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

BackgroundMultidrug-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.MethodsThe 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.DiscussionIf 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 registrationISRCTN Registry, ISRCTN92634082. Registered on 31 March 2016.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-3070-0) contains supplementary material, which is available to authorized users.

Anti-tuberculosis treatment strategies and drug development: challenges and priorities

“…Five regimens of various durations that include isoniazid and/or a rifamycin are recommended globally and considered equivalent by measure of effectiveness and hepatotoxicity, though they have not been directly compared in clinical trials 32 – 34 . Besides historic trials with pyrazinamide 35 , levofloxacin in children 36 and adults 37 , 38 and delamanid (PHOENIx MDR-TB) ( ClinicalTrials.gov , NCT03568383) are currently being tested as prophylactic therapy in household contacts of patients with MDR-TB.…”

Treatment of Drug-Resistant Tuberculosis

“…17 There are currently 3 ongoing randomized controlled trials evaluating the efficacy of treating contacts of persons with MDR-TB/XDR-TB. 30,31 Close contacts to patients with DR-TB may be considered for prophylactic treatment using the principles set out in Box 4:…”

Latent tuberculosis infection among contacts of patients with multidrug-resistant tuberculosis in New South Wales, Australia

“…In 2018, an estimated 10 million people fell ill with tuberculosis (TB) worldwide [ 1 , 2 ]. Among these, almost half a million people developed multidrug-resistant (MDR)-TB, defined as disease caused by Mycobacterium tuberculosis that is resistant to both isoniazid and rifampicin [ 1 – 4 ]. A diagnosis of MDR-TB presents a major challenge for patients, owing to the prolonged treatment, high incidence of adverse events, high mortality rates and substantial costs of treatment [ 5 , 6 ].…”