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


RESULTS
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).


CONCLUSIONS
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.
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan. amusa@iend.org
Ahmed M
AM
Musa
Brima
B
Younis
Ahmed
A
Fadlalla
Catherine
C
Royce
Manica
M
Balasegaram
Monique
M
Wasunna
Asrat
A
Hailu
Tansy
T
Edwards
Raymond
R
Omollo
Mahmoud
M
Mudawi
Gilbert
G
Kokwaro
Ahmed
A
El-Hassan
Eltahir
E
Khalil
D000293:Adolescent; D000328:Adult; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000469:parasitology; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007893:Leishmania donovani / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008297:Male; D008853:Microscopy; D008875:Middle Aged; D010303:Paromomycin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013397:Sudan; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D000981:Antiprotozoal Agents; D010303:Paromomycin