Malaria Clinical Trial
Official title:
Acute vs. Delayed Iron: Effect on Red Cell Iron Incorporation in Severe Malaria
The purpose of this study is to determine whether iron therapy given to iron-deficient Ugandan children with moderate-to-severe anemia and clinical malaria is better absorbed and incorporated into red blood cells if it is given concurrently with antimalarial treatment on Day 0 (immediate group) or 4 weeks after antimalarial treatment on Day 28 (delayed group). Use of iron stable isotopes 57Fe and 58Fe will permit measurement of red blood cell iron incorporation on Day 0 and Day 28 in all children. The investigators hypothesize that red cell iron incorporation at the time of initial supplement administration will be greater in children receiving delayed vs. immediate iron (Aim 1), and children in the delayed group will also have greater hematological recovery on Day 56 than children in the immediate group (Aim 2).
Approximately 1 million children < 5 y living in sub-Saharan Africa die from severe anemia
annually. This severe anemia frequently results from coexisting iron deficiency and malaria
infection, but the standard of care, concurrent iron therapy and antimalarial treatment, has
proven ineffective at curing the profound anemia and has promoted proliferation of the
parasite in some studies. The pro-inflammatory immune response mounted against malaria
down-regulates iron absorption in the gut, making provision of oral iron supplements during
malarial infection of questionable utility. The present study proposes to use iron stable
isotopes and a randomized design to test whether starting 4 weeks of iron therapy
immediately after antimalarial treatment or 4 weeks later is associated with greater iron
incorporation into red blood cells at the time of initial administration of iron therapy and
improved long-term hematological recovery. One hundred severely anemic (hemoglobin 5-9.9
g/dL) Ugandan children 6-59 mos with clinical signs of malaria who present to the Pediatric
Acute Care Ward of Mulago Hospital in Kampala, Uganda, will be randomized to start iron
immediately after antimalarial treatment on Day 0 (immediate group) or 4 weeks later on Day
28 (delayed group). Children will be assessed at the hospital on Day 0, Day 28 and Day 56
and will receive bi-weekly home visits for the 56-day study duration. The specific aims and
corresponding hypotheses of the proposed study are:
Aim 1: Identify the sequencing of antimalarial treatment and iron therapy that results in
the greatest red cell iron incorporation at the time of initial iron supplement
administration. The working hypothesis is that red cell iron incorporation will be greater
at the time of initial supplement administration in children starting iron 4 weeks after
antimalarial treatment (delayed group) compared to children starting iron concurrently with
antimalarial treatment (immediate group), due to more complete parasite clearance and
resolution of inflammation, permitting better iron uptake, distribution, and utilization.
Aim 2: Determine whether long-term hematological recovery is impacted by immediate vs.
delayed iron. The working hypothesis is that delayed iron treatment will be associated with
greater hemoglobin and improved iron status at Day 56 compared to immediate treatment due to
more complete parasite clearance and consequent improved iron absorption and use in the
delayed group.
The results of this study will establish a physiologically-based framework for the optimal
timing of antimalarial treatment and iron therapy upon which future interventions aimed at
improving iron status in malaria-endemic regions can be built, thus helping to reduce the
morbidity and mortality and ensure the full neurobehavioral development of the millions of
severely anemic children suffering from iron-deficiency and malaria.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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