A Novel Therapy With a One-Month Ultrashort Regimen to Halt Progression From Latent Infection to Active Tuberculosis Among Close Contacts (The TB‑YOUTH Study): Protocol for a Cluster Randomized Controlled Trial

Abstract

Abstract Background Close contacts of individuals with active pulmonary tuberculosis (TB) face an elevated risk of TB acquisition, necessitating systematic screening for latent TB infection and subsequent TB preventive treatment (TPT). Major TPT regimens require ≥3 months of drug exposure and demonstrate suboptimal safety profiles, significantly compromising treatment completion rates. Therefore, the development of shorter, safer chemoprophylaxis strategies represents a critical need in global TB control. Among close contacts, school-aged children and adolescents constitute the most vulnerable demographic subgroup, warranting prioritized intervention efforts. Objective The primary objective of this study is to demonstrate noninferiority of an ultrashort, 1-month TPT regimen of isoniazid plus rifapentine, administered 3 times a week (1HP) compared with the standard 3-month daily isoniazid plus rifampicin (3HR) regimen in preventing active TB, as measured by the 24-month cumulative incidence of active TB following randomization. Methods An investigator-initiated, prospective, multicenter, open-label, noninferiority, cluster-randomized controlled clinical trial is being implemented under the auspices of the national TB control program in China. Close contacts of school pulmonary TB index cases, regardless of diagnostic type, are actively screened for symptoms using interferon-gamma release assays, chest imaging, and sputum molecular diagnostic testing to detect TB infection and exclude active TB. Eligible latent TB infection cases will be randomized in a 1:1 cluster ratio to receive either the standard 3HR regimen or the novel ultrashort 1HPregimen for TPT, with subsequent follow-up for up to 2 years to assess disease progression. The primary composite end point includes microbiologically confirmed TB (sputum culture or molecular diagnostic testing) or clinically diagnosed TB. With 80% power to detect noninferiority (20% margin), the study requires 1760 participants per arm, accounting for cluster design effects. Results Recruitment started in September 2023. By the end of December 2025, a total of 2478 participants, comprising 627 index cases, had been enrolled, and recruitment is estimated to continue until September 2026. Data analysis will commence after the 2-year follow-up period, and the results are expected to be published by March 2029. Conclusions This cluster randomized controlled trial aims to establish the noninferiority of a novel, ultrashort 1HPregimen compared to the standard 3-month 3HR regimen for preventing active TB in infected school contacts. If successful, this well-tolerated 1-month regimen could significantly improve treatment completion and optimize preventive therapy delivery in high-transmission congregate settings, thereby contributing substantively to global TB control efforts.