Paromomycin for the Treatment of Visceral Leishmaniasis in Sudan: A Randomized, Open-Label, Dose-Finding Study

Dose-Finding Study. PLoS Negl Trop Dis 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 0 Brima Younis 0 Ahmed Fadlalla 0 Catherine Royce 0 Manica Balasegaram 0 Monique 0 Wasunna 0 Asrat Hailu 0 Tansy Edwards 0 Raymond Omollo 0 Mahmoud Mudawi 0 Gilbert Kokwaro 0 Ahmed El-Hassan 0 Eltahir Khalil 0 Diana N. J. Lockwood, London School of Hygiene and Tropical Medicine, United Kingdom 0 1 Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan, 2 Faculty of Medicine, Gedaref University , Gedaref, Sudan, 3 Drugs for Neglected Diseases initiative (DNDi), Geneva , Switzerland , 4 Centre for Clinical Research, Kenya Medical Research Institute (KEMRI), Nairobi, Kenya, 5 Addis Ababa University , Addis Ababa , Ethiopia , 6 London School of Hygiene and Tropical Medicine , London , United Kingdom , 7 Faculty of Pharmacy, University of Nairobi, Nairobi, Kenya, 8 Consortium for National Health Research (CNHR) , Nairobi , Kenya 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 www.plosntds.org - Funding: The study was funded through DNDi by the Department for International Development (DFID), UK; International Solidarity, Republic and Canton of Geneva, Switzerland; Medecins Sans Frontie`res International; the Medicor Foundation; the Ministry of Foreign and European Affairs (MAEE), France; the Region of Tuscany, Italy; the Spanish Agency of International Cooperation for Development (AECID); and other private foundations and individual donors who wish to remain anonymous. The sponsor (DNDi) was involved in study design, study monitoring, data analysis, decision to publish, and preparation of the manuscript. Other funding sources had no role in this study. All authors had full access to all data in the study and they held final responsibility for the decision to submit the manuscript for publication. Competing Interests: CR was working for DNDi at the time of the study. MB is currently working at DNDi. 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. Although 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 [35]. A multi-center phase III study in India showed that PM is a very efficacious, affordable, and safe treatment [6], and is now 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 Visceral leishmaniasis (VL) is a parasitic disease transmitted through the bite of sandflies. The WHO estimates 500,000 new cases of VL each year, with more than 90% of cases occurring in Southeast Asia, East Africa, and South America. If left untreated, VL can be fatal. We had previously conducted a large multi-center study in Sudan, East Africa, to assess the efficacy of paromomycin (PM) alone or in combination with sodium stibogluconate. Clinical studies in India have shown that 15 mg/kg/day PM for 21 days was an effective cure. However, the same treatment regimen was not efficacious in two study sites in Sudan. Here, our aim was to assess two high-dose regimens of PM in Sudan: 15 mg/kg/day for 28 days and 20 mg/kg/day for 21 days. The results suggest that, at these total doses, PM is more efficacious than when given daily at 15 mg/kg for 21 days, and that high doses are required to treat VL in Sudan. Efficacy of 20 mg/kg/day PM for 21 days is currently being evaluated in a prospective, comparative phase III trial in East Africa. alone at the dose shown to be efficacious in India (15 mg/kg/day for 21 days) against SSG alone (20 mg/kg/day for 30 days) and against a combination treatment of SSG and PM (same dose of individual treatments but for 17 days). PM monotherapy did not show adequate efficacy, particularly in Sudan where parasite clearance was below 50% in patients at 6 months after end of treatment (EOT), and the study had to be prematurely stopped [7]. In the current study, we sought to find an efficacious dose of PM for the treatment of VL in Sudan and to explore possible reasons for the failure of the drug at the previous dose studied of 15 mg/ kg/day for 21 days. In our previous study using this dose, conducted in 5 sites in Ethiopia, Kenya and Sudan, we found an overall end of treatment cure of 67.4% and 6-month posttreatment cure of 63.8% [7]. Cure at both sites in Sudan was below 50% [7]. The cure rate in this study of SSG was 92.2% at 6 months post-treatment [7]. Therefore a total dose increase of 33% w (...truncated)