A new trial design to accelerate tuberculosis drug development : the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP)
Date
2016-03-23
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
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.
Description
CITATION: Phillips, P. P. J., et al. 2016. A new trial design to accelerate tuberculosis drug development : the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP). BMC Medicine. 14:51, doi:10.1186/s12916-016-0597-3.
The original publication is available at https://bmcmedicine.biomedcentral.com
The original publication is available at https://bmcmedicine.biomedcentral.com
Keywords
Tuberculosis -- Treatment, Drugs -- Testing, Drug resistance in microorganisms
Citation
Phillips, P. P. J., et al. 2016. A new trial design to accelerate tuberculosis drug development : the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP). BMC Medicine. 14:51, doi:10.1186/s12916-016-0597-3