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Clinical Trial
. 2010 Oct 26;4(10):e855.
doi: 10.1371/journal.pntd.0000855.

Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study

Ahmed M Musa  1 , Brima Younis, Ahmed Fadlalla, Catherine Royce, Manica Balasegaram, Monique Wasunna, Asrat Hailu, Tansy Edwards, Raymond Omollo, Mahmoud Mudawi, Gilbert Kokwaro, Ahmed El-Hassan, Eltahir Khalil
Affiliations
Clinical Trial

Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study

Ahmed M Musa et al. PLoS Negl Trop Dis. .

Abstract

Background: A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.

Methods: This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg.

Findings: 42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively).

Conclusion: Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.

Trial registration: ClinicalTrials.gov NCT00255567.

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Conflict of interest statement

CR was working for DNDi at the time of the study. MB is currently working at DNDi.

Figures

Figure 1
Figure 1. Flowchart of patients.
Figure 2
Figure 2. Semi-log plot of mean (SD) paromomycin (PM) concentrations (µg/mL) versus time (hours) after a single intramuscular injection.
Plasma PM concentrations on day 1 (D1), day 14 (D14), and day 26 (D26) for VL patients who received either 15 mg/kg (n = 6) or 20 mg/kg PM (n = 3).
See this image and copyright information in PMC

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