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

Abstract

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

Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger

“…The study protocol and procedures have been described elsewhere [19]. The study was conducted in Oulessebougou district hospital, region of Koulikoro, Mali, and the primary healthcare center of Andoume, Maradi city, Niger.…”

“…The study was conducted in Oulessebougou district hospital, region of Koulikoro, Mali, and the primary healthcare center of Andoume, Maradi city, Niger. In these areas, malaria transmission is hyperendemic with seasonal peaks during the rainy season (between July and November [19]) and AL is recommended as first-line malaria treatment. Each year, during the hunger gap period (generally from June to October), acute malnutrition increases among young children [20, 21].…”

“…Any clinical or laboratory adverse event was reported by the investigator as described elsewhere [19]. Serious adverse events were reviewed by a Data Safety and Monitoring Board.…”

“…For each child, five capillary blood samples (50 μL spotted on filter paper) were collected; first, at 6, 12, 24, 36, or 48 hours (randomly allocated), second at 60 hours, third at 72 hours, fourth at day 7, and fifth at day 14 or day 21 (randomly allocated) post treatment initiation. Lumefantrine concentrations were measured at the Division of Clinical Pharmacology, University of Cape Town, using liquid chromatography tandem mass spectrometry as described previously [19]. …”

Severe Acute Malnutrition Results in Lower Lumefantrine Exposure in Children Treated With Artemether‐Lumefantrine for Uncomplicated Malaria

“…A subset of the whole study was chosen to be part of the PK study ( n = 131 for SAM children and n = 160 for non‐SAM children). Details on the study protocol as well as the clinical efficacy and safety have been published previously . This study was conducted at two hospitals, the Oulessebougou District Hospital, Koulikoro region, Mali, and at the primary healthcare center on Andoume, Maradi City, Niger.…”