Re-evaluating the Duration in Children of TB Treatment (REDUCE TB): A Phase 2 Duration Randomized Trial

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) remains a major global public health problem in children. In 2022 there were approximately 1.3 million new cases of TB in children <15 years of age, resulting in 214,000 deaths. TB treatment outcomes for pulmonary TB in children are good, but the current 4-6 month treatment durations are long, burdensome and costly. Shortened TB treatment regimens would be highly beneficial to children with TB, their caregivers, and TB programs, and are appropriate to evaluate given the very low burden of organisms (paucibacillary) in children compared to adults. Emerging data support that durations shorter than currently recommended are possible for children. A highly attractive candidate regimen for shorter treatment would use optimized doses of rifampicin (odRIF), a uniquely important and widely available existing TB drug. This approach has shown promising results in adult trials, and we completed a pediatric trial demonstrating the pharmacokinetics (PK) and safety of odRIF over 2 weeks. Definitive TB treatment shortening trials are large and costly, and are a high risk to funders and participants, especially due to challenges in selecting optimal treatment durations, particularly for children. The phase IIc duration randomization trial design models the duration-response curve of an intervention and addresses many of these challenges. This design is more efficient, less expensive, and de-risks future phase III trials. This innovative trial design is being used in adults with TB, but to date has not been applied to children with TB. Evaluating novel shorter TB treatment regimens requires a holistic approach that includes patient- centered outcomes in addition to assessment of efficacy, safety and tolerability. Previous pediatric trials have not included assessments of lung health and quality of life, resulting in limited data on these important outcomes and no data comparing these outcomes to children receiving different TB treatment regimens or durations. Data on these important patient-centered outcomes and on child and caregiver priorities and preferences for shortened TB treatment are critical yet neglected to date in trials. We will undertake REDUCE-TB, an innovative multi-center multi-arm open-label phase IIc trial using a duration randomization design with a treatment regimen of optimized dose RIF (od-RIF) with standard doses of isoniazid, pyrazinamide and ethambutol, in children 3 months to <10 years of age with drug- susceptible TB. Prior to the main trial, a Lead-in study will confirm the PK, safety, and tolerability of odRIF. Key patient-centered outcomes will be evaluated. This study will de-risk future definitive phase III treatment shortening trials in children by identifying the optimal duration of shortened treatment, leading directly to better, shorter TB treatment for children. This trial will also develop the methodological framework for use of duration randomized treatment trials in children with TB more broadly and advance more holistic trial approaches that include and rigorously evaluate key patient-centered outcomes.