Infant TB Infection Prevention Study (iTIPS): a randomised trial protocol evaluating isoniazid to prevent M. tuberculosis infection in HIV-exposed uninfected children

Sylvia M LaCourse, Barbra A Richardson, John Kinuthia, A J Warr, Elizabeth Maleche-Obimbo, Daniel Matemo, Lisa M Cranmer, Jaclyn N Escudero, Thomas R Hawn, Grace C John-Stewart, Sylvia M LaCourse, Barbra A Richardson, John Kinuthia, A J Warr, Elizabeth Maleche-Obimbo, Daniel Matemo, Lisa M Cranmer, Jaclyn N Escudero, Thomas R Hawn, Grace C John-Stewart

Abstract

Introduction: HIV-exposed uninfected (HEU) infants in tuberculosis (TB) endemic settings are at high risk of Mycobacterium tuberculosis (Mtb) infection and TB disease, even in the absence of known Mtb exposure. Because infancy is a time of rapid progression from primary infection to active TB disease, it is important to define when and how TB preventive interventions exert their effect in order to develop effective prevention strategies in this high-risk population.

Methods and analysis: We designed a non-blinded randomised controlled trial to determine efficacy of isoniazid (INH) to prevent primary Mtb infection among HEU children. Target sample size is 300 (150 infants in each arm). Children are enrolled at 6 weeks of age from maternal and child health clinics in Kenya and are randomised to receive 12 months of daily INH ~10 mg/kg plus pyridoxine or no INH. The primary endpoint is Mtb infection, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) or tuberculin skin test after 12 months post-enrolment. Secondary outcomes include severe adverse events, expanded Mtb infection definition using additional QFT-Plus supernatant markers and determining correlates of Mtb infection. Exploratory analyses include a combined outcome of TB infection, disease and mortality, and sensitivity analyses excluding infants with baseline TB-specific responses on flow cytometry.

Ethics and dissemination: An external and independent Data and Safety Monitoring Board monitors adverse events. Results will be disseminated through peer-reviewed journals, presentations at local and international conferences to national and global policy-makers, the local community and participants.

Trial registration number: NCT02613169; Pre-results.

Keywords: isoniazid; pediatric; prevention; protocol; tuberculosis.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study schema: aims of a randomised controlled trial to evaluate isoniazid (INH) to prevent Mycobacterium tuberculosis (Mtb) infection in HIV-exposed uninfected (HEU) infants.
Figure 2
Figure 2
Overall study strategy. HEU, HIV-exposed uninfected; IGRA, interferon-gamma release assay; INH, isoniazid; MCH, maternal child health; Mtb, Mycobacterium tuberculosis; PMTCT, prevention of maternal to child transmission; TST, tuberculin skin test.
Figure 3
Figure 3
CONSORT diagram. IGRA, interferon-gamma release assay; INH, isoniazid; Mtb, Mycobacterium tuberculosis; TST, tuberculin skin test.

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