Comparison of Two Regimens of Artemether-lumefantrine for the Treatment of Malaria in Pregnancy
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 3

Summary: 
      Malaria in pregnancy is a major cause of maternal and newborn morbidity and mortality in
      sub-Saharan Africa]. Effective antimalarial preventive and treatment regimens can
      significantly reduce malaria-related morbidity and mortality in the mother and baby. However,
      therapeutic choices are limited by concerns about possible toxicity to the fetus and because
      of these concerns pregnant women are normally excluded from clinical trials. This, combined
      with the lack of adverse events reporting system, results in a scarcity of data on drug
      safety and efficacy in pregnancy. Moreover, changes in the maternal physiology in pregnancy
      often alter the pharmacokinetic of drugs. Artemether-lumefantrine (ALN) is a highly
      efficacious artemisinin-based combination therapy approved by the World Health Organisation
      for use in the 2nd and 3rd trimesters, although it is still infrequently used in pregnancy
      and there is uncertainty as to the optimum dose. The pharmacokinetics of ALN are altered in
      pregnancy, resulting in reduced plasma concentrations and while the standard adult dose is
      still effective in high transmission settings, where pregnant women have higher levels of
      immunity, efficacy is reduced significantly in low transmission settings where women have
      lower levels of immunity. Inadequate antimalarial treatment dosing in pregnancy risks
      treatment failure or breakthrough infection and exposure of malaria parasites to
      sub-therapeutic drug concentrations thus selecting for drug resistance.
    

Detailed description: 
      The aim of the current trial is to compare the standard 3-day regimen of
      artemether-lumefantrine to a 5-day regimen of artemether-lumefantrine in a group of pregnant
      women and a control of non-pregnant women with uncomplicated P. falciparum malaria. The
      pharmacokinetics of lumefantrine is modified in pregnancy and the standard regimen used for
      treatment of adults might not be sufficient to cure malaria, therefore exposing pregnant
      women to sub-therapeutic drug levels and increased risk of clinical failure. Previous
      pharmacokinetic studies have shown that the standard 3-day treatment during pregnancy results
      in reduced plasma concentrations of artemether, dihydroartemisinin and lumefantrine and a
      faster elimination of lumefantrine. Low lumefantrine plasma concentrations at day 7 are
      associated with therapeutic failure. Population-based simulations suggest that increased dose
      and treatment duration are needed for adequate drug exposure in these patients. We propose to
      assess the pharmacokinetics of a longer regimen of artemether-lumefantrine, (10 doses of
      artemether-lumefantrine over five days) compared to the standard regimen, (6 doses of
      artemether-lumefantrine over three days) in a small group of pregnant African women with
      uncomplicated P. falciparum malaria. The longer regimen should ensure that curative plasma
      concentration of lumefantrine is reached, and is unlikely to result in any increased
      frequency of adverse events.
    

Intervention name(s): 3-day artemether-lumefantrine; 5-day artemether-lumefantrine
Intervention type(s): Drug; Drug
Intervention MeSH terms: Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Malaria; Pregnancy; Plasmodium falciparum