Article Text
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.
- pediatric
- tuberculosis
- prevention
- isoniazid
- protocol
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Footnotes
Contributors GJ-S, BAR, JK and SML designed the randomised clinical trial. SML, GJ-S, BAR, TRH, LMC, JK, DM, AJW and EM-O developed the study protocol. GJ-S is the principal investigator and protocol chair and TRH is the immunology principal investigator. JK is the protocol co-chair and country principal investigator. EM-O is the Pediatric Clinical TB lead. GJ-S, BAR and SML are responsible for the statistical design of the trial and data analysis of the primary outcomes. SML is the project director and drafted the statistical analysis plan overseen by BAR, the study biostatistician. SML, DM, AJW, JK and JNE participated in trial implementation and manuscript preparation. TRH designed the immunological studies and oversees the immunological work related to the trial. SML wrote the first draft of the manuscript. All authors critically revised, read and approved the final manuscript.
Funding This work was supported by the Thrasher Research Fund, National Institute of Allergy and Infectious Diseases (NIAID), Fulbright programme awarded to the Northern Pacific Global Health Fellows Program by the Fogarty International Center of the National Institutes of Health (NIH/Fogarty), and National Center for Advancing Translational Sciences at National Institutes of Health (NIH) (Thrasher to GJ-S, NIH/NIAID K23AI120793 to SML, NIH/NIAID 2K24AI137310 to TRH, NIH/Fogarty R25TW009345 to AJW and NIH UL1TR000423 for REDCap).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The protocol is approved by the University of Nairobi/Kenyatta National Hospital Ethics and Research Committee (P571/08/2015), Jaramogi Oginga Odinga Teaching and Referral Hospital, University of Washington Institutional Review Board (STUDY00000761), and Kenya Pharmacy and Poisons Board.
Provenance and peer review Not commissioned; externally peer reviewed.