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A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).

Publication ,  Journal Article
Phillips, PPJ; Dooley, KE; Gillespie, SH; Heinrich, N; Stout, JE; Nahid, P; Diacon, AH; Aarnoutse, RE; Kibiki, GS; Boeree, MJ; Hoelscher, M
Published in: BMC Med
March 23, 2016

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.

Duke Scholars

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Published In

BMC Med

DOI

EISSN

1741-7015

Publication Date

March 23, 2016

Volume

14

Start / End Page

51

Location

England

Related Subject Headings

  • Tuberculosis
  • Research Design
  • Humans
  • General & Internal Medicine
  • Female
  • Drug Discovery
  • Bayes Theorem
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 11 Medical and Health Sciences
 

Citation

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Phillips, P. P. J., Dooley, K. E., Gillespie, S. H., Heinrich, N., Stout, J. E., Nahid, P., … Hoelscher, M. (2016). A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP). BMC Med, 14, 51. https://doi.org/10.1186/s12916-016-0597-3
Phillips, Patrick P. J., Kelly E. Dooley, Stephen H. Gillespie, Norbert Heinrich, Jason E. Stout, Payam Nahid, Andreas H. Diacon, et al. “A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).BMC Med 14 (March 23, 2016): 51. https://doi.org/10.1186/s12916-016-0597-3.
Phillips PPJ, Dooley KE, Gillespie SH, Heinrich N, Stout JE, Nahid P, et al. A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP). BMC Med. 2016 Mar 23;14:51.
Phillips, Patrick P. J., et al. “A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).BMC Med, vol. 14, Mar. 2016, p. 51. Pubmed, doi:10.1186/s12916-016-0597-3.
Phillips PPJ, Dooley KE, Gillespie SH, Heinrich N, Stout JE, Nahid P, Diacon AH, Aarnoutse RE, Kibiki GS, Boeree MJ, Hoelscher M. A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP). BMC Med. 2016 Mar 23;14:51.
Journal cover image

Published In

BMC Med

DOI

EISSN

1741-7015

Publication Date

March 23, 2016

Volume

14

Start / End Page

51

Location

England

Related Subject Headings

  • Tuberculosis
  • Research Design
  • Humans
  • General & Internal Medicine
  • Female
  • Drug Discovery
  • Bayes Theorem
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 11 Medical and Health Sciences