A Novel One-month Ultra-Short Preventive Treatment for Halting Active Tuberculosis from Latent Infection Among Close Contacts (TB-YOUTH study): Study Protocol For A Cluster-Randomized Controlled Trial (Preprint)

<sec> <title>UNSTRUCTURED</title> Background Close contacts of individuals with active pulmonary tuberculosis (TB) face an elevated risk of TB acquisition, necessitating systematic screening for latent tuberculosis infection (LTBI) 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. The development of shorter, safer chemoprophylaxis strategies therefore 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. Method An investigator-initialed prospective, multicenter, open-label, non-inferiority, 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 types are actively screened with symptoms, interferon-gamma release assay (IGRA) test, chest imaging, and sputum molecular diagnostic testing to detect TB infection and exclude active TB. Eligible LTBI cases will be randomized at a 1:1 cluster ratio to receive either a standard 3HR regimen (3-month daily isoniazid plus rifampicin) or a novel 1H3P3 ultra-short regimen (one-month isoniazid plus rifapentine three times a week) for TPT with subsequent follow-up to two years for disease progression. The primary composite endpoint includes microbiologically confirmed TB (sputum culture or molecular diagnostic testing) or clinically diagnosed TB. With 80% power to detect non-inferiority (20% margin), the study requires 1,760 participants per arm, accounting for cluster design effects. Discussion Shortening treatment duration is a key to improve adherence to TPT, thus achieving optimal protective efficacy. This trial evaluates a promising ultra-short, well-tolerated TPT regimen with an active control. Cluster randomization was adopted to reduce interference in school-setting, potential limitations include implementation challenges by enlarged sample size, complicated cluster assignment and limited generalizability by school-based population. If successful, this ultra-short, well-tolerated regimen could optimize TPT delivery, particularly in congregate settings. Integrating with active screening, our findings may inform scalable TB control strategies, advancing progress toward global TB elimination goals. Trial Registration ClinicalTrials.gov NCT06022146. https://clinicaltrials.gov/study/NCT06022146 </sec>