An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: study protocol for a randomized controlled trial

Abstract

Background: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined.

Methods/design: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient's Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen.

Discussion: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens.

Trial registration: ClinicalTrials.gov, NCT01918397 . Registered on 5 August 2013.

Keywords: Fluoroquinolones; Levofloxacin; Multidrug resistant tuberculosis; Optimized background regimen.

Conflict of interest statement

Ethics approval and consent to participate

Before the study began, the Institutional Review Boards of all involved institutions, including Boston University, Harvard University, University of Florida, University of Arkansas, Universidad Peruana Cayetano Heredia, Hospital San Juan de Lurigancho, Instituto Nacional de Salud, Stellenbosch University and South African Medicines Control Council, reviewed and approved the study protocol and informed consent documents. The study is being conducted under an investigational new drug (IND) from the US Food and Drug Administration (FDA). A list of the reference numbers for all ethical bodies that approved the study can be found in Additional file 3. Patients who meet the inclusion criteria (see Table 1) are enrolled via the informed consent process. The approved consent form can be found in Additional file 4.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Standard Protocol Items: Recommendation For Interventional Trials (SPIRIT) figure

Fig. 2

Relationship between weight-banded dosing and expected mg/kg effective dose