Safety and efficacy of single dose versus multiple doses of AmBisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial

Abstract

Background: Anti-leishmanial drug regimens that include a single dose AmBisome could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown.

Methodology: A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1-5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR.

Principal findings: The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73-93%), 40% (95%CI 19-64%), and 58% (95%CI 41-73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label.

Conclusions: The tested AmBisome regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified.

Trials registration: www.clinicaltrials.govNCT00832208.

Conflict of interest statement

The authors have declared that no competing interests exist. Gilead Sciences, USA, provided the investigational product, AmBisome®. Gilead Sciences and the sponsors, DNDi, have professional collaborations. This collaboration does not alter our adherence to all PLOS NTDs policies on sharing data and materials.

Figures

Figure 1. Patient flow chart.

Consort Patient flow chart: AmBisome® multi dose vs. single dose, ITT Intention to treat, PP per protocol, LTFU Lost to Follow-up.

Figure 2. Summary of study design.

Interim analyses were based on day 30 cure in the Intention-to-Treat (ITT) population. iv intravenous, mg/kg/day milligram/kilogram body weight/day.

Figure 3. Parasite clearance from peripheral blood.

Comparison of parasite clearance rates from peripheral blood in single (10 mg/kg) and multiple dose (7×3 mg/kg) regimens of AmBisome®. Data are from 5 consenting patients in each of the 10 mg/kg single-dose and multiple-dose arms.