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


METHODS
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.


RESULTS
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.


BACKGROUND
www.clinicaltrials.govNCT00832208.
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
Eltahir A G
EA
Khalil
Arba Minch Hospital, Regional Health Bureau of SNNP State, Arba Minch, Ethiopia.
Teklu
T
Weldegebreal
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
Brima M
BM
Younis
Drugs for Neglected Diseases initiative (DNDi) Africa Regional Office, Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
Raymond
R
Omollo
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
Ahmed M
AM
Musa
University of Gondar, College of Medicine & Health Sciences, Gondar, Ethiopia.
Workagegnehu
W
Hailu
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
Abuzaid A
AA
Abuzaid
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Thomas P C
TP
Dorlo
University of Gondar, College of Medicine & Health Sciences, Gondar, Ethiopia.
Zewdu
Z
Hurissa
University of Gondar, College of Medicine & Health Sciences, Gondar, Ethiopia.
Sisay
S
Yifru
Arba Minch Hospital, Regional Health Bureau of SNNP State, Arba Minch, Ethiopia.
William
W
Haleke
MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Peter G
PG
Smith
Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
Sally
S
Ellis
Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
Manica
M
Balasegaram
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
Ahmed M
AM
EL-Hassan
Royal Tropical Institute, KIT Biomedical Research, Amsterdam, The Netherlands.
Gerard J
GJ
Schoone
Drugs for Neglected Diseases initiative (DNDi) Africa Regional Office, Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya ; Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
Monique
M
Wasunna
Drugs for Neglected Diseases initiative (DNDi) Africa Regional Office, Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya ; Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
Robert
R
Kimutai
MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Tansy
T
Edwards
School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
Asrat
A
Hailu
D000293:Adolescent; D000328:Adult; D000351:Africa, Eastern; D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects*; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008297:Male; D059208:Parasite Load; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome; D055815:Young Adult
D000981:Antiprotozoal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B