Efficacy and safety of fixed-dose artesunate-amodiaquine vs. artemether-lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children

Abstract

The safety and efficacy of the two most widely used fixed-dose artemisinin-based combination therapies (ACT), artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are well established for single episodes of uncomplicated Plasmodium falciparum malaria, but the effects of repeated, long-term use are not well documented. We conducted a 2-year randomized, open-label, longitudinal, phase IV clinical trial comparing the efficacy and safety of fixed-dose ASAQ and AL for repeated treatment of uncomplicated malaria in children under 5 years at Nagongera Health Centre, Uganda. Participants were randomized to ASAQ or AL and all subsequent malaria episodes were treated with the same regimen. 413 children were enrolled and experienced a total of 6027 malaria episodes (mean 15; range, 1-26). For the first malaria episode, the PCR-corrected-cure rate for ASAQ (97.5%) was non-inferior to that for AL (97.0%; 95% CI [-0.028; 0.037]). PCR-corrected cure rates for subsequent malaria episodes that had over 100 cases (episodes 2-18), ranged from 88.1% to 98.9% per episode, with no clear difference between the treatment arms. Parasites were completely cleared by day 3 for all malaria episodes and gametocyte carriage was less than 1% by day 21. Fever clearance was faster in the ASAQ group for the first episode. Treatment compliance for subsequent episodes (only first dose administration observed) was close to 100%. Adverse events though common were similar between treatment arms and mostly related to the disease. Serious adverse events were uncommon, comparable between treatment arms and resolved spontaneously. Anemia and neutropenia occurred in <0.5% of cases per episode, abnormal liver function tests occurred in 0.3% to 1.4% of cases. Both regimens were safe and effective for repeated treatment of malaria.

Trial registration: Current Controlled Trials NCT00699920.

Figure 1. Patient trial profile.

A total of 416 children were initially enrolled in the study and were randomized 1∶1 to 3 days of oral ASAQ or AL. Three patients in the AL group were excluded before receiving any treatment. During the 2-year study, another 21 in the ASAQ group and 18 in the AL group withdrew.

Figure 2. Malaria episodes experienced by patients during the 2 years of the study.

(A) Number of children per malaria episode. (B) Number of children with malaria episodes during each month between June, 2008 and April, 2010.

Figure 3. PCR-corrected ACPR rates.

Shown is the percent of children in the ASAQ and AL groups with PCR-corrected ACPR on day 28 by month, ITT Population.

Figure 4. Risk of recurrent parasitaemia.

Survival curve showing cumulative risk of infection after PCR correction up to 28 days in the PP population.

Figure 5. Parasite density.

(A) Shows the mean parasite density in the ASAQ and AL groups between days 0 and 42 of the first episode. (B) Shows the mean parasite density in the ASAQ and AL groups at D0 for all episodes.

Figure 6. Gametocyte carriage.

The proportion of children in the ASAQ and AL groups with gametocytes between days 0 and 42 of the first episode (A) and on any day on the follow up episodes (B).

Figure 7. Blood Hb concentrations.

Mean blood Hb concentrations in the ASAQ and AL groups between days 0 and 42 of the first episode (A) and on day 0 for all episodes (B). The dashed lined indicates the lower limit of the normal range for blood Hb concentration (10 mg/dL).

Figure 8. Incidence of AEs by episode.

The incidence of AEs experienced per episode by children in the ASAQ and AL groups.