Statistical considerations for pediatric multidrug-resistant tuberculosis efficacy trials

Abstract

Summary Inclusion of newly licensed or repurposed drugs in regimens to treat children for multidrug–resistant–tuberculosis may lead to therapy that is shorter than traditional regimens and composed only of oral medications. As an all–oral regimen may be more acceptable and have a better safety profile than current regimens, demonstrating non–inferiority may be satisfactory. Demonstrating non–inferior efficacy requires setting a non–inferiority margin and safeguarding study assay sensitivity. Multi–arm multi–stage designs may currently not be appropriate in pediatric trials because of the lack of sensitive and specific intermediate outcomes. However, including an arm with an agent to ameliorate toxicity would be efficient. Covariates can be used to stratify randomization, define subgroups, and improve efficiency of analysis. Enriching the sample for the confirmed–TB subgroup to ensure that they are well represented may be important. Primary outcomes using a fixed time point from randomization for all study arms will result in variation in post–treatment duration but may be the best choice. While blinding of site personnel and patients may not be possible when regimens differ substantially in drugs and modes of administration, blinding should be maintained for independent endpoint review groups and other personnel. Type I error and family–wise error rates should be tightly controlled.

A framework for considering the risk‐benefit trade‐off in designing noninferiority trials using composite outcome approaches

“…Thus, Seddon et al 32 TA B L E 6 MADE using the weighted component outcome for noninferiority. Kim et al 33 also discussed the value of using a noninferiority efficacy trial to "identify regimens that are expected to be better or not unacceptably worse than the control and, because of the potential improvements in risk-benefit profile, may be useful in evaluating a shortened, all-oral MDR-TB regimen in children." However, the choice of the noninferiority margin continues to be a major design issue, not only in pediatric trials but in adult trials as well.…”

“…However, the choice of the noninferiority margin continues to be a major design issue, not only in pediatric trials but in adult trials as well. 33 Several of the current adult MDR-TB noninferiority trials have used 10% as the margin (eg, the STREAM trial 11 ); however, there is lack of formal justification on the appropriateness of this quantity for these trials.…”

“…In this numerical study, we evaluate the operating characteristics informed by a hypothetical pediatric MDR‐TB trial of a novel all‐oral shortened treatment regimen, described in Kim et al, 33 using the DOOR approach. We compare them to those of a noninferiority design with NIM that is based on the value of MADE derived from the same parametric assumptions used in the DOOR approach.…”

“…Thus, Seddon et al 32 made the case for the need for pediatric MDR‐TB treatment efficacy trials designed for noninferiority. Kim et al 33 also discussed the value of using a noninferiority efficacy trial to “identify regimens that are expected to be better or not unacceptably worse than the control and, because of the potential improvements in risk‐benefit profile, may be useful in evaluating a shortened, all‐oral MDR‐TB regimen in children.” However, the choice of the noninferiority margin continues to be a major design issue, not only in pediatric trials but in adult trials as well 33 . Several of the current adult MDR‐TB noninferiority trials have used 10% as the margin (eg, the STREAM trial 11 ); however, there is lack of formal justification on the appropriateness of this quantity for these trials.…”