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Safety and efficacy of single dose versus multiple doses of AmBisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial.
PLoS Negl Trop Dis. 2014; 8(1):e2613.PN

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.

Authors+Show Affiliations

Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.Arba Minch Hospital, Regional Health Bureau of SNNP State, Arba Minch, Ethiopia.Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.Drugs for Neglected Diseases initiative (DNDi) Africa Regional Office, Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.University of Gondar, College of Medicine & Health Sciences, Gondar, Ethiopia.Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands.University of Gondar, College of Medicine & Health Sciences, Gondar, Ethiopia.University of Gondar, College of Medicine & Health Sciences, Gondar, Ethiopia.Arba Minch Hospital, Regional Health Bureau of SNNP State, Arba Minch, Ethiopia.MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom.Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.Royal Tropical Institute, KIT Biomedical Research, Amsterdam, The Netherlands.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.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.MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom.School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24454970

Citation

Khalil, Eltahir A G., et al. "Safety and Efficacy of Single Dose Versus Multiple Doses of AmBisome for Treatment of Visceral Leishmaniasis in Eastern Africa: a Randomised Trial." PLoS Neglected Tropical Diseases, vol. 8, no. 1, 2014, pp. e2613.
Khalil EA, Weldegebreal T, Younis BM, et al. Safety and efficacy of single dose versus multiple doses of AmBisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial. PLoS Negl Trop Dis. 2014;8(1):e2613.
Khalil, E. A., Weldegebreal, T., Younis, B. M., Omollo, R., Musa, A. M., Hailu, W., Abuzaid, A. A., Dorlo, T. P., Hurissa, Z., Yifru, S., Haleke, W., Smith, P. G., Ellis, S., Balasegaram, M., EL-Hassan, A. M., Schoone, G. J., Wasunna, M., Kimutai, R., Edwards, T., & Hailu, A. (2014). Safety and efficacy of single dose versus multiple doses of AmBisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial. PLoS Neglected Tropical Diseases, 8(1), e2613. https://doi.org/10.1371/journal.pntd.0002613
Khalil EA, et al. Safety and Efficacy of Single Dose Versus Multiple Doses of AmBisome for Treatment of Visceral Leishmaniasis in Eastern Africa: a Randomised Trial. PLoS Negl Trop Dis. 2014;8(1):e2613. PubMed PMID: 24454970.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety and efficacy of single dose versus multiple doses of AmBisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial. AU - Khalil,Eltahir A G, AU - Weldegebreal,Teklu, AU - Younis,Brima M, AU - Omollo,Raymond, AU - Musa,Ahmed M, AU - Hailu,Workagegnehu, AU - Abuzaid,Abuzaid A, AU - Dorlo,Thomas P C, AU - Hurissa,Zewdu, AU - Yifru,Sisay, AU - Haleke,William, AU - Smith,Peter G, AU - Ellis,Sally, AU - Balasegaram,Manica, AU - EL-Hassan,Ahmed M, AU - Schoone,Gerard J, AU - Wasunna,Monique, AU - Kimutai,Robert, AU - Edwards,Tansy, AU - Hailu,Asrat, Y1 - 2014/01/16/ PY - 2013/04/14/received PY - 2013/11/18/accepted PY - 2014/1/24/entrez PY - 2014/1/24/pubmed PY - 2014/9/10/medline SP - e2613 EP - e2613 JF - PLoS neglected tropical diseases JO - PLoS Negl Trop Dis VL - 8 IS - 1 N2 - 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. SN - 1935-2735 UR - https://www.unboundmedicine.com/medline/citation/24454970/Safety_and_efficacy_of_single_dose_versus_multiple_doses_of_AmBisome_for_treatment_of_visceral_leishmaniasis_in_eastern_Africa:_a_randomised_trial_ L2 - https://dx.plos.org/10.1371/journal.pntd.0002613 DB - PRIME DP - Unbound Medicine ER -