title: A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).
abstract: BACKGROUND
  The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world's greatest infectious disease killer.
  
  
  METHODS
  We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice.
  
  
  RESULTS
  With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation.
  
  
  CONCLUSIONS
  Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.
authors.affiliation: MRC Clinical Trials Unit at University College London, Aviation House, 125 Kingsway, London, WC2B 6NH, UK. patrick.phillips@ucl.ac.uk.
authors.forename: Patrick P J
authors.identifier: http://orcid.org/0000-0002-6336-7024
authors.initials: PP
authors.lastname: Phillips
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.affiliation: School of Medicine, University of St. Andrews, St. Andrews, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gillespie
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Center of the Ludwig-Maximilians-University (LMU), Munich, Germany.|German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Heinrich
authors.affiliation: School of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Stout
authors.affiliation: University of California San Francisco, San Francisco, California, USA.
authors.forename: Payam
authors.initials: P
authors.lastname: Nahid
authors.affiliation: Division of Physiology, Department of Medical Biochemistry, Stellenbosch University, Tygerberg, South Africa.|TASK Applied Science, Bellville, South Africa.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.affiliation: East African Health Research Commission (EAHRC), East African Community, Arusha, Tanzania.
authors.forename: Gibson S
authors.initials: GS
authors.lastname: Kibiki
authors.affiliation: Department of Lung Diseases, Radboud University Medical Center, UCCZ Dekkerswald, Nijmegen, The Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Boeree
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Center of the Ludwig-Maximilians-University (LMU), Munich, Germany.|German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
mesh_terms: D001499:Bayes Theorem; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006801:Humans; D012107:Research Design; D014376:Tuberculosis / Q000188:drug therapy*
keywords: Clinical trials; Drug development; Middle development; Phase IIC; Regimen development; STEP; Tuberculosis