Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP)

Abstract

Background: Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment.

Methods: The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15-20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18-24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial.

Discussion: If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy.

Trial registration: ISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

Keywords: Child; MDR; Placebo; Prevention; Randomised; Resistant; TB; Trial; Tuberculosis.

Conflict of interest statement

Ethics approval and consent to participate

The trial has been approved by the Stellenbosch University Human Research Ethics Committee (M16/02/009) and the University of the Witwatersrand Ethics Committee (160409).

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Figures

Fig. 1

The series of activities conducted by the study team to identify eligible child contacts of multidrug-resistant tuberculosis index cases

Fig. 2

Schedule of evaluations. SCR screening, BL baseline – at randomisation, U/S unscheduled, TB tuberculosis, ALT alanine aminotransferase, BR bilirubin, DST drug susceptibility test, FBC full blood count, IGRA interferon-gamma release assay, WHO World Health Organization. *If intercurrent exposure to an isoniazid- or rifampicin-susceptible TB case, preventive therapy will be offered. **At selected sites only. #Based on clinical indication only – TB symptoms at baseline, or at follow-up: new or persistent symptoms, or CXR changes at any time including endpoint evaluation. HIV testing at 48 weeks will be repeated in HIV-negative participants. If HIV status is already known to be positive at screening, the CD4 count and HIV viral load should be completed at baseline in HIV-infected children. HIV viral load is standard of care in HIV-infected children

Fig. 3

Schema of the trial documenting numbers of households and individuals to be recruited and numbers in each trial arm