Dataset Information

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 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 registration

ISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

SUBMITTER: Seddon JA

PROVIDER: S-EPMC6302301 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

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).

Seddon James A JA Garcia-Prats Anthony J AJ Purchase Susan E SE Osman Muhammad M Demers Anne-Marie AM Hoddinott Graeme G Crook Angela M AM Owen-Powell Ellen E Thomason Margaret J MJ Turkova Anna A Gibb Diana M DM Fairlie Lee L Martinson Neil N Schaaf H Simon HS Hesseling Anneke C AC

Trials 20181220 1

<h4>Background</h4>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 ...[more]

PMID: 30572905

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Project description:Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

Dataset Information

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).

Background

Methods

Trial registration

Publications

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).

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