Protecting households on exposure to newly diagnosed index multidrug-resistant tuberculosis patients: Study protocol for the PHOENIx phase 3 clinical trial.

INTRODUCTION: Data to guide tuberculosis (TB) preventive treatment (TPT) of close contacts of people with multidrug-resistant tuberculosis (MDR-TB) are limited. While levofloxacin-based TPT has been shown safe and efficacious, alternatives are needed for those exposed to fluoroquinolone-resistant Mycobacterium tuberculosis (M. tb). The PHOENIx trial evaluates whether using a novel nitroimidazole, delamanid, in high-risk household contacts (HHCs) of patients with MDR-TB reduces their risk of developing active TB.

METHODS/DESIGN: PHOENIx is a phase 3, open-label, multicenter clinical trial with a cluster-randomized superiority design (households form the clusters). The study objectives are to compare efficacy and safety of 26&#xa0;weeks of delamanid versus isoniazid for preventing confirmed or probable TB during 96&#xa0;weeks of follow-up among HHCs of adults with pulmonary MDR-TB. HHCs are defined as young children <5&#xa0;years, people living with HIV or non-HIV immunosuppression, or people with evidence of M. tb infection. The study was originally designed to enroll 3452 HHCs to provide 90&#xa0;% power to detect a 50&#xa0;% reduction in the cumulative proportion of HHCs developing confirmed or probable TB during 96&#xa0;weeks of follow-up from 5&#xa0;% in the isoniazid arm to 2.5&#xa0;% in the delamanid arm. The design included a sample size re-evaluation to address uncertainty in study design assumptions.

DISCUSSION: Preventing MDR-TB is a global priority. Alternatives to levofloxacin-based TPT are needed since fluoroquinolone resistance is growing. PHOENIx, a phase 3 trial evaluating delamanid, is poised to inform WHO guidelines.