Window Prophylaxis for Pediatric Tuberculosis Prevention Trial

Official title

Window Prophylaxis for Mycobacterium Tuberculosis Infection Prevention in Child and Adolescent Household Contacts: a Cluster-Randomized Controlled Trial

Overview

The goal of this cluster-randomized controlled trial is to evaluate the effectiveness of tuberculosis preventive treatment (TPT) administered during the "window period" to prevent new Mycobacterium tuberculosis infections in children and adolescents. The main question it aims to answer is: Can immediate TPT reduce the incidence of IGRA conversions in children and adolescents who are household contacts of a newly diagnosed pulmonary tuberculosis patient? Researchers will compare the incidence of new tuberculosis infections-measured by IGRA conversion at 12 weeks-between participants who receive immediate TPT while still uninfected (baseline IGRA-negative) and those who receive standard care, in which TPT is not offered to IGRA-negative contacts. Participants will be: 1. Tested for M. tuberculosis infection using the Interferon-Gamma Release Assay (IGRA), specifically the QuantiFERON-TB Gold Plus, at enrollment and after 12 weeks of follow-up. 2. Take weekly isoniazid and rifapentine for 12 weeks if: 1. They are assigned to the intervention arm (regardless of baseline IGRA result), or 2. They are in the control arm and test IGRA-positive at baseline. Additionally, participants from the control arm who experience an IGRA conversion at 12 weeks (following the primary outcome assessment) will also receive TPT, as per standard of care.

Detailed description

Mycobacterium tuberculosis acquisition following exposure is a common occurrence, but it remains challenging to diagnose, often requiring serial testing, as immunological responses (e.g., tuberculin skin test or interferon-gamma release assays) can take weeks to provide evidence of infection. Although tuberculosis infection is generally asymptomatic, research has shown that active mycobacterial replication and inflammation occur, and its long-term effects are not well understood due to the complexity of host-pathogen interactions and delayed disease progression. While antituberculosis prophylaxis has traditionally aimed at preventing the progression from established tuberculosis infection to active tuberculosis disease, recent studies suggest that prophylaxis administered during the "window period" after exposure may also prevent its acquisition, particularly in very young children.

This trial will help determine the effectiveness of tuberculosis prophylaxis administered during the window period in preventing the acquisition of tuberculosis infection in children and adolescents exposed in household settings. If successful, the findings may inform broader strategies for tuberculosis prevention, particularly in reducing reservoirs of Mycobacterium tuberculosis and contributing to the global tuberculosis elimination efforts.

Interventions

• Drug Tuberculosis window prophylaxis with weekly rifapentine and isoniazid for 12 weeks
  Weekly isoniazid and rifapentine for 12 weeks (3HP regimen) will be provided to all participants.
• Drug Standard of care tuberculosis prophylaxis with weekly rifapentine and isoniazid for 12 weeks
  Weekly isoniazid and rifapentine for 12 weeks (3HP regimen) will be provided only to participants with a positive IGRA result at baseline.

Primary outcome measures

• Incidence of new tuberculosis infections (all IGRA conversions) from enrollment until the end of follow-up in both study arms [Time frame: At the end of follow-up at 12 weeks (accepted range: ≥ 12 - ≤16 weeks)]

Secondary outcome measures (5)

• Incidence of new tuberculosis infections (IGRA conversions) with high IGRA thresholds (IFN-γ ≥1.0 IU/mL) at the end of follow-up in both study arms [Time frame: At the end of follow-up at 12 weeks (accepted range ≥12 - ≤16 weeks)]
• Incidence of active tuberculosis development until the end of follow-up in both study arms [Time frame: From 4 weeks after enrollment to the end of follow-up at 12 weeks (accepted range ≥ 4 - ≤16 weeks)]
• Prevalence of tuberculosis infections (all IGRA positive) at the end of follow-up in both study arms [Time frame: At the end of follow-up at 12 weeks (accepted range ≥ 12 - ≤16 weeks)]
• Incidence of 3HP-related adverse events at 12 weeks in both study arms [Time frame: From TPT initiation to completion or last dose received, in both study arms (accepted range ≥ 1 day - ≤16 weeks)]
• To evaluate temporal changes in IFN-γ levels between baseline and follow-up among individuals receiving or not receiving tuberculosis preventive treatment [Time frame: At the end of follow-up at 12 weeks (accepted range: ≥ 12 - ≤16 weeks)]

Eligibility criteria

Inclusion criteria

• Household contacts of patient (index case) with a new diagnosis of microbiologically confirmed pulmonary tuberculosis
• Age ≥5 to <18 years old

Exclusion criteria

• Suspected active tuberculosis in initial assessment (clinical or radiological)
• Current pregnancy or breastfeeding
• Immunocompromised
• Allergy or contraindication to isoniazid or rifapentine
• Chronic liver disease or alcohol use disorder
• History of previous treatment for active or latent tuberculosis infection
• Previous tuberculin skin test
• Household contacts of a tuberculosis index patient with a known or suspected drug-resistant M. tuberculosis strain
• Household contacts or a tuberculosis index patient currently living away from home for more than four weeks
• Household contacts of a tuberculosis index patient who have already received more than 15 daily doses of antituberculous treatment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

Chile · 13 centers

• Hospital Dr. Carlos Cisterna — Calama
• Hospital de Coquimbo — Coquimbo
• Hospital San Juan de Dios de La Serena — La Serena
• Hospital de Niños Roberto del Río — Independencia
• Hospital Luis Calvo Mackenna — Providencia
• Complejo Asistencial Dr. Sótero Del Río — Puente Alto
• Hospital CRS El Pino — San Bernardo
• Hospital Clínico Félix Bulnes — Santiago
• … and 5 more centers

Identifiers

NCT: NCT07086820 · 240519001 · FONDECYT N° 1250853

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗