercular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D023801:Directly Observed Therapy; D004359:Drug Therapy, Combination; D024841:Fluoroquinolones / Q000009:adverse effects / Q000627:therapeutic use*; D000077734:Gatifloxacin; D006801:Humans; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D000077734:Gatifloxacin