A multi-center, open-label trial to compare the efficacy and pharmacokinetics of Artemether-Lumefantrine in children with severe acute malnutrition versus children without severe acute malnutrition: study protocol for the MAL-NUT study

BMC Infectious Diseases

Study Protocol

Lise Denoeud-Ndam¹  Francesco Grandesso¹  Ousmane Guindo¹  Elisabeth Baudin¹  Jean-François Etard²  Issaka Sagara³  Abdoulaye A. Djimde³  Ogobara K. Doumbo³  Alassane Dicko³  Angeles M. Lima Parra⁴  Pedro Pablo Palma⁴  Estrella Lasry⁵  Kasia Stepniewska⁶  Karen I. Barnes⁷ 

[1]Epicentre, Paris, France

[2]Epicentre, Paris, France

[3]TransVIHMI UMI 233, Institut de recherche pour le développement (IRD) – Inserm U 1175 – Montpellier 1 University, Montpellier, France

[4]Malaria Research and Training Center, Faculte de Médecine, Pharmacie et d’Odonto-stomatologie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali

[5]Medecins sans Frontieres, Barcelona, Spain

[6]Medecins sans Frontieres, Paris, France

[7]Worldwide Antimalarial Resistance Network (WWARN), Oxford, UK

[8]Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

[9]Worldwide Antimalarial Resistance Network (WWARN), Oxford, UK

[10]Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa

关键词: Malaria;    Severe acute malnutrition;    Artemether-lumefantrine fixed combination;    Pharmacokinetics;    Efficacy;    Niger;    Mali;   

DOI  :  10.1186/s12879-015-0963-3

 received in 2014-12-12, accepted in 2015-05-27,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMalnutrition and malaria frequently coexist in sub-Saharan African countries. Studies on efficacy of antimalarial treatments usually follow the WHO standardized protocol in which severely malnourished children are systematically excluded.Few studies have assessed the efficacy of chloroquine, sulfadoxine-pyrimethamine and quinine in severe acute malnourished children. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for some antimalarials altered pharmacokinetic profiles and lower drug concentrations. However, similar research on the efficacy and pharmacokinetic profiles of artemisinin-combination therapies (ACTs) and especially artemether-lumefantrine in malnourished children is currently lacking.The main objective of this study is to assess whether artemether-lumefantrine is less efficacious in children suffering from severe acute malnutrition (SAM) compared to non-SAM children, and if so, to what extent this can be attributed to a sub-optimal pharmacokinetic profile.Methods/designIn two sites, Ouelessebougou, Mali and Maradi, Niger, children with uncomplicated microscopically-confirmed P. falciparum malaria aged between 6 and 59 months will be enrolled. Two non-SAM children will be enrolled after the enrolment of each SAM case. Children with severe manifestations of malaria or complications of acute malnutrition needing intensive treatment will be excluded.Treatment intakes will be supervised and children will be followed-up for 42 days, according to WHO guidance for surveillance of antimalarial drug efficacy. Polymerase Chain Reaction genotyping will be used to distinguish recrudescence from re-infection. SAM children will also benefit from the national nutritional rehabilitation program.Outcomes will be compared between the SAM and non-SAM populations. The primary outcome will be adequate clinical and parasitological response at day 28 after PCR correction, estimated by Kaplan-Meier analysis. To assess the pharmacokinetic profile of lumefantrine, a sparse sampling approach will be used with randomized allocation of sampling times (5 per child). A total of 180 SAM children and 360 non-SAM children will be recruited during the 2013 and 2014 malaria seasons.DiscussionThis study will provide important information that is currently lacking on the effect of SAM on therapeutic efficacy and pharmacokinetic profile of artemether-lumefantrine. If it shows lower therapeutic efficacy and decreased lumefantrine concentrations, it would inform dose optimization studies in SAM children.Trial registrationClinicalTrials.gov: NCT01958905

【 授权许可】

CC BY   
© Denoeud-Ndam et al. 2015