Abstract
BackgroundA 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.MethodsThis 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.Findings42 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).ConclusionData 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 RegistrationClinicalTrials.gov NCT00255567
Highlights
According to the WHO estimates, visceral leishmaniasis (VL) is a parasitic disease that affects more than 500,000 people globally each year [1], and has a fatality rate of up to 100% if left untreated [2]. 90% of cases occur in five countries: India, Bangladesh, Nepal, Sudan, and Brazil [1], with the affected communities mostly located in remote regions of these endemic areas without ready access to treatment. drugs currently exist to treat this parasitic infection, their use has been limited because of high cost, toxicity, or development of parasite resistance [3,4,5]
Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day paromomycin sulphate (PM) for 21 days and could be further evaluated in phase III studies in East Africa
In an effort to identify an effective treatment for VL in East Africa, we had previously initiated a multi-center phase III study in Sudan, Ethiopia, and Kenya comparing the efficacy of PM
Summary
According to the WHO estimates, visceral leishmaniasis (VL) is a parasitic disease that affects more than 500,000 people globally each year [1], and has a fatality rate of up to 100% if left untreated [2]. 90% of cases occur in five countries: India, Bangladesh, Nepal, Sudan, and Brazil [1], with the affected communities mostly located in remote regions of these endemic areas without ready access to treatment. drugs (mainly antimonials such as sodium stibogluconate [SSG]) currently exist to treat this parasitic infection, their use has been limited because of high cost, toxicity, or development of parasite resistance [3,4,5]. According to the WHO estimates, visceral leishmaniasis (VL) is a parasitic disease that affects more than 500,000 people globally each year [1], and has a fatality rate of up to 100% if left untreated [2]. A multi-center phase III study in India showed that PM is a very efficacious, affordable, and safe treatment [6], and is registered for VL treatment in India. In an effort to identify an effective treatment for VL in East Africa, we had previously initiated a multi-center phase III study in Sudan, Ethiopia, and Kenya comparing the efficacy of PM. 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 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 mg/kg/day for days
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