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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).

dc.contributor.author Aarnoutse, RE
dc.contributor.author Boeree, MJ
dc.contributor.author Diacon, AH
dc.contributor.author Dooley, KE
dc.contributor.author Gillespie, SH
dc.contributor.author Heinrich, N
dc.contributor.author Hoelscher, M
dc.contributor.author Kibiki, Gibson S
dc.contributor.author Nahid, P
dc.contributor.author Phillips, PPJ
dc.contributor.author Stout, Jason Eric
dc.coverage.spatial England
dc.date.accessioned 2017-04-01T13:16:35Z
dc.date.available 2017-04-01T13:16:35Z
dc.date.issued 2016-03-23
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/27004726
dc.identifier 10.1186/s12916-016-0597-3
dc.identifier.uri https://hdl.handle.net/10161/13890
dc.description.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.
dc.language eng
dc.relation.ispartof BMC Med
dc.relation.isversionof 10.1186/s12916-016-0597-3
dc.subject Clinical trials
dc.subject Drug development
dc.subject Middle development
dc.subject Phase IIC
dc.subject Regimen development
dc.subject STEP
dc.subject Tuberculosis
dc.subject Bayes Theorem
dc.subject Drug Discovery
dc.subject Female
dc.subject Humans
dc.subject Research Design
dc.subject Tuberculosis
dc.title A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/27004726
pubs.begin-page 51
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Infectious Diseases
pubs.organisational-group School of Medicine
pubs.publication-status Published online
pubs.volume 14
dc.identifier.eissn 1741-7015


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