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

Abstract

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 weeks of delamanid versus isoniazid for preventing confirmed or probable TB during 96 weeks of follow-up among HHCs of adults with pulmonary MDR-TB. HHCs are defined as young children <5 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 % power to detect a 50 % reduction in the cumulative proportion of HHCs developing confirmed or probable TB during 96 weeks of follow-up from 5 % in the isoniazid arm to 2.5 % 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.

Keywords: Cluster-randomized trial; Delamanid; Household contacts; Multidrug-resistant tuberculosis; Tuberculosis preventive treatment.