DRAMATIC Phase 2 Duration Randomized MDR-TB Treatment Trial
openNIAID - National Institute of Allergy and Infectious Diseases
Multidrug-resistant tuberculosis (MDR-TB) was estimated to occur 600,000 people in 2017. The roll-out of
the GeneXpert™ test has generating a substantial increase in the demand for MDR-TB treatment.
However, current MDR-TB treatment regimens take 9 months or longer to complete and have substantial
toxicity. Therefore, a shorter, less toxic treatment regimen is needed. We have designed a regimen that
does not contain PZA or an injectable agent and limits the administration of linezolid to the initial 8 weeks of
treatment, before the neuropathic side effects of linezolid occur. Animal studies support the likely efficacy of
this regimen.
Studies of fixed duration regimens to achieve treatment shortening are associated with high risk, since
there are no validated ways to predict what duration of treatment will be optimal. We have developed an
innovative Phase 2 study design (“duration-randomization”) to identify the shortest effective treatment
duration. In this design, participants are randomized to four durations of treatment from the shortest to the
longest likely effective duration. The results are then analyzed together to determine the optimal treatment
duration.
In the proposed multicenter, randomized, partially blinded, four-arm, phase 2 DRAMATIC Trial
(Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical Trial) we will examine the efficacy
and safety of an all-oral regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine given
for 16, 24, 32 or 40 weeks. By modeling the results of the four durations together, the design achieves
substantial statistical efficiency. The optimal treatment duration identified in this trial can then be validated
in a larger prospective Phase 3 clinical trial. In addition, recent studies have demonstrated that baseline
patient characteristics can predict TB treatment outcomes; we will therefore stratify participants into those
with “extensive” and those with “non-extensive” disease to provide guidance for clinical treatment.
Aim 1: To identify the optimal duration of an experimental MDR-TB treatment regimen consistent
with a successful treatment outcome.
Aim 2: To describe the relationship between baseline prognostic risk strata and successful MDR-TB
treatment outcome.
Aim 3: To establish that the rRNA synthesis ratio, a novel biologic marker based on M. tb precursor
rRNA, is associated with relapse at the individual-level across the range of durations studied in the trial.
Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability of TB
control programs to treat the growing number of patients. The DRAMATIC Trial will employ an innovative
and efficient new design to establish a robust, nontoxic MDR-TB treatment regimen and identify the
minimal duration for which it needs to be administered. These results will speed the process of moving
forward to a confirmatory phase 3 clinical trial and increase the likelihood that such a trial is successful.
RELEVANCE (See instructions):
In the proposed multicenter, randomized, partially blinded, four-arm, phase 2 DRAMATIC Trial we will
examine the efficacy and safety of an all-oral regimen of bedaquiline, delamanid, levofloxacin, linezolid,
and clofazimine given for 16, 24, 32 or 40 weeks. By modeling the results of the four durations together, the
design achieves substantial statistical efficiency. The goals of the study are to demonstrate the safety of
the regimen, to identify the shortest effective treatment duration, and to examine whether baseline
participant characteristics can be used to tailor treatment duration.
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Program Director/Principal Investigator (Last, First, Middle): Nahid, Payam
Up to $482K
health research